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FDA approves oral form of ALS drug edaravone
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Reducing Attacks and Neuropathic Pain in NMOSD
Patients with neuromyelitis optica spectrum disorder (NMOSD) experience unpredictable episodes of inflammation involving the optic nerve, spine, or both. Debilitating neuropathic pain accompanies the healing process, which lasts anywhere from 2 to 6 months after an attack.
In this ReCAP, Dr Michael Levy, of Harvard Medical School in Boston, Massachusetts, outlines the heavy psychological and economic burdens associated with NMOSD and reports on three new targeted therapies that have been approved to prevent relapse and delay disease progression.
He then looks at current pharmaceutical treatments for NMOSD pain, before reporting promising trial data exploring transcutaneous electrical nerve stimulation as a safe and cost-effective treatment for neuropathic pain.
--
Michael Levy, MD, PhD, Associate Professor, Department of Neurology, Harvard Medical School, Boston, Massachusetts
Michael Levy, MD, PhD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Horizon; Genentech; UCB; Sanofi; Quest
Received research grant from: National Institutes of Health; Sanofi; Genentech; Horizon; Alexion
Patients with neuromyelitis optica spectrum disorder (NMOSD) experience unpredictable episodes of inflammation involving the optic nerve, spine, or both. Debilitating neuropathic pain accompanies the healing process, which lasts anywhere from 2 to 6 months after an attack.
In this ReCAP, Dr Michael Levy, of Harvard Medical School in Boston, Massachusetts, outlines the heavy psychological and economic burdens associated with NMOSD and reports on three new targeted therapies that have been approved to prevent relapse and delay disease progression.
He then looks at current pharmaceutical treatments for NMOSD pain, before reporting promising trial data exploring transcutaneous electrical nerve stimulation as a safe and cost-effective treatment for neuropathic pain.
--
Michael Levy, MD, PhD, Associate Professor, Department of Neurology, Harvard Medical School, Boston, Massachusetts
Michael Levy, MD, PhD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Horizon; Genentech; UCB; Sanofi; Quest
Received research grant from: National Institutes of Health; Sanofi; Genentech; Horizon; Alexion
Patients with neuromyelitis optica spectrum disorder (NMOSD) experience unpredictable episodes of inflammation involving the optic nerve, spine, or both. Debilitating neuropathic pain accompanies the healing process, which lasts anywhere from 2 to 6 months after an attack.
In this ReCAP, Dr Michael Levy, of Harvard Medical School in Boston, Massachusetts, outlines the heavy psychological and economic burdens associated with NMOSD and reports on three new targeted therapies that have been approved to prevent relapse and delay disease progression.
He then looks at current pharmaceutical treatments for NMOSD pain, before reporting promising trial data exploring transcutaneous electrical nerve stimulation as a safe and cost-effective treatment for neuropathic pain.
--
Michael Levy, MD, PhD, Associate Professor, Department of Neurology, Harvard Medical School, Boston, Massachusetts
Michael Levy, MD, PhD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Horizon; Genentech; UCB; Sanofi; Quest
Received research grant from: National Institutes of Health; Sanofi; Genentech; Horizon; Alexion
Steroids counter ataxia telangiectasia
SEATTLE –
The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.
“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.
Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.
The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.
The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.
It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.
The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
A ‘promising and impressive’ study
The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.
The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.
In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.
An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.
SEATTLE –
The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.
“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.
Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.
The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.
The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.
It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.
The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
A ‘promising and impressive’ study
The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.
The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.
In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.
An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.
SEATTLE –
The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.
“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.
Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.
The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.
The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.
It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.
The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
A ‘promising and impressive’ study
The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.
The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.
In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.
An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.
AT AAN 2022
Nanoparticle shows promise for ALS
SEATTLE – , which was the change in the summated motor unit index (MUNIX) from baseline to week 36.
The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.
Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.
CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.
The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
Good safety signal
The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.
A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.
Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
Ongoing research
In September 2021, Clene announced a second expanded access program for people with ALS.
The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).
At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).
Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).
The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.
SEATTLE – , which was the change in the summated motor unit index (MUNIX) from baseline to week 36.
The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.
Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.
CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.
The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
Good safety signal
The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.
A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.
Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
Ongoing research
In September 2021, Clene announced a second expanded access program for people with ALS.
The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).
At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).
Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).
The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.
SEATTLE – , which was the change in the summated motor unit index (MUNIX) from baseline to week 36.
The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.
Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.
CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.
The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
Good safety signal
The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.
A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.
Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
Ongoing research
In September 2021, Clene announced a second expanded access program for people with ALS.
The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).
At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).
Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).
The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.
AT AAN 2022
FDA advisory panel rejects new ALS drug
Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.
The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.
“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.
The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
Phase 3 study in the works
This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.
This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.
During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.
However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.
Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.
A version of this article first appeared on WebMD.com.
Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.
The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.
“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.
The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
Phase 3 study in the works
This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.
This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.
During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.
However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.
Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.
A version of this article first appeared on WebMD.com.
Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.
The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.
“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.
The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
Phase 3 study in the works
This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.
This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.
During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.
However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.
Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.
A version of this article first appeared on WebMD.com.
Tremors and memory loss precede Parkinson’s in diverse population
Tremors and memory symptoms were identified among individuals in a primary care setting as early as 10 years before a Parkinson’s disease diagnosis in a new study.
Most research on the causes and early signs of Parkinson’s disease (PD) have involved patients of Northern European ancestry, Cristina Simonet, MD, of Queen Mary University of London, and colleagues wrote in their paper, published in JAMA Neurology.
Additionally, data on how PD might manifest in different ethnic groups are limited, they said.
In their nested case-control, the researchers examined data from electronic health records of an ethnically diverse population of 1,016,277 adults seen in primary care practices between 1990 and Feb. 6, 2018. They compared individuals with PD with those without PD or other neurologic conditions.
The researchers identified 10 age and sex-matched controls for each PD case, and also conducted an unmatched analysis after adjusting for age and sex. The final study population included 1,055 patients with PD and 1,009,523 controls. The population of PD cases was 15.7% Black, 19.7% South Asian, 50.9% White, and 8.3% other; the population of controls was 13.3% Black, 21.5% South Asian, 43.7% White, and 11.3% other.
