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‘No Hint of Benefit’ in Large Colchicine Trial
WASHINGTON —
The CLEAR SYNERGY (OASIS 9) study, called “the largest trial ever of colchicine in acute MI,” showed no hint of benefit in an adverse event curve for colchicine relative to placebo over 5 years, which suggests that the role of this drug after myocardial infarction (MI) “is uncertain,” Sanjit Jolly, MD, an interventional cardiologist at Hamilton Health Sciences and a professor of medicine at McMaster University in Hamilton, Ontario, Canada, reported at Transcatheter Cardiovascular Therapeutics (TCT) 2024.
For the primary composite outcome — cardiovascular death, MI, stroke, and ischemia-driven revascularization — the event curves in the colchicine and placebo groups remained essentially superimposed over 5 years of follow-up, with only a slight separation after 4 years. The hazard ratio for the primary endpoint showed a 1% difference in favor of colchicine (hazard ratio [HR], 0.99; P = .93).
There were no meaningful differences in any of the individual endpoint components; all 95% CIs straddled the line of unity. Rates of cardiovascular death (3.3% vs 3.2%) and stroke (1.4% vs 1.2%) were numerically higher in the colchicine group than in the placebo group. Rates of MI (2.9% vs 3.1%) and ischemia-driven revascularization (4.6% vs 4.7%) were numerically lower in the colchicine group.
No Difference
No adverse outcomes, including all-cause death (4.6% vs 5.1%), approached significance, with the exception of noncardiovascular death (13.0% vs 1.9%). For this outcome, the 95% CI stopped just short of the line of unity (HR, 0.68; 95% CI, 0.46-0.99).
Rates of adverse events (31.9% vs 31.7%; P = .86), serious adverse events (6.7% vs 7.4%; P = .22), and serious infections (2.5% vs 2.9%; P = .85) were similar in the colchicine and placebo groups, but diarrhea, a known side effect of colchicine, was higher in the colchicine group (10.2% vs 6.6%; P < .001).
Given these results, a panelist questioned the use of the word “uncertain” to describe the findings during the late-breaker session in which these results were presented.
“I think you are selling yourself short,” said J. Dawn Abbott, MD, director of the Interventional Cardiology Fellowship Training Program at the Lifespan Cardiovascular Institute, Brown University in Providence, Rhode Island. Based on the size and conduct of this trial, she called the results “definitive” and suggested that the guidelines should be adjusted.
The OASIS 9 Trial
In OASIS 9, 3528 patients were randomized to colchicine, and 3534 were randomized to placebo. A second randomization in both groups was to spironolactone or placebo; these results will be presented at the upcoming American Heart Association (AHA) 2024 meeting. Both analyses will be published in The New England Journal of Medicine at that time, Jolly reported.
The study involved 104 sites in Australia, Egypt, Europe, Nepal, and North America. Follow-up in both groups exceeded 99%. Most patients had an ST-elevation MI (STEMI), but about 5% of those enrolled had a non-STEMI. Less than 10% of patients had experienced a previous MI.
Less than 5% of patients were discharged on sodium-glucose cotransporter 2 therapy, and more than 95% were discharged on aspirin and a statin. Nearly 80% were discharged on an angiotensin-converting enzyme inhibitor, and most patients received an anticoagulant. More than 95% of patients were implanted with a drug-eluting stent.
At month 3, C-reactive protein levels were significantly lower in the colchicine group than in the placebo group. C-reactive protein is a biomarker for the anti-inflammatory effect that is considered to be colchicine’s primary mechanism of action. An anti-inflammatory effect has been cited as the probable explanation for the positive results shown in the COLCOT and LODOCO2 trials, published in 2019 and 2020, respectively.
In COLCOT, which randomized 4745 patients who experienced an acute MI in the previous 30 days, colchicine was associated with a 23% reduction in a composite major cardiovascular adverse events endpoint relative to placebo (HR, 0.77; P = .02). In LODOCO2, which randomized 5522 patients with chronic coronary disease, colchicine was associated with a 31% reduction in an adverse event composite endpoint (HR, 0.68; P < .0001).
However, two more recent trials — CONVINCE and CHANCE-3 — showed no difference between colchicine and placebo for the endpoint of recurrent stroke at 90 days. CONVINCE, with approximately 3000 patients, was relatively small, whereas CHANCE-3 randomized more than 8000 patients and showed no effect on the risk for stroke (HR, 0.98; 95% CI, 0.83-1.16).
New Data Challenge Guidelines
Of these trials, COLCOT was the most similar to OASIS 9, according to Jolly. Among the differences, OASIS 9 was initiated earlier and was larger than the other trials, so it had more power to address the study question.
Given the absence of benefit, Jolly indicated that OASIS 9 might disrupt both the joint American College of Cardiology and AHA guidelines, which gave colchicine a class 2b recommendation in 2023, and the European Society of Cardiology guidelines, which gave colchicine a 2a recommendation.
“This is a big deal for me,” said Ajay J. Kirtane, director of the Interventional Cardiovascular Care program at Columbia University in New York City. As someone who is now using colchicine routinely, these data have changed his opinion.
The previous data supporting the use of colchicine “were just so-so,” he explained. “Now I have a good rationale” for foregoing the routine use of this therapy.
Jolly said that he had put his own father on colchicine after an acute MI on the basis of the guidelines, but immediately took him off this therapy when the data from OASIS 9 were unblinded.
“The only signal from this trial was an increased risk of diarrhea,” Jolly said. The results, at the very least, suggest that colchicine “is not for everyone” after an acute MI, although he emphasized that these results do not rule out the potential for benefit from anti-inflammatory therapy. Ongoing trials, including one targeting interleukin 6, a cytokine associated with inflammation, remain of interest, he added.
A version of this article first appeared on Medscape.com.
WASHINGTON —
The CLEAR SYNERGY (OASIS 9) study, called “the largest trial ever of colchicine in acute MI,” showed no hint of benefit in an adverse event curve for colchicine relative to placebo over 5 years, which suggests that the role of this drug after myocardial infarction (MI) “is uncertain,” Sanjit Jolly, MD, an interventional cardiologist at Hamilton Health Sciences and a professor of medicine at McMaster University in Hamilton, Ontario, Canada, reported at Transcatheter Cardiovascular Therapeutics (TCT) 2024.
