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Are cellular therapies the future of autoimmune disease?
A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.
Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.
In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.
In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.
Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.
“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
A ‘reboot’ for the immune system
B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.
“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.
In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.
Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.
The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.
But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.
“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”
So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
Risks of intensive therapy
But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.
The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.
The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
Alternatives to standard CAR T-cell therapies
Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.
DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.
“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”
This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.
In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.
While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.
These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.
This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
Precision immunotherapy
For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.
“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.
She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.
“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”
The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.
Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.
He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.
“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”
Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.
A version of this article first appeared on Medscape.com.
A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.
Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.
In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.
In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.
Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.
“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
A ‘reboot’ for the immune system
B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.
“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.
In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.
Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.
The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.
But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.
“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”
So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
Risks of intensive therapy
But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.
The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.
The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
Alternatives to standard CAR T-cell therapies
Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.
DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.
“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”
This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.
In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.
While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.
These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.
This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
Precision immunotherapy
For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.
“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.
She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.
“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”
The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.
Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.
He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.
“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”
Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.
A version of this article first appeared on Medscape.com.
A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.
Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.
In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.
In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.
Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.
“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
A ‘reboot’ for the immune system
B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.
“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.
In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.
Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.
The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.
But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.
“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”
So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
Risks of intensive therapy
But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.
The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.
The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
Alternatives to standard CAR T-cell therapies
Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.
DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.
“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”
This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.
In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.
While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.
These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.
This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
Precision immunotherapy
For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.
“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.
She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.
“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”
The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.
Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.
He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.
“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”
Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.
A version of this article first appeared on Medscape.com.
New evidence early treatment improves preclinical MS outcomes
TOPLINE:
new research shows.
METHODOLOGY:
Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.
The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.
Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.
Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.
The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
TAKEAWAY:
Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.
The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).
All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.
The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
IN PRACTICE:
“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.
SOURCE:
The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.
LIMITATIONS:
The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.
DISCLOSURES:
The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
TOPLINE:
new research shows.
METHODOLOGY:
Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.
The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.
Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.
Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.
The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
TAKEAWAY:
Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.
The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).
All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.
The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
IN PRACTICE:
“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.
SOURCE:
The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.
LIMITATIONS:
The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.
DISCLOSURES:
The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
TOPLINE:
new research shows.
METHODOLOGY:
Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.
The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.
Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.
Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.
The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
TAKEAWAY:
Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.
The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).
All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.
The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
IN PRACTICE:
“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.
SOURCE:
The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.
LIMITATIONS:
The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.
DISCLOSURES:
The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
MS drugs during pregnancy show no safety signals
AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.
“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”
Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.
“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
Counseling during the childbearing years
That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.
“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”
Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.
“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”
She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
Cladribine shows no miscarriage, malformations
Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.
Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.
Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.
”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”
Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.
“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
Ocrelizumab and ofatumumab: No infections so far
Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.
Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.
One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.
“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.
Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.
Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.
The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.
In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.
The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.
“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
Ozanimod outcomes within general population’s ‘expected ranges’
The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.
“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.
Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.
The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.
In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.
The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”
“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”
The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.
“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”
Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.
“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
Counseling during the childbearing years
That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.
“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”
Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.
“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”
She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
Cladribine shows no miscarriage, malformations
Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.
Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.
Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.
”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”
Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.
“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
Ocrelizumab and ofatumumab: No infections so far
Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.
Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.
One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.
“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.
Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.
Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.
The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.
In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.
The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.
“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
Ozanimod outcomes within general population’s ‘expected ranges’
The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.
“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.
Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.
The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.
In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.
The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”
“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”
The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.
“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”
Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.
“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
Counseling during the childbearing years
That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.
“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”
Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.
“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”
She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
Cladribine shows no miscarriage, malformations
Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.
Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.
Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.
”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”
Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.
“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
Ocrelizumab and ofatumumab: No infections so far
Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.
Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.
One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.
“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.
Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.
Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.
The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.
In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.
The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.
“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
Ozanimod outcomes within general population’s ‘expected ranges’
The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.
“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.
Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.
The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.
In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.
The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”
“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”
The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
FROM CMSC 2023
Diversity in Multiple Sclerosis Care: How the Field of Underrepresented Minorities Has Evolved, and Where We Still See Areas for Improvement
The persistent notion that multiple sclerosis (MS) is predominantly a White patient’s disease has been challenged by scientific data and our clinical experience in the field. Recent research has shown a higher risk of MS in non-White populations than originally thought. This may be surprising, but new data are influencing the way we now approach MS in under-represented minorities, bringing this topic to the forefront of scientific interest.
The early conviction that “there is no MS in minorities” led to underdiagnosis and misdiagnosis of MS in those patients, which in turn deepened these patients’ distrust of physicians and reluctance to seek further medical care, very often delivered by non-minority providers. Inequities in social determinants of health, low health literacy, and lack of private insurance, along with structural racism in healthcare, has further hindered active engagement with an already marginalized patient population in their MS care. This lack of engagement and lack of minorities in scientific research has proved to be unfavorable for MS research as well, creating large and persistent knowledge gaps in understanding MS course, severity, and response to treatment specific to this group. A 2014 PubMed search found 52,000 publications on MS in English, but in only 136 of those were minority patients with MS (Black or Hispanic/Latino) the primary research focus. In 2019, the same search indicated that the subsequent 5 years produced only 30 more articles focusing solely on minority patients.