“We observed a constellation of symptoms noted by general practitioners up to a decade before diagnosis of PD,” the researchers said. Symptoms were identified across three time intervals (less than 2 years, 2-5 years, and 5-10 years before diagnosis) to better evaluate exposure outcome associations.
In the matched analysis of midlife risk factors, epilepsy showed the strongest association with PD diagnosis across all time periods, and type 2 diabetes or hypertension 5-10 years before diagnosis was associated with later PD.
Prediagnostic signs of PD included both motor and nonmotor manifestations.
The matched analysis revealed a significant increased association between tremor and memory symptoms less than 2 years before diagnosis (adjusted odds ratios of 151.24 and 8.73, respectively) as well as up to 10 years before diagnosis for tremors and up to 5 years for memory symptoms (aOR, 11.4 and 3.09, respectively) in PD patients, compared with controls.
Other strong associations between PD and early nonmotor features in cases, compared with controls, included hypotension (aOR, 6.81), constipation (aOR, 3.29), and depression (aOR, 4.61).
In addition, the researchers found associations for epilepsy that had not been identified in previous studies, and these associations persisted in a replication analysis.
The study findings were limited by several factors, mainly the use of routine primary care data with underascertained factors of interest, and potential mislabeling of PD, the researchers noted. Other limitations included the lack of data on prescription medication for PD, and the recording of memory problems in primary care without supportive testing to confirm cognitive impairment.
The results support a range of comorbidities and symptoms that may present in primary care, and clinicians should consider PD as a possible cause, the researchers wrote.
Make early referral a priority
The study is important because of the lack of diversity in Parkinson’s disease research, lead author Dr. Simonet said in an interview.
“Over the last decade, the global population suffering from Parkinson’s disease has more than doubled,” she said. Causes may include the increasing numbers of older people with longer life expectancy. “However, it seems there are other factors, including environmental, genetic, and lifestyle, that might play a role in increasing the prevalence of Parkinson’s disease.”
“More representative studies, including minority ethnic groups and those living in areas of high social and economic deprivation, are needed,” Dr. Simonet emphasized.
She said that there is little research on the association with epilepsy and hearing loss in early PD, and “for that reason, our results should encourage further studies to confirm a possible link between these manifestations and Parkinson’s disease.”
Early detection may drive better diagnoses
The current study is important for understanding the prediagnostic features and risk factors that may allow for earlier detection of Parkinson’s disease, William Hung, MD, a geriatrics and palliative care specialist of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Prior to this study, there was limited understanding of these features.
“One surprise [in the findings] was that ethnicity and socioeconomic deprivation do not appear to be associated with the risk of PD, in contrast to other illnesses such as dementia,” said Dr. Hung. “The array of prediagnostic features associated with PD is not surprising, but nonetheless important for clinicians to know to consider whether PD could be the underlying cause.”
The take-home message for primary care is that “there are features, such as hearing loss, history of epilepsy, autonomic symptoms, motor symptoms, among others, for which clinicians should consider PD as part of the differential diagnosis as underlying cause and consider referral to specialists for diagnostic clarification,” said Dr. Hung.
“Additional research is needed to translate these findings to care, perhaps developing decision aids, interventions that may help with diagnosis and evaluation,” as is work on understanding the link between PD and symptoms such as hearing loss and epilepsy, he said.
Primary care offers opportunity to identify risk factors
The current study represents an important step in early recognition of PD, with implications for helping patients access treatments promptly and improve their quality of life, Bhavana Patel, DO, Shannon Chiu, MD, and Melissa J. Armstrong, MD, of the University of Florida, Gainesville, wrote in an accompanying editorial.
“The primary care setting is commonly where symptoms heralding the onset of PD are first discussed. However, little is known regarding the prediagnostic manifestations of PD that are seen in primary care clinics, particularly in underserved populations,” they wrote.
The study included many risk factors and prodromal markers associated with research criteria for prodromal PD, but did not include several risk and prodromal markers in the Movement Disorders Society research criteria, “such as symptoms suggestive of REM sleep behavior disorder, excessive daytime sleepiness (which overlaps with, but is distinct from, fatigue), urinary dysfunction, pesticide and solvent exposure, caffeine use, level of physical activity, and family history,” they said.
Even in individuals with diagnosed PD, certain symptoms, particularly nonmotor symptoms, are commonly underreported,” and primary care clinicians may not recognize these symptoms as PD risk factors, the authors noted.
However, “in addition to contributing to possible models of modifiable risk factors for PD, study results may also further inform algorithms designed to predict PD diagnoses in primary care,” they said. The study also highlights the need for more multivariable models to better identify PD risk factors and strategies for early identification of PD in primary care.
Several study coauthors received funding related to the study from Barts Charity, Health Data Research UK, the Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities, as well as the National Institute for Health Research UCLH Biomedical Research Centre. Lead author Dr. Simonet and Dr. Hung had no financial conflicts to disclose. Dr. Patel disclosed support from the National Institute on Aging, the Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia, and the American Brain Foundation and the Mary E. Groff Charitable Trust. Dr. Chiu reported receiving grants from Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia and the Smallwood Foundation. Dr. Armstrong disclosed funding from the National Institute on Aging, the Florida Department of Health, the Lewy Body Dementia Association, the Alzheimer’s Therapeutic Research Institute/Alzheimer’s Clinical Trial Consortium, the Alzheimer’s Disease Cooperative Study as Data Safety Monitoring Board the Parkinson’s Foundation, and the American Academy of Neurology.
Tremors and memory symptoms were identified among individuals in a primary care setting as early as 10 years before a Parkinson’s disease diagnosis in a new study.
Most research on the causes and early signs of Parkinson’s disease (PD) have involved patients of Northern European ancestry, Cristina Simonet, MD, of Queen Mary University of London, and colleagues wrote in their paper, published in JAMA Neurology.
Additionally, data on how PD might manifest in different ethnic groups are limited, they said.
In their nested case-control, the researchers examined data from electronic health records of an ethnically diverse population of 1,016,277 adults seen in primary care practices between 1990 and Feb. 6, 2018. They compared individuals with PD with those without PD or other neurologic conditions.