For the primary composite outcome — cardiovascular death, MI, stroke, and ischemia-driven revascularization — the event curves in the colchicine and placebo groups remained essentially superimposed over 5 years of follow-up, with only a slight separation after 4 years. The hazard ratio for the primary endpoint showed a 1% difference in favor of colchicine (hazard ratio [HR], 0.99; P = .93).
There were no meaningful differences in any of the individual endpoint components; all 95% CIs straddled the line of unity. Rates of cardiovascular death (3.3% vs 3.2%) and stroke (1.4% vs 1.2%) were numerically higher in the colchicine group than in the placebo group. Rates of MI (2.9% vs 3.1%) and ischemia-driven revascularization (4.6% vs 4.7%) were numerically lower in the colchicine group.
No Difference
No adverse outcomes, including all-cause death (4.6% vs 5.1%), approached significance, with the exception of noncardiovascular death (13.0% vs 1.9%). For this outcome, the 95% CI stopped just short of the line of unity (HR, 0.68; 95% CI, 0.46-0.99).
Rates of adverse events (31.9% vs 31.7%; P = .86), serious adverse events (6.7% vs 7.4%; P = .22), and serious infections (2.5% vs 2.9%; P = .85) were similar in the colchicine and placebo groups, but diarrhea, a known side effect of colchicine, was higher in the colchicine group (10.2% vs 6.6%; P < .001).
Given these results, a panelist questioned the use of the word “uncertain” to describe the findings during the late-breaker session in which these results were presented.
“I think you are selling yourself short,” said J. Dawn Abbott, MD, director of the Interventional Cardiology Fellowship Training Program at the Lifespan Cardiovascular Institute, Brown University in Providence, Rhode Island. Based on the size and conduct of this trial, she called the results “definitive” and suggested that the guidelines should be adjusted.
The OASIS 9 Trial
In OASIS 9, 3528 patients were randomized to colchicine, and 3534 were randomized to placebo. A second randomization in both groups was to spironolactone or placebo; these results will be presented at the upcoming American Heart Association (AHA) 2024 meeting. Both analyses will be published in The New England Journal of Medicine at that time, Jolly reported.
The study involved 104 sites in Australia, Egypt, Europe, Nepal, and North America. Follow-up in both groups exceeded 99%. Most patients had an ST-elevation MI (STEMI), but about 5% of those enrolled had a non-STEMI. Less than 10% of patients had experienced a previous MI.
Less than 5% of patients were discharged on sodium-glucose cotransporter 2 therapy, and more than 95% were discharged on aspirin and a statin. Nearly 80% were discharged on an angiotensin-converting enzyme inhibitor, and most patients received an anticoagulant. More than 95% of patients were implanted with a drug-eluting stent.
At month 3, C-reactive protein levels were significantly lower in the colchicine group than in the placebo group. C-reactive protein is a biomarker for the anti-inflammatory effect that is considered to be colchicine’s primary mechanism of action. An anti-inflammatory effect has been cited as the probable explanation for the positive results shown in the COLCOT and LODOCO2 trials, published in 2019 and 2020, respectively.
In COLCOT, which randomized 4745 patients who experienced an acute MI in the previous 30 days, colchicine was associated with a 23% reduction in a composite major cardiovascular adverse events endpoint relative to placebo (HR, 0.77; P = .02). In LODOCO2, which randomized 5522 patients with chronic coronary disease, colchicine was associated with a 31% reduction in an adverse event composite endpoint (HR, 0.68; P < .0001).
However, two more recent trials — CONVINCE and CHANCE-3 — showed no difference between colchicine and placebo for the endpoint of recurrent stroke at 90 days. CONVINCE, with approximately 3000 patients, was relatively small, whereas CHANCE-3 randomized more than 8000 patients and showed no effect on the risk for stroke (HR, 0.98; 95% CI, 0.83-1.16).
New Data Challenge Guidelines
Of these trials, COLCOT was the most similar to OASIS 9, according to Jolly. Among the differences, OASIS 9 was initiated earlier and was larger than the other trials, so it had more power to address the study question.
Given the absence of benefit, Jolly indicated that OASIS 9 might disrupt both the joint American College of Cardiology and AHA guidelines, which gave colchicine a class 2b recommendation in 2023, and the European Society of Cardiology guidelines, which gave colchicine a 2a recommendation.
“This is a big deal for me,” said Ajay J. Kirtane, director of the Interventional Cardiovascular Care program at Columbia University in New York City. As someone who is now using colchicine routinely, these data have changed his opinion.
The previous data supporting the use of colchicine “were just so-so,” he explained. “Now I have a good rationale” for foregoing the routine use of this therapy.
Jolly said that he had put his own father on colchicine after an acute MI on the basis of the guidelines, but immediately took him off this therapy when the data from OASIS 9 were unblinded.
“The only signal from this trial was an increased risk of diarrhea,” Jolly said. The results, at the very least, suggest that colchicine “is not for everyone” after an acute MI, although he emphasized that these results do not rule out the potential for benefit from anti-inflammatory therapy. Ongoing trials, including one targeting interleukin 6, a cytokine associated with inflammation, remain of interest, he added.
A version of this article first appeared on Medscape.com.
WASHINGTON —
The CLEAR SYNERGY (OASIS 9) study, called “the largest trial ever of colchicine in acute MI,” showed no hint of benefit in an adverse event curve for colchicine relative to placebo over 5 years, which suggests that the role of this drug after myocardial infarction (MI) “is uncertain,” Sanjit Jolly, MD, an interventional cardiologist at Hamilton Health Sciences and a professor of medicine at McMaster University in Hamilton, Ontario, Canada, reported at Transcatheter Cardiovascular Therapeutics (TCT) 2024.
For the primary composite outcome — cardiovascular death, MI, stroke, and ischemia-driven revascularization — the event curves in the colchicine and placebo groups remained essentially superimposed over 5 years of follow-up, with only a slight separation after 4 years. The hazard ratio for the primary endpoint showed a 1% difference in favor of colchicine (hazard ratio [HR], 0.99; P = .93).
There were no meaningful differences in any of the individual endpoint components; all 95% CIs straddled the line of unity. Rates of cardiovascular death (3.3% vs 3.2%) and stroke (1.4% vs 1.2%) were numerically higher in the colchicine group than in the placebo group. Rates of MI (2.9% vs 3.1%) and ischemia-driven revascularization (4.6% vs 4.7%) were numerically lower in the colchicine group.