Research participation of underrepresented minorities is another area where we, as a field, continue to fail these patients. A review of participant enrollment in MS clinical trials that took place between 1993 and 2006 showed a significant decrease in the percentage of enrolled Black patients (from 7% to about 4%). This trend did not improve by the DEFINE treatment trial (2012), in which only 2% of enrolled patients were Black. Of the 1246 participants in the 2019 SUNBEAM MS study, only 2 were Black. Low numbers of minority patients in trials prevent us from drawing any reasonable conclusion as to the efficacy of disease-modifying agents in those patients and make the goal of personalized medicine for this group impossible.
The results of the research conducted on these groups are compelling and should be prompting further work. Not only do Black patients have a higher risk of MS, but there is also now convincing evidence that MS in minorities is more severe overall, causing early progression of disability and necessitating assistive gait devices such as a cane or wheelchair. Minority patients tend to have more extensive involvement of spinal cord and infra-tentorial brain structures during the disease, which could explain the increased likelihood of more severe disease and earlier disability. Minority patients were admitted to nursing homes at a younger age, with greater physical and cognitive impairment than nonminority patients. A study looking at MS mortality between 1999 and 2015 found that Black males with MS had the highest mortality rate before age 45, and Black females before age 53. MS mortality increased with age but peaked at age 55 to 64 for Black patients and 65 to 74 for White patients. Underrepresented minorities are also less likely to use community resources, case management, medical equipment, and home nursing services. When looking at other measures of disease impact on these patients, studies evaluating magnetic resonance imaging (MRI) data showed higher lesion volume in Black patients with MS, as well as a higher degree of brain demyelination and atrophy when compared with White patients.
Treatment strategies currently used for underrepresented minority patients, as well as estimations of medication efficacy, treatment responses, and adverse-event profiles are largely driven by data from clinical trials with only minimal representation of those patients. How can we propose a patient-tailored and individualized treatment plan without these crucial data? Given that, to this day, not a single trial has focused solely on underrepresented minorities, we are left with either post hoc exploratory subgroup analyses of existing trials or pragmatic, observational, and very often retrospective studies using chart analysis. Notwithstanding the methodological flaws of either approach, prior studies did suggest worse response to platform therapies in Black patients, but equal response to high-efficacy therapies when compared with White patients.
Definitive biological underpinnings of disparities in disease severity have not been identified. In recent years, the field of health outcomes research has suggested we move away from considering racial categories as biologically distinct and instead focus on long-overlooked sociodemographic and modifiable lifestyle
factors. The role of diet, exercise, body mass index, smoking, and vascular comorbidities as risk factors associated with worse MS outcomes has been previously shown; however, these factors have not been rigorously assessed in underrepresented populations with MS. Recent studies focused on uncovering what drives the differences in MS severity in underrepresented populations disagree on the role biological differences, socioeconomic disparities, and structural racism in both healthcare settings and society play in answering this question. While it is plausible that a combination of these factors might explain our observations, more research on larger, underserved patient populations and better-defined measures of socioeconomic differences are needed to answer this complex question.
The path of recognizing and correcting our mistakes is not simple but must be done, and our underrepresented minority patients depend on our swift action. There are many places where we as a field of experts can and must do better—in communities, healthcare systems, and society in general.
Increasing community health literacy around MS, rebuilding trust, and addressing structural racism on every level is important. Outreach and educational programs that include in-person meetings and leverage social media platforms can help empower patients and their families—and hopefully increase trust in healthcare providers. Devising targeted interventions focusing on modifiable factors of a healthy lifestyle such as diet and exercise can increase community engagement and strengthen the support system for our patients. Increasing diversity in our own field of physicians, nurses, and other healthcare providers can also aid in strengthening mutual relationships.
Improving access to comprehensive MS care for underrepresented minorities who very often also lack robust insurance coverage is paramount. Recipients of comprehensive care are more likely to participate in research, as these patients receive more well-rounded care and have a lower risk of mismanaged comorbidities. Their involvement in the treatment plan is higher, which also improves compliance with treatment. Patients in comprehensive care centers are more likely to receive newer treatment agents with better efficacy without hindrance of monitoring barriers, and they are likely to benefit from treatment strategies using newly approved agents soon after US Food and Drug Administration approval.
Increasing research participation and, ideally, conducting a clinical trial devoted solely to studying MS in underrepresented minorities is something for which we should actively strive. Identifying the main factors prohibiting enrollment and retention of a high number of minority participants in trials is critical to success. Multiple deterrents in day-to-day life, very often directly connected to economic hardship and racism, pose a very real threat to equitable trial participation. To even consider a successful trial for underrepresented minorities, we must do better in devising strategies and accommodations to help overcome those barriers.
The underserved minorities with MS deserve and need our attention and focus. These patients have largely been neglected and forgotten, but now are emerging at the forefront of our attention—where they belong.
The persistent notion that multiple sclerosis (MS) is predominantly a White patient’s disease has been challenged by scientific data and our clinical experience in the field. Recent research has shown a higher risk of MS in non-White populations than originally thought. This may be surprising, but new data are influencing the way we now approach MS in under-represented minorities, bringing this topic to the forefront of scientific interest.
The early conviction that “there is no MS in minorities” led to underdiagnosis and misdiagnosis of MS in those patients, which in turn deepened these patients’ distrust of physicians and reluctance to seek further medical care, very often delivered by non-minority providers. Inequities in social determinants of health, low health literacy, and lack of private insurance, along with structural racism in healthcare, has further hindered active engagement with an already marginalized patient population in their MS care. This lack of engagement and lack of minorities in scientific research has proved to be unfavorable for MS research as well, creating large and persistent knowledge gaps in understanding MS course, severity, and response to treatment specific to this group. A 2014 PubMed search found 52,000 publications on MS in English, but in only 136 of those were minority patients with MS (Black or Hispanic/Latino) the primary research focus. In 2019, the same search indicated that the subsequent 5 years produced only 30 more articles focusing solely on minority patients.