The researchers identified 10 age and sex-matched controls for each PD case, and also conducted an unmatched analysis after adjusting for age and sex. The final study population included 1,055 patients with PD and 1,009,523 controls. The population of PD cases was 15.7% Black, 19.7% South Asian, 50.9% White, and 8.3% other; the population of controls was 13.3% Black, 21.5% South Asian, 43.7% White, and 11.3% other.
“We observed a constellation of symptoms noted by general practitioners up to a decade before diagnosis of PD,” the researchers said. Symptoms were identified across three time intervals (less than 2 years, 2-5 years, and 5-10 years before diagnosis) to better evaluate exposure outcome associations.
In the matched analysis of midlife risk factors, epilepsy showed the strongest association with PD diagnosis across all time periods, and type 2 diabetes or hypertension 5-10 years before diagnosis was associated with later PD.
Prediagnostic signs of PD included both motor and nonmotor manifestations.
The matched analysis revealed a significant increased association between tremor and memory symptoms less than 2 years before diagnosis (adjusted odds ratios of 151.24 and 8.73, respectively) as well as up to 10 years before diagnosis for tremors and up to 5 years for memory symptoms (aOR, 11.4 and 3.09, respectively) in PD patients, compared with controls.
Other strong associations between PD and early nonmotor features in cases, compared with controls, included hypotension (aOR, 6.81), constipation (aOR, 3.29), and depression (aOR, 4.61).
In addition, the researchers found associations for epilepsy that had not been identified in previous studies, and these associations persisted in a replication analysis.
The study findings were limited by several factors, mainly the use of routine primary care data with underascertained factors of interest, and potential mislabeling of PD, the researchers noted. Other limitations included the lack of data on prescription medication for PD, and the recording of memory problems in primary care without supportive testing to confirm cognitive impairment.
The results support a range of comorbidities and symptoms that may present in primary care, and clinicians should consider PD as a possible cause, the researchers wrote.
Make early referral a priority
The study is important because of the lack of diversity in Parkinson’s disease research, lead author Dr. Simonet said in an interview.
“Over the last decade, the global population suffering from Parkinson’s disease has more than doubled,” she said. Causes may include the increasing numbers of older people with longer life expectancy. “However, it seems there are other factors, including environmental, genetic, and lifestyle, that might play a role in increasing the prevalence of Parkinson’s disease.”
“More representative studies, including minority ethnic groups and those living in areas of high social and economic deprivation, are needed,” Dr. Simonet emphasized.
She said that there is little research on the association with epilepsy and hearing loss in early PD, and “for that reason, our results should encourage further studies to confirm a possible link between these manifestations and Parkinson’s disease.”
Early detection may drive better diagnoses
The current study is important for understanding the prediagnostic features and risk factors that may allow for earlier detection of Parkinson’s disease, William Hung, MD, a geriatrics and palliative care specialist of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Prior to this study, there was limited understanding of these features.
“One surprise [in the findings] was that ethnicity and socioeconomic deprivation do not appear to be associated with the risk of PD, in contrast to other illnesses such as dementia,” said Dr. Hung. “The array of prediagnostic features associated with PD is not surprising, but nonetheless important for clinicians to know to consider whether PD could be the underlying cause.”
The take-home message for primary care is that “there are features, such as hearing loss, history of epilepsy, autonomic symptoms, motor symptoms, among others, for which clinicians should consider PD as part of the differential diagnosis as underlying cause and consider referral to specialists for diagnostic clarification,” said Dr. Hung.
“Additional research is needed to translate these findings to care, perhaps developing decision aids, interventions that may help with diagnosis and evaluation,” as is work on understanding the link between PD and symptoms such as hearing loss and epilepsy, he said.
Primary care offers opportunity to identify risk factors
The current study represents an important step in early recognition of PD, with implications for helping patients access treatments promptly and improve their quality of life, Bhavana Patel, DO, Shannon Chiu, MD, and Melissa J. Armstrong, MD, of the University of Florida, Gainesville, wrote in an accompanying editorial.
“The primary care setting is commonly where symptoms heralding the onset of PD are first discussed. However, little is known regarding the prediagnostic manifestations of PD that are seen in primary care clinics, particularly in underserved populations,” they wrote.
The study included many risk factors and prodromal markers associated with research criteria for prodromal PD, but did not include several risk and prodromal markers in the Movement Disorders Society research criteria, “such as symptoms suggestive of REM sleep behavior disorder, excessive daytime sleepiness (which overlaps with, but is distinct from, fatigue), urinary dysfunction, pesticide and solvent exposure, caffeine use, level of physical activity, and family history,” they said.
Even in individuals with diagnosed PD, certain symptoms, particularly nonmotor symptoms, are commonly underreported,” and primary care clinicians may not recognize these symptoms as PD risk factors, the authors noted.
However, “in addition to contributing to possible models of modifiable risk factors for PD, study results may also further inform algorithms designed to predict PD diagnoses in primary care,” they said. The study also highlights the need for more multivariable models to better identify PD risk factors and strategies for early identification of PD in primary care.
Several study coauthors received funding related to the study from Barts Charity, Health Data Research UK, the Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities, as well as the National Institute for Health Research UCLH Biomedical Research Centre. Lead author Dr. Simonet and Dr. Hung had no financial conflicts to disclose. Dr. Patel disclosed support from the National Institute on Aging, the Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia, and the American Brain Foundation and the Mary E. Groff Charitable Trust. Dr. Chiu reported receiving grants from Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia and the Smallwood Foundation. Dr. Armstrong disclosed funding from the National Institute on Aging, the Florida Department of Health, the Lewy Body Dementia Association, the Alzheimer’s Therapeutic Research Institute/Alzheimer’s Clinical Trial Consortium, the Alzheimer’s Disease Cooperative Study as Data Safety Monitoring Board the Parkinson’s Foundation, and the American Academy of Neurology.
Tremors and memory symptoms were identified among individuals in a primary care setting as early as 10 years before a Parkinson’s disease diagnosis in a new study.
Most research on the causes and early signs of Parkinson’s disease (PD) have involved patients of Northern European ancestry, Cristina Simonet, MD, of Queen Mary University of London, and colleagues wrote in their paper, published in JAMA Neurology.
Additionally, data on how PD might manifest in different ethnic groups are limited, they said.