No Difference
No adverse outcomes, including all-cause death (4.6% vs 5.1%), approached significance, with the exception of noncardiovascular death (13.0% vs 1.9%). For this outcome, the 95% CI stopped just short of the line of unity (HR, 0.68; 95% CI, 0.46-0.99).
Rates of adverse events (31.9% vs 31.7%; P = .86), serious adverse events (6.7% vs 7.4%; P = .22), and serious infections (2.5% vs 2.9%; P = .85) were similar in the colchicine and placebo groups, but diarrhea, a known side effect of colchicine, was higher in the colchicine group (10.2% vs 6.6%; P < .001).
Given these results, a panelist questioned the use of the word “uncertain” to describe the findings during the late-breaker session in which these results were presented.
“I think you are selling yourself short,” said J. Dawn Abbott, MD, director of the Interventional Cardiology Fellowship Training Program at the Lifespan Cardiovascular Institute, Brown University in Providence, Rhode Island. Based on the size and conduct of this trial, she called the results “definitive” and suggested that the guidelines should be adjusted.
The OASIS 9 Trial
In OASIS 9, 3528 patients were randomized to colchicine, and 3534 were randomized to placebo. A second randomization in both groups was to spironolactone or placebo; these results will be presented at the upcoming American Heart Association (AHA) 2024 meeting. Both analyses will be published in The New England Journal of Medicine at that time, Jolly reported.
The study involved 104 sites in Australia, Egypt, Europe, Nepal, and North America. Follow-up in both groups exceeded 99%. Most patients had an ST-elevation MI (STEMI), but about 5% of those enrolled had a non-STEMI. Less than 10% of patients had experienced a previous MI.
Less than 5% of patients were discharged on sodium-glucose cotransporter 2 therapy, and more than 95% were discharged on aspirin and a statin. Nearly 80% were discharged on an angiotensin-converting enzyme inhibitor, and most patients received an anticoagulant. More than 95% of patients were implanted with a drug-eluting stent.
At month 3, C-reactive protein levels were significantly lower in the colchicine group than in the placebo group. C-reactive protein is a biomarker for the anti-inflammatory effect that is considered to be colchicine’s primary mechanism of action. An anti-inflammatory effect has been cited as the probable explanation for the positive results shown in the COLCOT and LODOCO2 trials, published in 2019 and 2020, respectively.
In COLCOT, which randomized 4745 patients who experienced an acute MI in the previous 30 days, colchicine was associated with a 23% reduction in a composite major cardiovascular adverse events endpoint relative to placebo (HR, 0.77; P = .02). In LODOCO2, which randomized 5522 patients with chronic coronary disease, colchicine was associated with a 31% reduction in an adverse event composite endpoint (HR, 0.68; P < .0001).
However, two more recent trials — CONVINCE and CHANCE-3 — showed no difference between colchicine and placebo for the endpoint of recurrent stroke at 90 days. CONVINCE, with approximately 3000 patients, was relatively small, whereas CHANCE-3 randomized more than 8000 patients and showed no effect on the risk for stroke (HR, 0.98; 95% CI, 0.83-1.16).
New Data Challenge Guidelines
Of these trials, COLCOT was the most similar to OASIS 9, according to Jolly. Among the differences, OASIS 9 was initiated earlier and was larger than the other trials, so it had more power to address the study question.
Given the absence of benefit, Jolly indicated that OASIS 9 might disrupt both the joint American College of Cardiology and AHA guidelines, which gave colchicine a class 2b recommendation in 2023, and the European Society of Cardiology guidelines, which gave colchicine a 2a recommendation.
“This is a big deal for me,” said Ajay J. Kirtane, director of the Interventional Cardiovascular Care program at Columbia University in New York City. As someone who is now using colchicine routinely, these data have changed his opinion.
The previous data supporting the use of colchicine “were just so-so,” he explained. “Now I have a good rationale” for foregoing the routine use of this therapy.
Jolly said that he had put his own father on colchicine after an acute MI on the basis of the guidelines, but immediately took him off this therapy when the data from OASIS 9 were unblinded.
“The only signal from this trial was an increased risk of diarrhea,” Jolly said. The results, at the very least, suggest that colchicine “is not for everyone” after an acute MI, although he emphasized that these results do not rule out the potential for benefit from anti-inflammatory therapy. Ongoing trials, including one targeting interleukin 6, a cytokine associated with inflammation, remain of interest, he added.
A version of this article first appeared on Medscape.com.
FROM TCT 2024
Multi-Refractory MM: After Immunotherapy, What?
Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.
“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.
“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.
Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.
A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.
The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.
As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.
Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
CELMoDs Active After CAR T-Cell Therapy
Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.
These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.
There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.
However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.
It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*
Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.
“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.
This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
Recycling MM Therapies Deserves Consideration
In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.
Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.
Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.
This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.
“Better T-cell assays may help,” he said.
Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.
*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
A version of this article appeared on Medscape.com.
Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.
“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.
“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.
Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.
A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.
The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.
As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.
Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
CELMoDs Active After CAR T-Cell Therapy
Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.
These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.
There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.
However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.
It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*
Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.
“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.
This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
Recycling MM Therapies Deserves Consideration
In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.
Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.
Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.
This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.
“Better T-cell assays may help,” he said.
Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.
*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
A version of this article appeared on Medscape.com.
Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.
“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.
“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.
Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.
A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.
The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.
As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.
Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
CELMoDs Active After CAR T-Cell Therapy
Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.
These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.
There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.
However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.
It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*
Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.
“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.
This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
Recycling MM Therapies Deserves Consideration
In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.
Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.
Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.
This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.
“Better T-cell assays may help,” he said.
Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.
*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
A version of this article appeared on Medscape.com.
Lymphoma Debate: CAR T Not a Clear Winner
Acknowledging that hers was the weakest position, even the specialist who defended novel targeted therapies mounted a staunch defense of real-world patients being treated outside of tertiary centers.
“I was told by many of my colleagues that I got the short end of the stick in this debate, but I am actually here to convince everybody that targeted therapies continue to play an important role, despite the fact that they are the least sexy of these treatment options,” said Joanna Rhodes, MD, director of the Lymphoma Program at Rutgers Cancer Institute, Hoboken, New Jersey.