Research participation of underrepresented minorities is another area where we, as a field, continue to fail these patients. A review of participant enrollment in MS clinical trials that took place between 1993 and 2006 showed a significant decrease in the percentage of enrolled Black patients (from 7% to about 4%). This trend did not improve by the DEFINE treatment trial (2012), in which only 2% of enrolled patients were Black. Of the 1246 participants in the 2019 SUNBEAM MS study, only 2 were Black. Low numbers of minority patients in trials prevent us from drawing any reasonable conclusion as to the efficacy of disease-modifying agents in those patients and make the goal of personalized medicine for this group impossible.
The results of the research conducted on these groups are compelling and should be prompting further work. Not only do Black patients have a higher risk of MS, but there is also now convincing evidence that MS in minorities is more severe overall, causing early progression of disability and necessitating assistive gait devices such as a cane or wheelchair. Minority patients tend to have more extensive involvement of spinal cord and infra-tentorial brain structures during the disease, which could explain the increased likelihood of more severe disease and earlier disability. Minority patients were admitted to nursing homes at a younger age, with greater physical and cognitive impairment than nonminority patients. A study looking at MS mortality between 1999 and 2015 found that Black males with MS had the highest mortality rate before age 45, and Black females before age 53. MS mortality increased with age but peaked at age 55 to 64 for Black patients and 65 to 74 for White patients. Underrepresented minorities are also less likely to use community resources, case management, medical equipment, and home nursing services. When looking at other measures of disease impact on these patients, studies evaluating magnetic resonance imaging (MRI) data showed higher lesion volume in Black patients with MS, as well as a higher degree of brain demyelination and atrophy when compared with White patients.
Treatment strategies currently used for underrepresented minority patients, as well as estimations of medication efficacy, treatment responses, and adverse-event profiles are largely driven by data from clinical trials with only minimal representation of those patients. How can we propose a patient-tailored and individualized treatment plan without these crucial data? Given that, to this day, not a single trial has focused solely on underrepresented minorities, we are left with either post hoc exploratory subgroup analyses of existing trials or pragmatic, observational, and very often retrospective studies using chart analysis. Notwithstanding the methodological flaws of either approach, prior studies did suggest worse response to platform therapies in Black patients, but equal response to high-efficacy therapies when compared with White patients.
Definitive biological underpinnings of disparities in disease severity have not been identified. In recent years, the field of health outcomes research has suggested we move away from considering racial categories as biologically distinct and instead focus on long-overlooked sociodemographic and modifiable lifestyle
factors. The role of diet, exercise, body mass index, smoking, and vascular comorbidities as risk factors associated with worse MS outcomes has been previously shown; however, these factors have not been rigorously assessed in underrepresented populations with MS. Recent studies focused on uncovering what drives the differences in MS severity in underrepresented populations disagree on the role biological differences, socioeconomic disparities, and structural racism in both healthcare settings and society play in answering this question. While it is plausible that a combination of these factors might explain our observations, more research on larger, underserved patient populations and better-defined measures of socioeconomic differences are needed to answer this complex question.
The path of recognizing and correcting our mistakes is not simple but must be done, and our underrepresented minority patients depend on our swift action. There are many places where we as a field of experts can and must do better—in communities, healthcare systems, and society in general.
Increasing community health literacy around MS, rebuilding trust, and addressing structural racism on every level is important. Outreach and educational programs that include in-person meetings and leverage social media platforms can help empower patients and their families—and hopefully increase trust in healthcare providers. Devising targeted interventions focusing on modifiable factors of a healthy lifestyle such as diet and exercise can increase community engagement and strengthen the support system for our patients. Increasing diversity in our own field of physicians, nurses, and other healthcare providers can also aid in strengthening mutual relationships.
Improving access to comprehensive MS care for underrepresented minorities who very often also lack robust insurance coverage is paramount. Recipients of comprehensive care are more likely to participate in research, as these patients receive more well-rounded care and have a lower risk of mismanaged comorbidities. Their involvement in the treatment plan is higher, which also improves compliance with treatment. Patients in comprehensive care centers are more likely to receive newer treatment agents with better efficacy without hindrance of monitoring barriers, and they are likely to benefit from treatment strategies using newly approved agents soon after US Food and Drug Administration approval.
Increasing research participation and, ideally, conducting a clinical trial devoted solely to studying MS in underrepresented minorities is something for which we should actively strive. Identifying the main factors prohibiting enrollment and retention of a high number of minority participants in trials is critical to success. Multiple deterrents in day-to-day life, very often directly connected to economic hardship and racism, pose a very real threat to equitable trial participation. To even consider a successful trial for underrepresented minorities, we must do better in devising strategies and accommodations to help overcome those barriers.
The underserved minorities with MS deserve and need our attention and focus. These patients have largely been neglected and forgotten, but now are emerging at the forefront of our attention—where they belong.
The persistent notion that multiple sclerosis (MS) is predominantly a White patient’s disease has been challenged by scientific data and our clinical experience in the field. Recent research has shown a higher risk of MS in non-White populations than originally thought. This may be surprising, but new data are influencing the way we now approach MS in under-represented minorities, bringing this topic to the forefront of scientific interest.