In their nested case-control, the researchers examined data from electronic health records of an ethnically diverse population of 1,016,277 adults seen in primary care practices between 1990 and Feb. 6, 2018. They compared individuals with PD with those without PD or other neurologic conditions.
The researchers identified 10 age and sex-matched controls for each PD case, and also conducted an unmatched analysis after adjusting for age and sex. The final study population included 1,055 patients with PD and 1,009,523 controls. The population of PD cases was 15.7% Black, 19.7% South Asian, 50.9% White, and 8.3% other; the population of controls was 13.3% Black, 21.5% South Asian, 43.7% White, and 11.3% other.
“We observed a constellation of symptoms noted by general practitioners up to a decade before diagnosis of PD,” the researchers said. Symptoms were identified across three time intervals (less than 2 years, 2-5 years, and 5-10 years before diagnosis) to better evaluate exposure outcome associations.
In the matched analysis of midlife risk factors, epilepsy showed the strongest association with PD diagnosis across all time periods, and type 2 diabetes or hypertension 5-10 years before diagnosis was associated with later PD.
Prediagnostic signs of PD included both motor and nonmotor manifestations.
The matched analysis revealed a significant increased association between tremor and memory symptoms less than 2 years before diagnosis (adjusted odds ratios of 151.24 and 8.73, respectively) as well as up to 10 years before diagnosis for tremors and up to 5 years for memory symptoms (aOR, 11.4 and 3.09, respectively) in PD patients, compared with controls.
Other strong associations between PD and early nonmotor features in cases, compared with controls, included hypotension (aOR, 6.81), constipation (aOR, 3.29), and depression (aOR, 4.61).
In addition, the researchers found associations for epilepsy that had not been identified in previous studies, and these associations persisted in a replication analysis.
The study findings were limited by several factors, mainly the use of routine primary care data with underascertained factors of interest, and potential mislabeling of PD, the researchers noted. Other limitations included the lack of data on prescription medication for PD, and the recording of memory problems in primary care without supportive testing to confirm cognitive impairment.
The results support a range of comorbidities and symptoms that may present in primary care, and clinicians should consider PD as a possible cause, the researchers wrote.
Make early referral a priority
The study is important because of the lack of diversity in Parkinson’s disease research, lead author Dr. Simonet said in an interview.
“Over the last decade, the global population suffering from Parkinson’s disease has more than doubled,” she said. Causes may include the increasing numbers of older people with longer life expectancy. “However, it seems there are other factors, including environmental, genetic, and lifestyle, that might play a role in increasing the prevalence of Parkinson’s disease.”
“More representative studies, including minority ethnic groups and those living in areas of high social and economic deprivation, are needed,” Dr. Simonet emphasized.
She said that there is little research on the association with epilepsy and hearing loss in early PD, and “for that reason, our results should encourage further studies to confirm a possible link between these manifestations and Parkinson’s disease.”
Early detection may drive better diagnoses
The current study is important for understanding the prediagnostic features and risk factors that may allow for earlier detection of Parkinson’s disease, William Hung, MD, a geriatrics and palliative care specialist of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Prior to this study, there was limited understanding of these features.
“One surprise [in the findings] was that ethnicity and socioeconomic deprivation do not appear to be associated with the risk of PD, in contrast to other illnesses such as dementia,” said Dr. Hung. “The array of prediagnostic features associated with PD is not surprising, but nonetheless important for clinicians to know to consider whether PD could be the underlying cause.”
The take-home message for primary care is that “there are features, such as hearing loss, history of epilepsy, autonomic symptoms, motor symptoms, among others, for which clinicians should consider PD as part of the differential diagnosis as underlying cause and consider referral to specialists for diagnostic clarification,” said Dr. Hung.
“Additional research is needed to translate these findings to care, perhaps developing decision aids, interventions that may help with diagnosis and evaluation,” as is work on understanding the link between PD and symptoms such as hearing loss and epilepsy, he said.
Primary care offers opportunity to identify risk factors
The current study represents an important step in early recognition of PD, with implications for helping patients access treatments promptly and improve their quality of life, Bhavana Patel, DO, Shannon Chiu, MD, and Melissa J. Armstrong, MD, of the University of Florida, Gainesville, wrote in an accompanying editorial.
“The primary care setting is commonly where symptoms heralding the onset of PD are first discussed. However, little is known regarding the prediagnostic manifestations of PD that are seen in primary care clinics, particularly in underserved populations,” they wrote.
The study included many risk factors and prodromal markers associated with research criteria for prodromal PD, but did not include several risk and prodromal markers in the Movement Disorders Society research criteria, “such as symptoms suggestive of REM sleep behavior disorder, excessive daytime sleepiness (which overlaps with, but is distinct from, fatigue), urinary dysfunction, pesticide and solvent exposure, caffeine use, level of physical activity, and family history,” they said.
Even in individuals with diagnosed PD, certain symptoms, particularly nonmotor symptoms, are commonly underreported,” and primary care clinicians may not recognize these symptoms as PD risk factors, the authors noted.
However, “in addition to contributing to possible models of modifiable risk factors for PD, study results may also further inform algorithms designed to predict PD diagnoses in primary care,” they said. The study also highlights the need for more multivariable models to better identify PD risk factors and strategies for early identification of PD in primary care.
Several study coauthors received funding related to the study from Barts Charity, Health Data Research UK, the Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities, as well as the National Institute for Health Research UCLH Biomedical Research Centre. Lead author Dr. Simonet and Dr. Hung had no financial conflicts to disclose. Dr. Patel disclosed support from the National Institute on Aging, the Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia, and the American Brain Foundation and the Mary E. Groff Charitable Trust. Dr. Chiu reported receiving grants from Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia and the Smallwood Foundation. Dr. Armstrong disclosed funding from the National Institute on Aging, the Florida Department of Health, the Lewy Body Dementia Association, the Alzheimer’s Therapeutic Research Institute/Alzheimer’s Clinical Trial Consortium, the Alzheimer’s Disease Cooperative Study as Data Safety Monitoring Board the Parkinson’s Foundation, and the American Academy of Neurology.
FROM JAMA NEUROLOGY
Long COVID patients may develop nerve damage: Study
according to a new study published in the journal Neurology: Neuroimmunology & Neuroinflammation (doi: 10.1212/NXI.0000000000001146).