Targeted Therapies Still Relevant to Advanced FL
Although even the newest or coming targeted therapies, such as the EZH2 inhibitor tazemetostat or next-generation Bruton tyrosine kinase inhibitors, are not likely to achieve the deep responses and long-term progression-free survival possible with BsAbs or CAR T-cell therapy, the sustained disease control they offer for many patients with R/R FL is not trivial, according to Rhodes.
“The majority of these [advanced follicular lymphoma] patients are being managed in the community,” Rhodes argued at the 2024 Lymphoma, Leukemia, & Myeloma Congress. Access to tertiary centers where the most advanced therapies are available in some cases might not even be feasible.
Moreover, there are barriers to CAR T cells and BsAbs even at centers where these are available, Rhodes said. On a long list of barriers, lack of caregiver support is an example of one common disqualification at her own institution.
The experience with CAR T cells in R/R FL has been relatively short, so Rhodes used data on CAR T cells for B-cell lymphoma to make her point. It is not just that the proportion of eligible patients is limited.
“The majority of B-cell lymphoma patients who are eligible for CAR T cells are not getting them,” she said. “It will be the same for FL.”
In other words, Rhodes indicated that it is premature to count out targeted oral agents or lenalidomide despite the excitement surrounding BsAbs and CAR T cells. The targeted agents and immunomodulatory drugs remain appropriate choices for patients unable or unwilling to travel to tertiary centers for treatment, for frail patients, and for well-informed patients who understand their options and still consider better tolerated therapies to be more consistent with their perception of an adequate risk-benefit ratio.
BsAbs Vie With CAR T Cells in Advanced FL
Hers might be a valid summary, but it did not derail arguments about whether CAR T-cell therapy should be prioritized over BsAbs or the other way around for patients who are candidates for both.
There are two BsAbs currently approved for R/R FL: glofitamab and mosunetuzumab. More are coming, according to Nina Wagner-Johnston, MD, director of hematologic malignancies at Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. She provided several reasons why BsAbs might be considered before CAR T-cell therapies in at least some individuals.
“The biggest advantage is that these therapies…are off the shelf,” she said. This avoids the delay of T-cell manufacturing, the potential need for bridging therapies, and the need for conditioning regimens. With more experience, BsAbs offer the potential for treatment even in a community-practice setting, particularly for maintenance dosing.
“I do think this is a safe treatment in patients who are elderly or unfit,” Wagner-Johnston said, suggesting she tends to lean toward prioritizing BsAbs over CAR T cells when the ability to tolerate an aggressive strategy is a concern. She specified that these drugs are associated with a low relative incidence of grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, and faster B-cell aplasia recovery.
The third participant in the debate, who described the efficacy and safety of the three currently approved CAR T-cell therapies for R/R FL, did not agree with this characterization. Daniel J. Landsburg, MD, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia, acknowledged that BsAb agents have an important role to play in the advanced FL setting, but he thinks that CAR T-cell therapies should be prioritized in at least some patients.
In particular, he would not rule out CAR T-cell therapy in patients with comorbidities or other characteristics that raise questions about fitness for aggressive treatment.
“In fact, you might want to treat a frail patient just one time with CAR T-cell therapy rather than dose after dose with a bispecific drug,” he said.
No Data to Compare BsAbs and CAR T-Cells Directly
Both agreed that there have been no trials directly comparing a BsAb therapy vs CAR T cells, so there is no definitive answer, and Landsburg was reluctant to take a hard line on reserving BsAbs until after CAR T-cell therapy has been tried.
“Because BsAbs and CAR Ts are approved in the third-line setting, you might consider debulking a patient getting ready for a CAR T with a bispecific,” Landsburg said. However, he acknowledged that the next step becomes complex if patients achieved a complete response after just a few BsAb doses.
“Do you stop what is already working?” Landsburg asked rhetorically, suggesting that the best way forward is not always clear.
For R/R FL, currently there are three approved products: axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi). The entry criteria and design of the three pivotal trials differed, so their specific indications vary. Looking across the trials, Landsburg suggested that there might be differences in activity as defined by objective response rates or risk for cytokine release syndrome, but these remain theoretical without head-to-head comparisons.
“My suspicion is we are going to see very similar — quote, unquote — long-term survival curves for patients treated with any of these therapies,” he said, noting that progression-free survival at 3 years has been in the vicinity of 50% for the trials that have had long enough follow-up to judge.
Rather than trying to pick the best agent, he suggested that it makes more sense now to concentrate on strategies to improve response irrespective of CAR T-cell product; these include paying attention to total metabolic tumor volume at the time of infusion, optimizing bridging therapies, and thinking about T-cell fitness, which might be impaired in some patients by recent exposure to bendamustine.
Overall, with multiple ongoing studies with both CAR T-cell therapies and BsAbs in R/R FL — as well with targeted small-molecule agents and immunomodulatory drugs — all of the debate participants acknowledged that choices in R/R FL will evolve.
“I actually think that combinations will be the future,” Wagner-Johnston said. Singling out tazemetostat and a BsAb and one approach that seems promising, she also predicted that some of the therapies in advanced disease are likely to be moved forward to earlier stages of FL therapy.
Rhodes reported ties with AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Bristol Myers Squibb, Epizyme, Genentech, Genmab, Janssen, Loxo Oncology, MorphoSys, Pharmacyclics, and Pfizer. Wagner-Johnston disclosed relationships with Cuno Science, Dava Oncology, Epizyme, Grünenthal, Karyopharm, and Seagen. Landsburg reported ties with ADC Therapeutics, Calithera, Curis, Epizyme, Karyopharm, MorphoSys, and Novartis.
A version of this article appeared on Medscape.com.
Acknowledging that hers was the weakest position, even the specialist who defended novel targeted therapies mounted a staunch defense of real-world patients being treated outside of tertiary centers.
“I was told by many of my colleagues that I got the short end of the stick in this debate, but I am actually here to convince everybody that targeted therapies continue to play an important role, despite the fact that they are the least sexy of these treatment options,” said Joanna Rhodes, MD, director of the Lymphoma Program at Rutgers Cancer Institute, Hoboken, New Jersey.
Targeted Therapies Still Relevant to Advanced FL
Although even the newest or coming targeted therapies, such as the EZH2 inhibitor tazemetostat or next-generation Bruton tyrosine kinase inhibitors, are not likely to achieve the deep responses and long-term progression-free survival possible with BsAbs or CAR T-cell therapy, the sustained disease control they offer for many patients with R/R FL is not trivial, according to Rhodes.