The early conviction that “there is no MS in minorities” led to underdiagnosis and misdiagnosis of MS in those patients, which in turn deepened these patients’ distrust of physicians and reluctance to seek further medical care, very often delivered by non-minority providers. Inequities in social determinants of health, low health literacy, and lack of private insurance, along with structural racism in healthcare, has further hindered active engagement with an already marginalized patient population in their MS care. This lack of engagement and lack of minorities in scientific research has proved to be unfavorable for MS research as well, creating large and persistent knowledge gaps in understanding MS course, severity, and response to treatment specific to this group. A 2014 PubMed search found 52,000 publications on MS in English, but in only 136 of those were minority patients with MS (Black or Hispanic/Latino) the primary research focus. In 2019, the same search indicated that the subsequent 5 years produced only 30 more articles focusing solely on minority patients.
Research participation of underrepresented minorities is another area where we, as a field, continue to fail these patients. A review of participant enrollment in MS clinical trials that took place between 1993 and 2006 showed a significant decrease in the percentage of enrolled Black patients (from 7% to about 4%). This trend did not improve by the DEFINE treatment trial (2012), in which only 2% of enrolled patients were Black. Of the 1246 participants in the 2019 SUNBEAM MS study, only 2 were Black. Low numbers of minority patients in trials prevent us from drawing any reasonable conclusion as to the efficacy of disease-modifying agents in those patients and make the goal of personalized medicine for this group impossible.
The results of the research conducted on these groups are compelling and should be prompting further work. Not only do Black patients have a higher risk of MS, but there is also now convincing evidence that MS in minorities is more severe overall, causing early progression of disability and necessitating assistive gait devices such as a cane or wheelchair. Minority patients tend to have more extensive involvement of spinal cord and infra-tentorial brain structures during the disease, which could explain the increased likelihood of more severe disease and earlier disability. Minority patients were admitted to nursing homes at a younger age, with greater physical and cognitive impairment than nonminority patients. A study looking at MS mortality between 1999 and 2015 found that Black males with MS had the highest mortality rate before age 45, and Black females before age 53. MS mortality increased with age but peaked at age 55 to 64 for Black patients and 65 to 74 for White patients. Underrepresented minorities are also less likely to use community resources, case management, medical equipment, and home nursing services. When looking at other measures of disease impact on these patients, studies evaluating magnetic resonance imaging (MRI) data showed higher lesion volume in Black patients with MS, as well as a higher degree of brain demyelination and atrophy when compared with White patients.
Treatment strategies currently used for underrepresented minority patients, as well as estimations of medication efficacy, treatment responses, and adverse-event profiles are largely driven by data from clinical trials with only minimal representation of those patients. How can we propose a patient-tailored and individualized treatment plan without these crucial data? Given that, to this day, not a single trial has focused solely on underrepresented minorities, we are left with either post hoc exploratory subgroup analyses of existing trials or pragmatic, observational, and very often retrospective studies using chart analysis. Notwithstanding the methodological flaws of either approach, prior studies did suggest worse response to platform therapies in Black patients, but equal response to high-efficacy therapies when compared with White patients.
Definitive biological underpinnings of disparities in disease severity have not been identified. In recent years, the field of health outcomes research has suggested we move away from considering racial categories as biologically distinct and instead focus on long-overlooked sociodemographic and modifiable lifestyle
factors. The role of diet, exercise, body mass index, smoking, and vascular comorbidities as risk factors associated with worse MS outcomes has been previously shown; however, these factors have not been rigorously assessed in underrepresented populations with MS. Recent studies focused on uncovering what drives the differences in MS severity in underrepresented populations disagree on the role biological differences, socioeconomic disparities, and structural racism in both healthcare settings and society play in answering this question. While it is plausible that a combination of these factors might explain our observations, more research on larger, underserved patient populations and better-defined measures of socioeconomic differences are needed to answer this complex question.
The path of recognizing and correcting our mistakes is not simple but must be done, and our underrepresented minority patients depend on our swift action. There are many places where we as a field of experts can and must do better—in communities, healthcare systems, and society in general.
Increasing community health literacy around MS, rebuilding trust, and addressing structural racism on every level is important. Outreach and educational programs that include in-person meetings and leverage social media platforms can help empower patients and their families—and hopefully increase trust in healthcare providers. Devising targeted interventions focusing on modifiable factors of a healthy lifestyle such as diet and exercise can increase community engagement and strengthen the support system for our patients. Increasing diversity in our own field of physicians, nurses, and other healthcare providers can also aid in strengthening mutual relationships.
Improving access to comprehensive MS care for underrepresented minorities who very often also lack robust insurance coverage is paramount. Recipients of comprehensive care are more likely to participate in research, as these patients receive more well-rounded care and have a lower risk of mismanaged comorbidities. Their involvement in the treatment plan is higher, which also improves compliance with treatment. Patients in comprehensive care centers are more likely to receive newer treatment agents with better efficacy without hindrance of monitoring barriers, and they are likely to benefit from treatment strategies using newly approved agents soon after US Food and Drug Administration approval.
Increasing research participation and, ideally, conducting a clinical trial devoted solely to studying MS in underrepresented minorities is something for which we should actively strive. Identifying the main factors prohibiting enrollment and retention of a high number of minority participants in trials is critical to success. Multiple deterrents in day-to-day life, very often directly connected to economic hardship and racism, pose a very real threat to equitable trial participation. To even consider a successful trial for underrepresented minorities, we must do better in devising strategies and accommodations to help overcome those barriers.
The underserved minorities with MS deserve and need our attention and focus. These patients have largely been neglected and forgotten, but now are emerging at the forefront of our attention—where they belong.