The nerve damage, which has been seen even among mild coronavirus cases, appears to be caused by immunity problems triggered by infection.
“This is one of the early papers looking into causes of long COVID, which will steadily increase in importance as acute COVID wanes,” Anne Louise Oaklander, MD, the lead study author and a neurologist at Massachusetts General Hospital, Boston, said in a statement.
“Our findings suggest that some long COVID patients had damage to their peripheral nerve fibers and that damage to the small-fiber type of nerve cell may be prominent,” she said.
The research team analyzed data from 17 COVID-19 survivors with lingering symptoms who had no history or risks of neuropathy, or nerve damage or disease. The patients were from 10 states and territories, and all but one had mild infections.
They found that 10 patients – or 59% – had at least one test that confirmed neuropathy. Two patients had rare neuropathies that affected muscle nerves, and 10 were diagnosed with small-fiber neuropathy, which is a cause of chronic pain. Common symptoms included fatigue, weakness, changes in their senses, and pain in their hands and feet.
For treatment, 11 patients were given immunotherapies such as corticosteroids or intravenous immunoglobulins, and the five patients who received repeated IgG treatments appeared to benefit. Over time, 52% of patients improved, though none had all of their symptoms go away.
“Research from our team and others is clarifying what the different types of post-COVID neuropathy are and how best to diagnose and treat them,” she said. “Most long COVID neuropathies described so far appear to reflect immune responses to the virus that went off course.”
Dr. Oaklander noted that researchers haven’t been able to do clinical trials to evaluate specific post-COVID neuropathy treatments. But some existing treatments may help.
“Some patients seem to improve from standard treatments for other immune-related neuropathies,” she said.
A version of this article first appeared on WebMD.com.
according to a new study published in the journal Neurology: Neuroimmunology & Neuroinflammation (doi: 10.1212/NXI.0000000000001146).
The nerve damage, which has been seen even among mild coronavirus cases, appears to be caused by immunity problems triggered by infection.
“This is one of the early papers looking into causes of long COVID, which will steadily increase in importance as acute COVID wanes,” Anne Louise Oaklander, MD, the lead study author and a neurologist at Massachusetts General Hospital, Boston, said in a statement.
“Our findings suggest that some long COVID patients had damage to their peripheral nerve fibers and that damage to the small-fiber type of nerve cell may be prominent,” she said.
The research team analyzed data from 17 COVID-19 survivors with lingering symptoms who had no history or risks of neuropathy, or nerve damage or disease. The patients were from 10 states and territories, and all but one had mild infections.
They found that 10 patients – or 59% – had at least one test that confirmed neuropathy. Two patients had rare neuropathies that affected muscle nerves, and 10 were diagnosed with small-fiber neuropathy, which is a cause of chronic pain. Common symptoms included fatigue, weakness, changes in their senses, and pain in their hands and feet.
For treatment, 11 patients were given immunotherapies such as corticosteroids or intravenous immunoglobulins, and the five patients who received repeated IgG treatments appeared to benefit. Over time, 52% of patients improved, though none had all of their symptoms go away.
“Research from our team and others is clarifying what the different types of post-COVID neuropathy are and how best to diagnose and treat them,” she said. “Most long COVID neuropathies described so far appear to reflect immune responses to the virus that went off course.”
Dr. Oaklander noted that researchers haven’t been able to do clinical trials to evaluate specific post-COVID neuropathy treatments. But some existing treatments may help.
“Some patients seem to improve from standard treatments for other immune-related neuropathies,” she said.
A version of this article first appeared on WebMD.com.
according to a new study published in the journal Neurology: Neuroimmunology & Neuroinflammation (doi: 10.1212/NXI.0000000000001146).
The nerve damage, which has been seen even among mild coronavirus cases, appears to be caused by immunity problems triggered by infection.
“This is one of the early papers looking into causes of long COVID, which will steadily increase in importance as acute COVID wanes,” Anne Louise Oaklander, MD, the lead study author and a neurologist at Massachusetts General Hospital, Boston, said in a statement.
“Our findings suggest that some long COVID patients had damage to their peripheral nerve fibers and that damage to the small-fiber type of nerve cell may be prominent,” she said.
The research team analyzed data from 17 COVID-19 survivors with lingering symptoms who had no history or risks of neuropathy, or nerve damage or disease. The patients were from 10 states and territories, and all but one had mild infections.
They found that 10 patients – or 59% – had at least one test that confirmed neuropathy. Two patients had rare neuropathies that affected muscle nerves, and 10 were diagnosed with small-fiber neuropathy, which is a cause of chronic pain. Common symptoms included fatigue, weakness, changes in their senses, and pain in their hands and feet.
For treatment, 11 patients were given immunotherapies such as corticosteroids or intravenous immunoglobulins, and the five patients who received repeated IgG treatments appeared to benefit. Over time, 52% of patients improved, though none had all of their symptoms go away.
“Research from our team and others is clarifying what the different types of post-COVID neuropathy are and how best to diagnose and treat them,” she said. “Most long COVID neuropathies described so far appear to reflect immune responses to the virus that went off course.”
Dr. Oaklander noted that researchers haven’t been able to do clinical trials to evaluate specific post-COVID neuropathy treatments. But some existing treatments may help.
“Some patients seem to improve from standard treatments for other immune-related neuropathies,” she said.
A version of this article first appeared on WebMD.com.
FROM NEUROLOGY: NEUROIMMUNOLOGY & NEUROINFLAMMATION
Strep infection and tics in children: new data
Group A streptococcus (GAS) infection is not associated with new-onset tic disorders in at-risk children, findings from a large prospective study show.
The results mean that if preteens present with a new-onset tic condition, “they’re unlikely to have it as a result of a group A streptococcal throat infection,” study author Anette Eleonore Schrag, MD, PhD, professor, department of clinical neuroscience, Institute of Neurology, University College London, told this news organization.
Therefore, clinicians should not automatically prescribe antibiotics for children with tics, which sometimes occurs, said Dr. Schrag.
The study was published online Feb. 2 in Neurology.
Ongoing controversy
Research shows that genetic and environmental factors contribute to chronic tic disorders (CTDs) and Tourette syndrome (TS). Prenatal exposure to maternal smoking and central nervous system (CNS) stimulants, as well as psychosocial stress, may play a role.