“The majority of these [advanced follicular lymphoma] patients are being managed in the community,” Rhodes argued at the 2024 Lymphoma, Leukemia, & Myeloma Congress. Access to tertiary centers where the most advanced therapies are available in some cases might not even be feasible.
Moreover, there are barriers to CAR T cells and BsAbs even at centers where these are available, Rhodes said. On a long list of barriers, lack of caregiver support is an example of one common disqualification at her own institution.
The experience with CAR T cells in R/R FL has been relatively short, so Rhodes used data on CAR T cells for B-cell lymphoma to make her point. It is not just that the proportion of eligible patients is limited.
“The majority of B-cell lymphoma patients who are eligible for CAR T cells are not getting them,” she said. “It will be the same for FL.”
In other words, Rhodes indicated that it is premature to count out targeted oral agents or lenalidomide despite the excitement surrounding BsAbs and CAR T cells. The targeted agents and immunomodulatory drugs remain appropriate choices for patients unable or unwilling to travel to tertiary centers for treatment, for frail patients, and for well-informed patients who understand their options and still consider better tolerated therapies to be more consistent with their perception of an adequate risk-benefit ratio.
BsAbs Vie With CAR T Cells in Advanced FL
Hers might be a valid summary, but it did not derail arguments about whether CAR T-cell therapy should be prioritized over BsAbs or the other way around for patients who are candidates for both.
There are two BsAbs currently approved for R/R FL: glofitamab and mosunetuzumab. More are coming, according to Nina Wagner-Johnston, MD, director of hematologic malignancies at Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. She provided several reasons why BsAbs might be considered before CAR T-cell therapies in at least some individuals.
“The biggest advantage is that these therapies…are off the shelf,” she said. This avoids the delay of T-cell manufacturing, the potential need for bridging therapies, and the need for conditioning regimens. With more experience, BsAbs offer the potential for treatment even in a community-practice setting, particularly for maintenance dosing.
“I do think this is a safe treatment in patients who are elderly or unfit,” Wagner-Johnston said, suggesting she tends to lean toward prioritizing BsAbs over CAR T cells when the ability to tolerate an aggressive strategy is a concern. She specified that these drugs are associated with a low relative incidence of grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, and faster B-cell aplasia recovery.
The third participant in the debate, who described the efficacy and safety of the three currently approved CAR T-cell therapies for R/R FL, did not agree with this characterization. Daniel J. Landsburg, MD, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia, acknowledged that BsAb agents have an important role to play in the advanced FL setting, but he thinks that CAR T-cell therapies should be prioritized in at least some patients.
In particular, he would not rule out CAR T-cell therapy in patients with comorbidities or other characteristics that raise questions about fitness for aggressive treatment.
“In fact, you might want to treat a frail patient just one time with CAR T-cell therapy rather than dose after dose with a bispecific drug,” he said.
No Data to Compare BsAbs and CAR T-Cells Directly
Both agreed that there have been no trials directly comparing a BsAb therapy vs CAR T cells, so there is no definitive answer, and Landsburg was reluctant to take a hard line on reserving BsAbs until after CAR T-cell therapy has been tried.
“Because BsAbs and CAR Ts are approved in the third-line setting, you might consider debulking a patient getting ready for a CAR T with a bispecific,” Landsburg said. However, he acknowledged that the next step becomes complex if patients achieved a complete response after just a few BsAb doses.
“Do you stop what is already working?” Landsburg asked rhetorically, suggesting that the best way forward is not always clear.
For R/R FL, currently there are three approved products: axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi). The entry criteria and design of the three pivotal trials differed, so their specific indications vary. Looking across the trials, Landsburg suggested that there might be differences in activity as defined by objective response rates or risk for cytokine release syndrome, but these remain theoretical without head-to-head comparisons.
“My suspicion is we are going to see very similar — quote, unquote — long-term survival curves for patients treated with any of these therapies,” he said, noting that progression-free survival at 3 years has been in the vicinity of 50% for the trials that have had long enough follow-up to judge.
Rather than trying to pick the best agent, he suggested that it makes more sense now to concentrate on strategies to improve response irrespective of CAR T-cell product; these include paying attention to total metabolic tumor volume at the time of infusion, optimizing bridging therapies, and thinking about T-cell fitness, which might be impaired in some patients by recent exposure to bendamustine.
Overall, with multiple ongoing studies with both CAR T-cell therapies and BsAbs in R/R FL — as well with targeted small-molecule agents and immunomodulatory drugs — all of the debate participants acknowledged that choices in R/R FL will evolve.
“I actually think that combinations will be the future,” Wagner-Johnston said. Singling out tazemetostat and a BsAb and one approach that seems promising, she also predicted that some of the therapies in advanced disease are likely to be moved forward to earlier stages of FL therapy.
Rhodes reported ties with AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Bristol Myers Squibb, Epizyme, Genentech, Genmab, Janssen, Loxo Oncology, MorphoSys, Pharmacyclics, and Pfizer. Wagner-Johnston disclosed relationships with Cuno Science, Dava Oncology, Epizyme, Grünenthal, Karyopharm, and Seagen. Landsburg reported ties with ADC Therapeutics, Calithera, Curis, Epizyme, Karyopharm, MorphoSys, and Novartis.
A version of this article appeared on Medscape.com.
Acknowledging that hers was the weakest position, even the specialist who defended novel targeted therapies mounted a staunch defense of real-world patients being treated outside of tertiary centers.
“I was told by many of my colleagues that I got the short end of the stick in this debate, but I am actually here to convince everybody that targeted therapies continue to play an important role, despite the fact that they are the least sexy of these treatment options,” said Joanna Rhodes, MD, director of the Lymphoma Program at Rutgers Cancer Institute, Hoboken, New Jersey.
Targeted Therapies Still Relevant to Advanced FL
Although even the newest or coming targeted therapies, such as the EZH2 inhibitor tazemetostat or next-generation Bruton tyrosine kinase inhibitors, are not likely to achieve the deep responses and long-term progression-free survival possible with BsAbs or CAR T-cell therapy, the sustained disease control they offer for many patients with R/R FL is not trivial, according to Rhodes.