FDA okays first biosimilar for multiple sclerosis
including clinically isolated syndrome, relapsing remitting MS, and active secondary progressive disease.
“Biosimilar medications offer additional effective treatment options that have the potential to increase access for people living with relapsing forms of multiple sclerosis. [This] approval could have a meaningful impact for patients managing their disease,” Paul R. Lee, MD, PhD, director of the division of neurology II, FDA Center for Drug Evaluation and Research, said in a statement.
The natalizumab biosimilar is given using the same dosing and administration schedule. Like the reference product, it is indicated for adults with moderately to severely active Crohn’s disease unresponsive to other medications.
The approval of the natalizumab biosimilar is based on results of the phase 3 Antelope trial, which showed no clinically meaningful differences between it and the reference product.
The trial included 264 adults (mean age, 36 years; 61% women) with relapsing remitting MS from 48 centers in seven Eastern European countries.
All were randomly assigned to receive intravenous infusions every 4 weeks of 300 mg of the natalizumab biosimilar or the reference product for a total of 12 infusions.
At 24 and 48 weeks, there were no between-group differences in annualized relapse rates or Expanded Disability Status Scale scores, which were similar between treatment groups at baseline. There were also no significant differences in safety, tolerability, or immunogenicity.
The prescribing information for both natalizumab products includes a boxed warning about the increased risk of progressive multifocal leukoencephalopathy (PML), a viral infection of the brain that usually leads to death or severe disability.
Risk factors for the development of PML include the presence of antibodies to the JC virus, longer duration of therapy, and prior use of immunosuppressants.
“These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab products, and health care providers should monitor patients and withhold treatment immediately at the first sign or symptom suggestive of PML,” the FDA advises.
Because of the risks of PML, natalizumab products are available only through a restricted drug distribution program under a risk evaluation and mitigation strategy.
In a statement, Sandoz said it’s committed to having the product available in the United States “as soon as possible.”
A version of this article appeared on Medscape.com.
including clinically isolated syndrome, relapsing remitting MS, and active secondary progressive disease.
“Biosimilar medications offer additional effective treatment options that have the potential to increase access for people living with relapsing forms of multiple sclerosis. [This] approval could have a meaningful impact for patients managing their disease,” Paul R. Lee, MD, PhD, director of the division of neurology II, FDA Center for Drug Evaluation and Research, said in a statement.
The natalizumab biosimilar is given using the same dosing and administration schedule. Like the reference product, it is indicated for adults with moderately to severely active Crohn’s disease unresponsive to other medications.
The approval of the natalizumab biosimilar is based on results of the phase 3 Antelope trial, which showed no clinically meaningful differences between it and the reference product.
The trial included 264 adults (mean age, 36 years; 61% women) with relapsing remitting MS from 48 centers in seven Eastern European countries.
All were randomly assigned to receive intravenous infusions every 4 weeks of 300 mg of the natalizumab biosimilar or the reference product for a total of 12 infusions.
At 24 and 48 weeks, there were no between-group differences in annualized relapse rates or Expanded Disability Status Scale scores, which were similar between treatment groups at baseline. There were also no significant differences in safety, tolerability, or immunogenicity.
The prescribing information for both natalizumab products includes a boxed warning about the increased risk of progressive multifocal leukoencephalopathy (PML), a viral infection of the brain that usually leads to death or severe disability.
Risk factors for the development of PML include the presence of antibodies to the JC virus, longer duration of therapy, and prior use of immunosuppressants.
“These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab products, and health care providers should monitor patients and withhold treatment immediately at the first sign or symptom suggestive of PML,” the FDA advises.
Because of the risks of PML, natalizumab products are available only through a restricted drug distribution program under a risk evaluation and mitigation strategy.
In a statement, Sandoz said it’s committed to having the product available in the United States “as soon as possible.”
A version of this article appeared on Medscape.com.
including clinically isolated syndrome, relapsing remitting MS, and active secondary progressive disease.
“Biosimilar medications offer additional effective treatment options that have the potential to increase access for people living with relapsing forms of multiple sclerosis. [This] approval could have a meaningful impact for patients managing their disease,” Paul R. Lee, MD, PhD, director of the division of neurology II, FDA Center for Drug Evaluation and Research, said in a statement.
The natalizumab biosimilar is given using the same dosing and administration schedule. Like the reference product, it is indicated for adults with moderately to severely active Crohn’s disease unresponsive to other medications.
The approval of the natalizumab biosimilar is based on results of the phase 3 Antelope trial, which showed no clinically meaningful differences between it and the reference product.
The trial included 264 adults (mean age, 36 years; 61% women) with relapsing remitting MS from 48 centers in seven Eastern European countries.
All were randomly assigned to receive intravenous infusions every 4 weeks of 300 mg of the natalizumab biosimilar or the reference product for a total of 12 infusions.
At 24 and 48 weeks, there were no between-group differences in annualized relapse rates or Expanded Disability Status Scale scores, which were similar between treatment groups at baseline. There were also no significant differences in safety, tolerability, or immunogenicity.
The prescribing information for both natalizumab products includes a boxed warning about the increased risk of progressive multifocal leukoencephalopathy (PML), a viral infection of the brain that usually leads to death or severe disability.
Risk factors for the development of PML include the presence of antibodies to the JC virus, longer duration of therapy, and prior use of immunosuppressants.
“These factors should be considered in the context of expected benefit when initiating and continuing treatment with natalizumab products, and health care providers should monitor patients and withhold treatment immediately at the first sign or symptom suggestive of PML,” the FDA advises.