There has been an ongoing controversy regarding the possible role of GAS in tics, with some studies showing an association and others not showing a link. However, previous studies have been retrospective, registry based, or had limited sample size.
This new prospective study is the first in children without a tic disorder but who were at relatively high risk of developing one. The children were followed to assess development of streptococcal infections and tics, said Dr. Schrag.
The study included 259 children aged 3-10 years (mean baseline age, 6.8 years; over half female) who had a first-degree relative such as a parent or sibling with TS or CTD.
The average age at TS onset is 7 years, peaking in prevalence and severity at about 9-12 years. GAS throat infections are common in this age group.
Although study participants did not have tics themselves, they represented “an enriched group,” said Dr. Schrag. “Because they had family history, we knew they were at increased risk for developing tics.”
Participants were evaluated every 2 months, alternating between scheduled hospital visits and telephone interviews. Parents kept a weekly diary and were instructed to bring their child in for assessment if they showed any signs of tics.
The average follow-up period was 1.6 years, but some of the children were followed for up to 48 months. During the study, there were a total of 1,944 assessments, including 939 telephone interviews and 1,005 clinical visits.
More common in boys
Investigators defined tic onset as the first occurrence of any sudden, rapid, recurrent, nonrhythmic involuntary movement and/or vocalization on at least three separate days within a period of 3 weeks.
The investigators assessed GAS exposure using parameters from throat swabs, serum anti-streptolysin O titers, and anti-DNAse B titers.
They used multiple definitions and combinations of GAS exposures “to make sure we weren’t missing any association because we didn’t use the right definition,” said Dr. Schrag. She explained a definitive strep infection is not always clear-cut.
At baseline, 17.0% participants tested positive for GAS, and 78.8% tested negative. No throat swab was available from 4.2% of participants.
During follow-up, the number of confirmed positive GAS exposures was 59, 102, 125, and 138, depending on the definition.
Researchers identified 61 tic cases during the study period. There was no evidence of an association of tic onset with GAS exposure after adjusting for age, sex, and parental education level.
However, there was a strong association between tic onset and sex, with girls being 60% less likely to develop tics than boys (hazard ratio, 0.4; 95% CI, 0.2-0.7; P < .01).
This result wasn’t particularly surprising, as it’s known that more boys develop tics than girls. “We just confirmed that in a prospective way,” said Dr. Schrag.
Results from sensitivity analyses confirmed the results. This was also the case with analyses that excluded visits with missing data on GAS exposure and that further adjusted for clinical site and psychotropic medication use.
Other pathogens?
Although the results showed no association between strep and tics in this population, it does not “close the door completely” on a potential relationship, said Dr. Schrag.
“By and large, the development of tics in children is not associated with group A strep, but differences in small subgroups can never be excluded by a study like this.”
Participants in this study were part of the European Multicentre Tics in Children Studies (EMTICS), a prospective cohort study exploring the role of environmental and genetic factors in pediatric CTD. That project is also looking at immune system factors, “which might play a role in the development of chronic tic disorder and associated conditions,” said Dr. Schrag.
It’s still possible, she added, that other pathogens could play a role in tic development. “That’s going to be the subject of further analysis and future studies,” she said.
Tamara Pringsheim, MD, professor of clinical neurosciences, psychiatry, pediatrics, and community health sciences, University of Calgary (Alta.), praised the research.
“This was a well-designed study, with a large sample of 260 children followed for up to 4 years, using a standardized protocol to assess for group A streptococcal infection and new onset of tics.”
The study, which did not uncover an association between GAS exposure and tic onset, “provides high level evidence that group A streptococcal exposure is not an important risk factor for the new onset of tics in children with a family history of tic disorders.”
The study received funding from the European Union Seventh Framework Program for research technological development and demonstration. Dr. Schrag reports receiving consultancy or advisory board honoraria from Biogen, Abbvie, Bial, and Neurotechnology; research support from the National Institute of Health Research, Parkinsons UK, and the Economic and Social Research Council and the European Commission; and Royalties from Oxford University Press. Dr. Pringsheim reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Group A streptococcus (GAS) infection is not associated with new-onset tic disorders in at-risk children, findings from a large prospective study show.
The results mean that if preteens present with a new-onset tic condition, “they’re unlikely to have it as a result of a group A streptococcal throat infection,” study author Anette Eleonore Schrag, MD, PhD, professor, department of clinical neuroscience, Institute of Neurology, University College London, told this news organization.
Therefore, clinicians should not automatically prescribe antibiotics for children with tics, which sometimes occurs, said Dr. Schrag.
The study was published online Feb. 2 in Neurology.
Ongoing controversy
Research shows that genetic and environmental factors contribute to chronic tic disorders (CTDs) and Tourette syndrome (TS). Prenatal exposure to maternal smoking and central nervous system (CNS) stimulants, as well as psychosocial stress, may play a role.
There has been an ongoing controversy regarding the possible role of GAS in tics, with some studies showing an association and others not showing a link. However, previous studies have been retrospective, registry based, or had limited sample size.
This new prospective study is the first in children without a tic disorder but who were at relatively high risk of developing one. The children were followed to assess development of streptococcal infections and tics, said Dr. Schrag.
The study included 259 children aged 3-10 years (mean baseline age, 6.8 years; over half female) who had a first-degree relative such as a parent or sibling with TS or CTD.
The average age at TS onset is 7 years, peaking in prevalence and severity at about 9-12 years. GAS throat infections are common in this age group.
Although study participants did not have tics themselves, they represented “an enriched group,” said Dr. Schrag. “Because they had family history, we knew they were at increased risk for developing tics.”
Participants were evaluated every 2 months, alternating between scheduled hospital visits and telephone interviews. Parents kept a weekly diary and were instructed to bring their child in for assessment if they showed any signs of tics.
The average follow-up period was 1.6 years, but some of the children were followed for up to 48 months. During the study, there were a total of 1,944 assessments, including 939 telephone interviews and 1,005 clinical visits.
More common in boys
Investigators defined tic onset as the first occurrence of any sudden, rapid, recurrent, nonrhythmic involuntary movement and/or vocalization on at least three separate days within a period of 3 weeks.