“The majority of these [advanced follicular lymphoma] patients are being managed in the community,” Rhodes argued at the 2024 Lymphoma, Leukemia, & Myeloma Congress. Access to tertiary centers where the most advanced therapies are available in some cases might not even be feasible.
Moreover, there are barriers to CAR T cells and BsAbs even at centers where these are available, Rhodes said. On a long list of barriers, lack of caregiver support is an example of one common disqualification at her own institution.
The experience with CAR T cells in R/R FL has been relatively short, so Rhodes used data on CAR T cells for B-cell lymphoma to make her point. It is not just that the proportion of eligible patients is limited.
“The majority of B-cell lymphoma patients who are eligible for CAR T cells are not getting them,” she said. “It will be the same for FL.”
In other words, Rhodes indicated that it is premature to count out targeted oral agents or lenalidomide despite the excitement surrounding BsAbs and CAR T cells. The targeted agents and immunomodulatory drugs remain appropriate choices for patients unable or unwilling to travel to tertiary centers for treatment, for frail patients, and for well-informed patients who understand their options and still consider better tolerated therapies to be more consistent with their perception of an adequate risk-benefit ratio.
BsAbs Vie With CAR T Cells in Advanced FL
Hers might be a valid summary, but it did not derail arguments about whether CAR T-cell therapy should be prioritized over BsAbs or the other way around for patients who are candidates for both.
There are two BsAbs currently approved for R/R FL: glofitamab and mosunetuzumab. More are coming, according to Nina Wagner-Johnston, MD, director of hematologic malignancies at Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. She provided several reasons why BsAbs might be considered before CAR T-cell therapies in at least some individuals.
“The biggest advantage is that these therapies…are off the shelf,” she said. This avoids the delay of T-cell manufacturing, the potential need for bridging therapies, and the need for conditioning regimens. With more experience, BsAbs offer the potential for treatment even in a community-practice setting, particularly for maintenance dosing.
“I do think this is a safe treatment in patients who are elderly or unfit,” Wagner-Johnston said, suggesting she tends to lean toward prioritizing BsAbs over CAR T cells when the ability to tolerate an aggressive strategy is a concern. She specified that these drugs are associated with a low relative incidence of grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, and faster B-cell aplasia recovery.
The third participant in the debate, who described the efficacy and safety of the three currently approved CAR T-cell therapies for R/R FL, did not agree with this characterization. Daniel J. Landsburg, MD, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia, acknowledged that BsAb agents have an important role to play in the advanced FL setting, but he thinks that CAR T-cell therapies should be prioritized in at least some patients.
In particular, he would not rule out CAR T-cell therapy in patients with comorbidities or other characteristics that raise questions about fitness for aggressive treatment.
“In fact, you might want to treat a frail patient just one time with CAR T-cell therapy rather than dose after dose with a bispecific drug,” he said.
No Data to Compare BsAbs and CAR T-Cells Directly
Both agreed that there have been no trials directly comparing a BsAb therapy vs CAR T cells, so there is no definitive answer, and Landsburg was reluctant to take a hard line on reserving BsAbs until after CAR T-cell therapy has been tried.
“Because BsAbs and CAR Ts are approved in the third-line setting, you might consider debulking a patient getting ready for a CAR T with a bispecific,” Landsburg said. However, he acknowledged that the next step becomes complex if patients achieved a complete response after just a few BsAb doses.
“Do you stop what is already working?” Landsburg asked rhetorically, suggesting that the best way forward is not always clear.
For R/R FL, currently there are three approved products: axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi). The entry criteria and design of the three pivotal trials differed, so their specific indications vary. Looking across the trials, Landsburg suggested that there might be differences in activity as defined by objective response rates or risk for cytokine release syndrome, but these remain theoretical without head-to-head comparisons.
“My suspicion is we are going to see very similar — quote, unquote — long-term survival curves for patients treated with any of these therapies,” he said, noting that progression-free survival at 3 years has been in the vicinity of 50% for the trials that have had long enough follow-up to judge.
Rather than trying to pick the best agent, he suggested that it makes more sense now to concentrate on strategies to improve response irrespective of CAR T-cell product; these include paying attention to total metabolic tumor volume at the time of infusion, optimizing bridging therapies, and thinking about T-cell fitness, which might be impaired in some patients by recent exposure to bendamustine.
Overall, with multiple ongoing studies with both CAR T-cell therapies and BsAbs in R/R FL — as well with targeted small-molecule agents and immunomodulatory drugs — all of the debate participants acknowledged that choices in R/R FL will evolve.
“I actually think that combinations will be the future,” Wagner-Johnston said. Singling out tazemetostat and a BsAb and one approach that seems promising, she also predicted that some of the therapies in advanced disease are likely to be moved forward to earlier stages of FL therapy.
Rhodes reported ties with AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Bristol Myers Squibb, Epizyme, Genentech, Genmab, Janssen, Loxo Oncology, MorphoSys, Pharmacyclics, and Pfizer. Wagner-Johnston disclosed relationships with Cuno Science, Dava Oncology, Epizyme, Grünenthal, Karyopharm, and Seagen. Landsburg reported ties with ADC Therapeutics, Calithera, Curis, Epizyme, Karyopharm, MorphoSys, and Novartis.
A version of this article appeared on Medscape.com.
Expert Updates Therapy for Waldenström Macroglobulinemia
Most importantly, determining the mutational status of patients with WM has become a first or early step in guiding first- and second-line therapies, according to Edward A. Stadtmauer, MD, professor of medicine, University of Pennsylvania, Philadelphia.
Presenting at the 2024 Lymphoma, Leukemia & Myeloma Congress in New York City, Stadtmauer discussed how MYD88 and CXCR4 gene mutations influence his therapeutic choices.
While delivering the Bruce Waterfall Memorial Lecture, funded by the International WM Foundation, he explained that the vast majority of patients with WM have a MYD88 mutation that is highly sensitive to Bruton tyrosine kinase (BTK) inhibitors.
Due to greater specificity on the BTK target, which has implications for safety and efficacy, the first-generation BTK inhibitor ibrutinib has been largely supplanted by next generation drugs such as zanubrutinib.
Deep Responses in WM Remain Elusive
The support for next-generation BTK inhibitors over ibrutinib; bendamustine plus rituximab (BR); or cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is, in his opinion, “a superior toxicity profile, high response rates, and prolonged response.” However, he conceded that the weaknesses of this approach include a low chance of a deep remission and the need for continuous therapy.