Because of the risks of PML, natalizumab products are available only through a restricted drug distribution program under a risk evaluation and mitigation strategy.
In a statement, Sandoz said it’s committed to having the product available in the United States “as soon as possible.”
A version of this article appeared on Medscape.com.
Early MS treatment tied to a major reduction in severe disability
a new study suggests.
Patients who received early treatment had a 45% lower risk of reaching a disability score of 3 and a 60% lower risk of advancing to secondary progressive MS compared with those who began treatment 18 months or more after symptoms presented.
Those with a score of 3 can still walk unassisted but have moderate disability in one of eight areas, such as motor function, vision or thinking skills, or mild disability in three or four areas.
“With a very early treatment, within 6 months from the first symptoms and even before the MS diagnosis, we are now able to decrease long-term disability. This means the earlier the better – time is brain,” lead author Alvaro Cobo-Calvo, MD, PhD, clinical neurologists and researcher with the Multiple Sclerosis Center of Catalonia in Barcelona and the Universitat Autonoma de Barcelona, said in an interview.
The findings were published online in Neurology.
Measuring disability
The observational, retrospective study included people aged 50 years or younger who received MS treatment within 6 months of their first clinical demyelinating event (n = 194), 6-16 months later (n = 192), or more than 16 months after the initial symptoms presented (n = 194).
The investigators noted that this cohort is one of the few that is considered “deeply phenotyped,” meaning it is followed prospectively over time with strict quality controls and systematic data collection methods.
MRIs were done within 3-5 months of the first symptoms, again at 12 months after the first event, and every 5 years over a median 11.2-year follow-up.
Disability levels were measured using the Expanded Disability Status Scale, with scores ranging from 0-10 and higher scores indicating more disability.
Patients who received treatment within 6 months of first symptoms were 45% less likely to have a disability score of 3 by the end of the study than did those who received treatment more than 16 months after that first event (hazard ratio, 0.55; 95% confidence interval, 0.32-0.97).
The earliest-treatment group also had a 60% lower risk of advancing to secondary progressive MS than did people in the latest-treatment group (HR, 0.40; 95% CI, 0.19-0.85).
Better disease stability
The researchers also found that earlier treatment was associated with a 53% better chance of disease stability 1 year after initial treatment (HR, 0.47; 95% CI, 0.28-0.80).
The early-treatment group also had a lower disability progression rate and lower severe disability in a self-reported test, compared with those who were treated later.
The investigators also found that patients who received early treatment were at lower risk for disability, even those with a higher baseline radiologic burden.
Current guidelines recommend early treatment of MS, but it is unclear whether disease-modifying treatments (DMTs) should be prescribed after the first MS symptoms or after a definitive MS diagnosis.
Earlier studies often evaluated treatment efficacy after MS diagnosis. This study began tracking efficacy when therapy began after the first symptoms. In some cases, that was before a diagnosis was given.
“It is important to be cautious when starting treatment and we need to know if the patient will evolve to MS or if the patient is diagnosed with MS based on current McDonald criteria.
“In our study, 70% of patients had MS at the time of the first symptoms according to McDonald 201, but the remainder started treatment without an ‘official’ diagnosis but with an event highly suggestive of MS,” Dr. Cobo-Calvo said.
He added that very early treatment after first symptoms is key to preserving neurologic functionality.
Controversy remains
Adding MRI results as a clinical variable is a novel approach, but the MRI risk score used in the study is a new tool that has not yet been validated, the authors of an accompanying editorial noted.
“The results of this study show that in order to achieve a balance between compared groups, matching on MRI has little to add to good-quality balancing on patients’ clinical and demographic features,” wrote Erin Longbrake, MD, PhD, of the department of neurology, Yale University, New Haven, Conn., and Tomas Kalincik, MD, PhD, of the Neuroimmunology Centre, department of neurology, Royal Melbourne Hospital and the CORe unit, department of medicine, University of Melbourne.
Despite growing evidence pointing to improved outcomes from administering DMTs soon after diagnosis, the timing and sequence of therapy remains an area of controversy, they added.
“While these uncertain diagnostic scenarios may tempt neurologists to ‘wait and see,’ the data presented here remind us that these patients remain at risk of accumulating disability,” the authors wrote. “Neurologists must therefore remain vigilant to ensure that diagnosis is made promptly, that patients are followed up effectively and that effective treatments are used liberally.”
The study was funded by the European Regional Development Fund, Instituto de Salud Carlos III. Dr. Cobo-Calvo has received a grant from Instituto de Salud Carlos III. Dr. Longbrake has consulted for Genentech and NGM Bio and received research support from Biogen & Genentech. Dr. Kalincik has received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi Genzyme, Teva, BioCSL, and Merck, and has received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck.
A version of this article first appeared on Medscape.com.
a new study suggests.
Patients who received early treatment had a 45% lower risk of reaching a disability score of 3 and a 60% lower risk of advancing to secondary progressive MS compared with those who began treatment 18 months or more after symptoms presented.
Those with a score of 3 can still walk unassisted but have moderate disability in one of eight areas, such as motor function, vision or thinking skills, or mild disability in three or four areas.
“With a very early treatment, within 6 months from the first symptoms and even before the MS diagnosis, we are now able to decrease long-term disability. This means the earlier the better – time is brain,” lead author Alvaro Cobo-Calvo, MD, PhD, clinical neurologists and researcher with the Multiple Sclerosis Center of Catalonia in Barcelona and the Universitat Autonoma de Barcelona, said in an interview.