The investigators assessed GAS exposure using parameters from throat swabs, serum anti-streptolysin O titers, and anti-DNAse B titers.
They used multiple definitions and combinations of GAS exposures “to make sure we weren’t missing any association because we didn’t use the right definition,” said Dr. Schrag. She explained a definitive strep infection is not always clear-cut.
At baseline, 17.0% participants tested positive for GAS, and 78.8% tested negative. No throat swab was available from 4.2% of participants.
During follow-up, the number of confirmed positive GAS exposures was 59, 102, 125, and 138, depending on the definition.
Researchers identified 61 tic cases during the study period. There was no evidence of an association of tic onset with GAS exposure after adjusting for age, sex, and parental education level.
However, there was a strong association between tic onset and sex, with girls being 60% less likely to develop tics than boys (hazard ratio, 0.4; 95% CI, 0.2-0.7; P < .01).
This result wasn’t particularly surprising, as it’s known that more boys develop tics than girls. “We just confirmed that in a prospective way,” said Dr. Schrag.
Results from sensitivity analyses confirmed the results. This was also the case with analyses that excluded visits with missing data on GAS exposure and that further adjusted for clinical site and psychotropic medication use.
Other pathogens?
Although the results showed no association between strep and tics in this population, it does not “close the door completely” on a potential relationship, said Dr. Schrag.
“By and large, the development of tics in children is not associated with group A strep, but differences in small subgroups can never be excluded by a study like this.”
Participants in this study were part of the European Multicentre Tics in Children Studies (EMTICS), a prospective cohort study exploring the role of environmental and genetic factors in pediatric CTD. That project is also looking at immune system factors, “which might play a role in the development of chronic tic disorder and associated conditions,” said Dr. Schrag.
It’s still possible, she added, that other pathogens could play a role in tic development. “That’s going to be the subject of further analysis and future studies,” she said.
Tamara Pringsheim, MD, professor of clinical neurosciences, psychiatry, pediatrics, and community health sciences, University of Calgary (Alta.), praised the research.
“This was a well-designed study, with a large sample of 260 children followed for up to 4 years, using a standardized protocol to assess for group A streptococcal infection and new onset of tics.”
The study, which did not uncover an association between GAS exposure and tic onset, “provides high level evidence that group A streptococcal exposure is not an important risk factor for the new onset of tics in children with a family history of tic disorders.”
The study received funding from the European Union Seventh Framework Program for research technological development and demonstration. Dr. Schrag reports receiving consultancy or advisory board honoraria from Biogen, Abbvie, Bial, and Neurotechnology; research support from the National Institute of Health Research, Parkinsons UK, and the Economic and Social Research Council and the European Commission; and Royalties from Oxford University Press. Dr. Pringsheim reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Group A streptococcus (GAS) infection is not associated with new-onset tic disorders in at-risk children, findings from a large prospective study show.
The results mean that if preteens present with a new-onset tic condition, “they’re unlikely to have it as a result of a group A streptococcal throat infection,” study author Anette Eleonore Schrag, MD, PhD, professor, department of clinical neuroscience, Institute of Neurology, University College London, told this news organization.
Therefore, clinicians should not automatically prescribe antibiotics for children with tics, which sometimes occurs, said Dr. Schrag.
The study was published online Feb. 2 in Neurology.
Ongoing controversy
Research shows that genetic and environmental factors contribute to chronic tic disorders (CTDs) and Tourette syndrome (TS). Prenatal exposure to maternal smoking and central nervous system (CNS) stimulants, as well as psychosocial stress, may play a role.
There has been an ongoing controversy regarding the possible role of GAS in tics, with some studies showing an association and others not showing a link. However, previous studies have been retrospective, registry based, or had limited sample size.
This new prospective study is the first in children without a tic disorder but who were at relatively high risk of developing one. The children were followed to assess development of streptococcal infections and tics, said Dr. Schrag.
The study included 259 children aged 3-10 years (mean baseline age, 6.8 years; over half female) who had a first-degree relative such as a parent or sibling with TS or CTD.
The average age at TS onset is 7 years, peaking in prevalence and severity at about 9-12 years. GAS throat infections are common in this age group.
Although study participants did not have tics themselves, they represented “an enriched group,” said Dr. Schrag. “Because they had family history, we knew they were at increased risk for developing tics.”
Participants were evaluated every 2 months, alternating between scheduled hospital visits and telephone interviews. Parents kept a weekly diary and were instructed to bring their child in for assessment if they showed any signs of tics.
The average follow-up period was 1.6 years, but some of the children were followed for up to 48 months. During the study, there were a total of 1,944 assessments, including 939 telephone interviews and 1,005 clinical visits.
More common in boys
Investigators defined tic onset as the first occurrence of any sudden, rapid, recurrent, nonrhythmic involuntary movement and/or vocalization on at least three separate days within a period of 3 weeks.
The investigators assessed GAS exposure using parameters from throat swabs, serum anti-streptolysin O titers, and anti-DNAse B titers.
They used multiple definitions and combinations of GAS exposures “to make sure we weren’t missing any association because we didn’t use the right definition,” said Dr. Schrag. She explained a definitive strep infection is not always clear-cut.
At baseline, 17.0% participants tested positive for GAS, and 78.8% tested negative. No throat swab was available from 4.2% of participants.
During follow-up, the number of confirmed positive GAS exposures was 59, 102, 125, and 138, depending on the definition.
Researchers identified 61 tic cases during the study period. There was no evidence of an association of tic onset with GAS exposure after adjusting for age, sex, and parental education level.
However, there was a strong association between tic onset and sex, with girls being 60% less likely to develop tics than boys (hazard ratio, 0.4; 95% CI, 0.2-0.7; P < .01).
This result wasn’t particularly surprising, as it’s known that more boys develop tics than girls. “We just confirmed that in a prospective way,” said Dr. Schrag.
Results from sensitivity analyses confirmed the results. This was also the case with analyses that excluded visits with missing data on GAS exposure and that further adjusted for clinical site and psychotropic medication use.
Other pathogens?
Although the results showed no association between strep and tics in this population, it does not “close the door completely” on a potential relationship, said Dr. Schrag.
“By and large, the development of tics in children is not associated with group A strep, but differences in small subgroups can never be excluded by a study like this.”