On account of these limitations, he typically favors the alkylating agent bendamustine plus the anti-CD20 rituximab over BTK inhibitors in the absence of MYD88 mutations. This once standard approach has become less commonly used in the era of BTK inhibitors, but it is also highly effective, is generally administered in a time-limited regimen, and may be more likely to push patients into a deep remission.
A similar rationale might be considered for CyBorD, but Stadtmauer believes that BR provides a higher rate of PFS with a lower risk for neuropathy, although he admitted this opinion is based on cross-study comparisons, not comparative trials.
While efforts to develop therapies capable of producing a deep response “should not be abandoned,” particularly with the T-cell engager therapies on the horizon, he is not convinced that the benefit-to-risk ratio of aggressive therapies is yet warranted in a disease the often progresses slowly.
“I must admit I am still under the philosophy that Waldenström’s is a chronic disease even if we are seeing a growing list of options for relapsed or poorly responding disease, so I am still not pushing patients too aggressively to knock them into a complete remission,” he said.
MYD88 mutations are not unique to WM, an uncommon, slow-growing form of non-Hodgkin lymphoma. They are found in a small proportion of patients with other hematologic disorders, such as marginal zone lymphomas, but Stadtmauer estimated they occur in 90% of patients with WM. They are common enough that they can help with diagnosis.
CXCR4 Mutations Predict Worse Outcomes
The CXCR4 mutation occurs in an estimated 40% of patients with WM. When present, they are associated with worse outcomes, including a faster time to progression and a reduced overall survival, according to Stadtmauer.
The prognostic impact of less common mutations, such as TP53 and TERT or deletions in LYN, are less well characterized, but Stadtmauer said that most mutations associated with WM result in constitutive or continuous activation in BTK, which, in turn drives WM cell proliferation and survival.
The importance of BTK in WM progression is the reason targeted inhibitors have assumed such a key role in first-line treatment, but Stadtmauer cautioned that these drugs, like other therapies, should not be initiated in asymptomatic patients. This has been stated in past and current guidelines.
More accurately, therapy should be held until just prior to symptomatic manifestations of disease, Stadtmauer specified.
For an optimal response, “you want to start therapy about 3 or 4 months before the symptoms begin,” said Stadtmauer characterizing efforts to do so as “the art of medicine.” Starting therapy just prior to symptoms is advantageous, but it involves following patients closely. Any single biomarker might not be enough.
“In an asymptomatic patient, the level of monoclonal IgM is not an indication to start therapy,” he said, citing studies showing no effect on subsequent disease control from treating this biomarker alone.
However, he listed the development of moderate peripheral neuropathy (PN) as an exception. Essentially, anything greater than mild PN is “still bad” in Stadtmauer’s opinion, so treatment is warranted.
The growing number of second-line options relieves some of the concern when patients progress. Stadtmauer said he is now using BR more often in the second-line drug now that he is using BTK inhibitor more in the first line.
The Bcl-2 inhibitor venetoclax is highly effective and is another first- or second-line option even if this agent, like BTK inhibitors, also appears to require continuous dosing, said Stadtmauer, citing a study that showed patients relapsed relatively rapidly when the drug was stopped.
He now thinks of regimens with proteasome inhibitors as third line.
In selected patients who do not tolerate the non-covalent second-generation BTK inhibitors in the first or second line, he said, “I move quickly to the covalent BTKi pirtobrutinib,” based on data suggesting responses that are at least as good but with a better tolerability profile.
T-Cell Engager Data Are Limited
Without spending much time on the T-cell engagers, such as CAR T-cells or bispecific antibodies, Stadtmauer said that the advances he sees on the horizon “are tremendous,” and the “future is bright.” Such approaches could yield deep responses that could extend control or even provide cure, but these are speculations until more patients have been treated and followed long term.
Morton Coleman, MD, director of the Center for Lymphoma and Myeloma at Weill Cornell Medicine and the chairperson of the LLM Congress, called the talk a valuable and practical summary from a knowledgeable source. BTK inhibitors have represented a major evolution in WM management, but Coleman appreciated the underlying concept that treatment still has to be individualized.
“I think one of the most important take home messages is that the characterization of the mutational profile in patients with Waldenström should be considered a standard of care,” Coleman said. Helpful now, the mutational profile is likely to have a more valuable role as treatment is increasingly individualized.
Stadtmauer reported financial relationships with AbbVie, Bristol Myers Squibb, Celgene, Janssen, and Sorrento. Coleman disclosed ties with AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Gilead, Loxo Oncology, Janssen, and Pharmacyclics.
A version of this article appeared on Medscape.com.
Most importantly, determining the mutational status of patients with WM has become a first or early step in guiding first- and second-line therapies, according to Edward A. Stadtmauer, MD, professor of medicine, University of Pennsylvania, Philadelphia.
Presenting at the 2024 Lymphoma, Leukemia & Myeloma Congress in New York City, Stadtmauer discussed how MYD88 and CXCR4 gene mutations influence his therapeutic choices.
While delivering the Bruce Waterfall Memorial Lecture, funded by the International WM Foundation, he explained that the vast majority of patients with WM have a MYD88 mutation that is highly sensitive to Bruton tyrosine kinase (BTK) inhibitors.
Due to greater specificity on the BTK target, which has implications for safety and efficacy, the first-generation BTK inhibitor ibrutinib has been largely supplanted by next generation drugs such as zanubrutinib.
Deep Responses in WM Remain Elusive
The support for next-generation BTK inhibitors over ibrutinib; bendamustine plus rituximab (BR); or cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is, in his opinion, “a superior toxicity profile, high response rates, and prolonged response.” However, he conceded that the weaknesses of this approach include a low chance of a deep remission and the need for continuous therapy.
On account of these limitations, he typically favors the alkylating agent bendamustine plus the anti-CD20 rituximab over BTK inhibitors in the absence of MYD88 mutations. This once standard approach has become less commonly used in the era of BTK inhibitors, but it is also highly effective, is generally administered in a time-limited regimen, and may be more likely to push patients into a deep remission.
A similar rationale might be considered for CyBorD, but Stadtmauer believes that BR provides a higher rate of PFS with a lower risk for neuropathy, although he admitted this opinion is based on cross-study comparisons, not comparative trials.