The findings were published online in Neurology.
Measuring disability
The observational, retrospective study included people aged 50 years or younger who received MS treatment within 6 months of their first clinical demyelinating event (n = 194), 6-16 months later (n = 192), or more than 16 months after the initial symptoms presented (n = 194).
The investigators noted that this cohort is one of the few that is considered “deeply phenotyped,” meaning it is followed prospectively over time with strict quality controls and systematic data collection methods.
MRIs were done within 3-5 months of the first symptoms, again at 12 months after the first event, and every 5 years over a median 11.2-year follow-up.
Disability levels were measured using the Expanded Disability Status Scale, with scores ranging from 0-10 and higher scores indicating more disability.
Patients who received treatment within 6 months of first symptoms were 45% less likely to have a disability score of 3 by the end of the study than did those who received treatment more than 16 months after that first event (hazard ratio, 0.55; 95% confidence interval, 0.32-0.97).
The earliest-treatment group also had a 60% lower risk of advancing to secondary progressive MS than did people in the latest-treatment group (HR, 0.40; 95% CI, 0.19-0.85).
Better disease stability
The researchers also found that earlier treatment was associated with a 53% better chance of disease stability 1 year after initial treatment (HR, 0.47; 95% CI, 0.28-0.80).
The early-treatment group also had a lower disability progression rate and lower severe disability in a self-reported test, compared with those who were treated later.
The investigators also found that patients who received early treatment were at lower risk for disability, even those with a higher baseline radiologic burden.
Current guidelines recommend early treatment of MS, but it is unclear whether disease-modifying treatments (DMTs) should be prescribed after the first MS symptoms or after a definitive MS diagnosis.
Earlier studies often evaluated treatment efficacy after MS diagnosis. This study began tracking efficacy when therapy began after the first symptoms. In some cases, that was before a diagnosis was given.
“It is important to be cautious when starting treatment and we need to know if the patient will evolve to MS or if the patient is diagnosed with MS based on current McDonald criteria.
“In our study, 70% of patients had MS at the time of the first symptoms according to McDonald 201, but the remainder started treatment without an ‘official’ diagnosis but with an event highly suggestive of MS,” Dr. Cobo-Calvo said.
He added that very early treatment after first symptoms is key to preserving neurologic functionality.
Controversy remains
Adding MRI results as a clinical variable is a novel approach, but the MRI risk score used in the study is a new tool that has not yet been validated, the authors of an accompanying editorial noted.
“The results of this study show that in order to achieve a balance between compared groups, matching on MRI has little to add to good-quality balancing on patients’ clinical and demographic features,” wrote Erin Longbrake, MD, PhD, of the department of neurology, Yale University, New Haven, Conn., and Tomas Kalincik, MD, PhD, of the Neuroimmunology Centre, department of neurology, Royal Melbourne Hospital and the CORe unit, department of medicine, University of Melbourne.
Despite growing evidence pointing to improved outcomes from administering DMTs soon after diagnosis, the timing and sequence of therapy remains an area of controversy, they added.
“While these uncertain diagnostic scenarios may tempt neurologists to ‘wait and see,’ the data presented here remind us that these patients remain at risk of accumulating disability,” the authors wrote. “Neurologists must therefore remain vigilant to ensure that diagnosis is made promptly, that patients are followed up effectively and that effective treatments are used liberally.”
The study was funded by the European Regional Development Fund, Instituto de Salud Carlos III. Dr. Cobo-Calvo has received a grant from Instituto de Salud Carlos III. Dr. Longbrake has consulted for Genentech and NGM Bio and received research support from Biogen & Genentech. Dr. Kalincik has received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi Genzyme, Teva, BioCSL, and Merck, and has received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck.
A version of this article first appeared on Medscape.com.
a new study suggests.
Patients who received early treatment had a 45% lower risk of reaching a disability score of 3 and a 60% lower risk of advancing to secondary progressive MS compared with those who began treatment 18 months or more after symptoms presented.
Those with a score of 3 can still walk unassisted but have moderate disability in one of eight areas, such as motor function, vision or thinking skills, or mild disability in three or four areas.
“With a very early treatment, within 6 months from the first symptoms and even before the MS diagnosis, we are now able to decrease long-term disability. This means the earlier the better – time is brain,” lead author Alvaro Cobo-Calvo, MD, PhD, clinical neurologists and researcher with the Multiple Sclerosis Center of Catalonia in Barcelona and the Universitat Autonoma de Barcelona, said in an interview.
The findings were published online in Neurology.
Measuring disability
The observational, retrospective study included people aged 50 years or younger who received MS treatment within 6 months of their first clinical demyelinating event (n = 194), 6-16 months later (n = 192), or more than 16 months after the initial symptoms presented (n = 194).
The investigators noted that this cohort is one of the few that is considered “deeply phenotyped,” meaning it is followed prospectively over time with strict quality controls and systematic data collection methods.
MRIs were done within 3-5 months of the first symptoms, again at 12 months after the first event, and every 5 years over a median 11.2-year follow-up.
Disability levels were measured using the Expanded Disability Status Scale, with scores ranging from 0-10 and higher scores indicating more disability.
Patients who received treatment within 6 months of first symptoms were 45% less likely to have a disability score of 3 by the end of the study than did those who received treatment more than 16 months after that first event (hazard ratio, 0.55; 95% confidence interval, 0.32-0.97).