Participants in this study were part of the European Multicentre Tics in Children Studies (EMTICS), a prospective cohort study exploring the role of environmental and genetic factors in pediatric CTD. That project is also looking at immune system factors, “which might play a role in the development of chronic tic disorder and associated conditions,” said Dr. Schrag.
It’s still possible, she added, that other pathogens could play a role in tic development. “That’s going to be the subject of further analysis and future studies,” she said.
Tamara Pringsheim, MD, professor of clinical neurosciences, psychiatry, pediatrics, and community health sciences, University of Calgary (Alta.), praised the research.
“This was a well-designed study, with a large sample of 260 children followed for up to 4 years, using a standardized protocol to assess for group A streptococcal infection and new onset of tics.”
The study, which did not uncover an association between GAS exposure and tic onset, “provides high level evidence that group A streptococcal exposure is not an important risk factor for the new onset of tics in children with a family history of tic disorders.”
The study received funding from the European Union Seventh Framework Program for research technological development and demonstration. Dr. Schrag reports receiving consultancy or advisory board honoraria from Biogen, Abbvie, Bial, and Neurotechnology; research support from the National Institute of Health Research, Parkinsons UK, and the Economic and Social Research Council and the European Commission; and Royalties from Oxford University Press. Dr. Pringsheim reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Newborn Screening for Spinal Muscular Atrophy in the United States
Click here to read the supplement
Newborn screening for spinal muscular atrophy (SMA) is essential to achieve optimal outcomes for patients with SMA by facilitating early identification and treatment before the onset of irreversible motor neuron loss.
Click here to read the supplement
Newborn screening for spinal muscular atrophy (SMA) is essential to achieve optimal outcomes for patients with SMA by facilitating early identification and treatment before the onset of irreversible motor neuron loss.
Click here to read the supplement
Newborn screening for spinal muscular atrophy (SMA) is essential to achieve optimal outcomes for patients with SMA by facilitating early identification and treatment before the onset of irreversible motor neuron loss.
FDA approves new myasthenia gravis drug
“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” Billy Dunn, MD, director, office of neuroscience, FDA Center for Drug Evaluation and Research, said in a news release.
This approval represents “an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases,” Dr. Dunn added.
Effective, well tolerated
The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have IgG antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.
Efgartigimod is an antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.
The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.
As previously reported, efgartigimod was effective and well tolerated in the phase 3, randomized, placebo-controlled ADAPT trial, which enrolled 187 adults with gMG regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis–Activities of Daily Living score of at least 5 (>50% nonocular) on a background of a stable dose of at least one MG drug.
For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed, depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.
Treatment with efgartigimod reduced disease burden and improved strength and quality of life in patients with gMG across four MG-specific scales. In addition, these benefits were observed early and were reproducible and durable.
The results were published in Lancet Neurology.
‘Important new advance’
Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work; and the side-effect profile is much like placebo,” said principal investigator James Howard Jr., MD, department of neurology, University of North Carolina at Chapel Hill.
The FDA granted efgartigimod fast track and orphan drug designation.
“People living with gMG have been in need of new treatment options that are targeted to the underlying pathogenesis of the disease and supported by clinical data,” Dr. Howard said in a company news release issued upon approval.
This approval “represents an important new advance for gMG patients and families affected by this debilitating disease. This therapy has the potential to reduce the disease burden of gMG and transform the way we treat this disease,” Dr. Howard added.
A version of this article first appeared on Medscape.com.
“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” Billy Dunn, MD, director, office of neuroscience, FDA Center for Drug Evaluation and Research, said in a news release.
This approval represents “an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases,” Dr. Dunn added.
Effective, well tolerated
The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have IgG antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.
Efgartigimod is an antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.
The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.
As previously reported, efgartigimod was effective and well tolerated in the phase 3, randomized, placebo-controlled ADAPT trial, which enrolled 187 adults with gMG regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis–Activities of Daily Living score of at least 5 (>50% nonocular) on a background of a stable dose of at least one MG drug.
For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed, depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.
Treatment with efgartigimod reduced disease burden and improved strength and quality of life in patients with gMG across four MG-specific scales. In addition, these benefits were observed early and were reproducible and durable.
The results were published in Lancet Neurology.
‘Important new advance’
Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work; and the side-effect profile is much like placebo,” said principal investigator James Howard Jr., MD, department of neurology, University of North Carolina at Chapel Hill.
The FDA granted efgartigimod fast track and orphan drug designation.
“People living with gMG have been in need of new treatment options that are targeted to the underlying pathogenesis of the disease and supported by clinical data,” Dr. Howard said in a company news release issued upon approval.
This approval “represents an important new advance for gMG patients and families affected by this debilitating disease. This therapy has the potential to reduce the disease burden of gMG and transform the way we treat this disease,” Dr. Howard added.
A version of this article first appeared on Medscape.com.
“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” Billy Dunn, MD, director, office of neuroscience, FDA Center for Drug Evaluation and Research, said in a news release.
This approval represents “an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases,” Dr. Dunn added.
Effective, well tolerated
The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have IgG antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.
Efgartigimod is an antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.
The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.
As previously reported, efgartigimod was effective and well tolerated in the phase 3, randomized, placebo-controlled ADAPT trial, which enrolled 187 adults with gMG regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis–Activities of Daily Living score of at least 5 (>50% nonocular) on a background of a stable dose of at least one MG drug.
For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed, depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.
Treatment with efgartigimod reduced disease burden and improved strength and quality of life in patients with gMG across four MG-specific scales. In addition, these benefits were observed early and were reproducible and durable.
The results were published in Lancet Neurology.
‘Important new advance’
Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work; and the side-effect profile is much like placebo,” said principal investigator James Howard Jr., MD, department of neurology, University of North Carolina at Chapel Hill.
The FDA granted efgartigimod fast track and orphan drug designation.
“People living with gMG have been in need of new treatment options that are targeted to the underlying pathogenesis of the disease and supported by clinical data,” Dr. Howard said in a company news release issued upon approval.
This approval “represents an important new advance for gMG patients and families affected by this debilitating disease. This therapy has the potential to reduce the disease burden of gMG and transform the way we treat this disease,” Dr. Howard added.
A version of this article first appeared on Medscape.com.