The earliest-treatment group also had a 60% lower risk of advancing to secondary progressive MS than did people in the latest-treatment group (HR, 0.40; 95% CI, 0.19-0.85).
Better disease stability
The researchers also found that earlier treatment was associated with a 53% better chance of disease stability 1 year after initial treatment (HR, 0.47; 95% CI, 0.28-0.80).
The early-treatment group also had a lower disability progression rate and lower severe disability in a self-reported test, compared with those who were treated later.
The investigators also found that patients who received early treatment were at lower risk for disability, even those with a higher baseline radiologic burden.
Current guidelines recommend early treatment of MS, but it is unclear whether disease-modifying treatments (DMTs) should be prescribed after the first MS symptoms or after a definitive MS diagnosis.
Earlier studies often evaluated treatment efficacy after MS diagnosis. This study began tracking efficacy when therapy began after the first symptoms. In some cases, that was before a diagnosis was given.
“It is important to be cautious when starting treatment and we need to know if the patient will evolve to MS or if the patient is diagnosed with MS based on current McDonald criteria.
“In our study, 70% of patients had MS at the time of the first symptoms according to McDonald 201, but the remainder started treatment without an ‘official’ diagnosis but with an event highly suggestive of MS,” Dr. Cobo-Calvo said.
He added that very early treatment after first symptoms is key to preserving neurologic functionality.
Controversy remains
Adding MRI results as a clinical variable is a novel approach, but the MRI risk score used in the study is a new tool that has not yet been validated, the authors of an accompanying editorial noted.
“The results of this study show that in order to achieve a balance between compared groups, matching on MRI has little to add to good-quality balancing on patients’ clinical and demographic features,” wrote Erin Longbrake, MD, PhD, of the department of neurology, Yale University, New Haven, Conn., and Tomas Kalincik, MD, PhD, of the Neuroimmunology Centre, department of neurology, Royal Melbourne Hospital and the CORe unit, department of medicine, University of Melbourne.
Despite growing evidence pointing to improved outcomes from administering DMTs soon after diagnosis, the timing and sequence of therapy remains an area of controversy, they added.
“While these uncertain diagnostic scenarios may tempt neurologists to ‘wait and see,’ the data presented here remind us that these patients remain at risk of accumulating disability,” the authors wrote. “Neurologists must therefore remain vigilant to ensure that diagnosis is made promptly, that patients are followed up effectively and that effective treatments are used liberally.”
The study was funded by the European Regional Development Fund, Instituto de Salud Carlos III. Dr. Cobo-Calvo has received a grant from Instituto de Salud Carlos III. Dr. Longbrake has consulted for Genentech and NGM Bio and received research support from Biogen & Genentech. Dr. Kalincik has received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi Genzyme, Teva, BioCSL, and Merck, and has received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Retinal thickness a new predictor of MS disability?
The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.
The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.
This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.
Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.
Retinal layers of interest
OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”
However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.
To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.
Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.
Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.
Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.
At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
Independent predictors of disability
To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.
After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.
Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).
Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”
For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.
Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
Strengths, limitations
Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).
Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.
Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.
This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.
“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.
The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.
In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.
However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.
“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
Important research
Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”
However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.
Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.
Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.
“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”
Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”
Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”
Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.
Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.
This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.
Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.
A version of this article appeared on Medscape.com.
The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.
The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.
This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.
Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.
Retinal layers of interest
OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”
However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.
To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.
Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.
Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.
Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.
At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
Independent predictors of disability
To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.
After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.
Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).
Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”
For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.
Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
Strengths, limitations
Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).
Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.
Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.
This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.
“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.
The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.
In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.
However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.
“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
Important research
Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”
However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.
Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.
Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.
“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”
Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”
Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”
Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.
Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.
This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.
Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.
A version of this article appeared on Medscape.com.
The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.
The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.
This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.
Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.
Retinal layers of interest
OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”
However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.
To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.
Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.
Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.
Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.
At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
Independent predictors of disability
To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.
After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.
Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).
Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”
For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.
Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
Strengths, limitations
Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).
Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.
Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.
This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.
“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.
The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.
In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.
However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.
“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
Important research
Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”
However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.
Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.
Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.
“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”
Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”
Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”
Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.
Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.
This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.
Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.
A version of this article appeared on Medscape.com.
FROM EAN 2023
Global burden of brain disorders surpasses cardiovascular disease and cancer
– at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.
“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.
“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”
Other factors related to brain disorders, she noted, include education level, obesity, and smoking.
“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.
The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
An ‘ambitious exercise’
Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”
A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.
They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
Increase in dementia, mental health conditions
The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”
The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.
Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.
Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.
Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.
To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).
This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.
The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.
This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.
The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.
“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
Worrying increase in stroke
Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.
“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”
Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”
“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.
The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
– at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.
“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.
“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”
Other factors related to brain disorders, she noted, include education level, obesity, and smoking.
“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.
The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
An ‘ambitious exercise’
Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”
A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.
They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
Increase in dementia, mental health conditions
The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”
The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.
Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.
Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.
Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.
To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).
This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.
The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.
This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.
The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.
“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
Worrying increase in stroke
Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.
“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”
Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”
“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.
The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
– at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.
“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.
“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”
Other factors related to brain disorders, she noted, include education level, obesity, and smoking.
“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.
The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
An ‘ambitious exercise’
Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”
A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.
They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
Increase in dementia, mental health conditions
The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”
The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.
Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.
Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.
Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.
To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).
This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.
The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.
This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.
The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.
“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
Worrying increase in stroke
Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.
“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”
Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”
“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.
The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Multiple sclerosis has a misdiagnosis problem
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
AT CMSC 2023
No apparent drug interaction with ozanimod and antidepressants
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
AT CMSC 2023