While efforts to develop therapies capable of producing a deep response “should not be abandoned,” particularly with the T-cell engager therapies on the horizon, he is not convinced that the benefit-to-risk ratio of aggressive therapies is yet warranted in a disease the often progresses slowly.
“I must admit I am still under the philosophy that Waldenström’s is a chronic disease even if we are seeing a growing list of options for relapsed or poorly responding disease, so I am still not pushing patients too aggressively to knock them into a complete remission,” he said.
MYD88 mutations are not unique to WM, an uncommon, slow-growing form of non-Hodgkin lymphoma. They are found in a small proportion of patients with other hematologic disorders, such as marginal zone lymphomas, but Stadtmauer estimated they occur in 90% of patients with WM. They are common enough that they can help with diagnosis.
CXCR4 Mutations Predict Worse Outcomes
The CXCR4 mutation occurs in an estimated 40% of patients with WM. When present, they are associated with worse outcomes, including a faster time to progression and a reduced overall survival, according to Stadtmauer.
The prognostic impact of less common mutations, such as TP53 and TERT or deletions in LYN, are less well characterized, but Stadtmauer said that most mutations associated with WM result in constitutive or continuous activation in BTK, which, in turn drives WM cell proliferation and survival.
The importance of BTK in WM progression is the reason targeted inhibitors have assumed such a key role in first-line treatment, but Stadtmauer cautioned that these drugs, like other therapies, should not be initiated in asymptomatic patients. This has been stated in past and current guidelines.
More accurately, therapy should be held until just prior to symptomatic manifestations of disease, Stadtmauer specified.
For an optimal response, “you want to start therapy about 3 or 4 months before the symptoms begin,” said Stadtmauer characterizing efforts to do so as “the art of medicine.” Starting therapy just prior to symptoms is advantageous, but it involves following patients closely. Any single biomarker might not be enough.
“In an asymptomatic patient, the level of monoclonal IgM is not an indication to start therapy,” he said, citing studies showing no effect on subsequent disease control from treating this biomarker alone.
However, he listed the development of moderate peripheral neuropathy (PN) as an exception. Essentially, anything greater than mild PN is “still bad” in Stadtmauer’s opinion, so treatment is warranted.
The growing number of second-line options relieves some of the concern when patients progress. Stadtmauer said he is now using BR more often in the second-line drug now that he is using BTK inhibitor more in the first line.
The Bcl-2 inhibitor venetoclax is highly effective and is another first- or second-line option even if this agent, like BTK inhibitors, also appears to require continuous dosing, said Stadtmauer, citing a study that showed patients relapsed relatively rapidly when the drug was stopped.
He now thinks of regimens with proteasome inhibitors as third line.
In selected patients who do not tolerate the non-covalent second-generation BTK inhibitors in the first or second line, he said, “I move quickly to the covalent BTKi pirtobrutinib,” based on data suggesting responses that are at least as good but with a better tolerability profile.
T-Cell Engager Data Are Limited
Without spending much time on the T-cell engagers, such as CAR T-cells or bispecific antibodies, Stadtmauer said that the advances he sees on the horizon “are tremendous,” and the “future is bright.” Such approaches could yield deep responses that could extend control or even provide cure, but these are speculations until more patients have been treated and followed long term.
Morton Coleman, MD, director of the Center for Lymphoma and Myeloma at Weill Cornell Medicine and the chairperson of the LLM Congress, called the talk a valuable and practical summary from a knowledgeable source. BTK inhibitors have represented a major evolution in WM management, but Coleman appreciated the underlying concept that treatment still has to be individualized.
“I think one of the most important take home messages is that the characterization of the mutational profile in patients with Waldenström should be considered a standard of care,” Coleman said. Helpful now, the mutational profile is likely to have a more valuable role as treatment is increasingly individualized.
Stadtmauer reported financial relationships with AbbVie, Bristol Myers Squibb, Celgene, Janssen, and Sorrento. Coleman disclosed ties with AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Gilead, Loxo Oncology, Janssen, and Pharmacyclics.
A version of this article appeared on Medscape.com.
Most importantly, determining the mutational status of patients with WM has become a first or early step in guiding first- and second-line therapies, according to Edward A. Stadtmauer, MD, professor of medicine, University of Pennsylvania, Philadelphia.
Presenting at the 2024 Lymphoma, Leukemia & Myeloma Congress in New York City, Stadtmauer discussed how MYD88 and CXCR4 gene mutations influence his therapeutic choices.
While delivering the Bruce Waterfall Memorial Lecture, funded by the International WM Foundation, he explained that the vast majority of patients with WM have a MYD88 mutation that is highly sensitive to Bruton tyrosine kinase (BTK) inhibitors.
Due to greater specificity on the BTK target, which has implications for safety and efficacy, the first-generation BTK inhibitor ibrutinib has been largely supplanted by next generation drugs such as zanubrutinib.
Deep Responses in WM Remain Elusive
The support for next-generation BTK inhibitors over ibrutinib; bendamustine plus rituximab (BR); or cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is, in his opinion, “a superior toxicity profile, high response rates, and prolonged response.” However, he conceded that the weaknesses of this approach include a low chance of a deep remission and the need for continuous therapy.
On account of these limitations, he typically favors the alkylating agent bendamustine plus the anti-CD20 rituximab over BTK inhibitors in the absence of MYD88 mutations. This once standard approach has become less commonly used in the era of BTK inhibitors, but it is also highly effective, is generally administered in a time-limited regimen, and may be more likely to push patients into a deep remission.
A similar rationale might be considered for CyBorD, but Stadtmauer believes that BR provides a higher rate of PFS with a lower risk for neuropathy, although he admitted this opinion is based on cross-study comparisons, not comparative trials.
While efforts to develop therapies capable of producing a deep response “should not be abandoned,” particularly with the T-cell engager therapies on the horizon, he is not convinced that the benefit-to-risk ratio of aggressive therapies is yet warranted in a disease the often progresses slowly.
“I must admit I am still under the philosophy that Waldenström’s is a chronic disease even if we are seeing a growing list of options for relapsed or poorly responding disease, so I am still not pushing patients too aggressively to knock them into a complete remission,” he said.
MYD88 mutations are not unique to WM, an uncommon, slow-growing form of non-Hodgkin lymphoma. They are found in a small proportion of patients with other hematologic disorders, such as marginal zone lymphomas, but Stadtmauer estimated they occur in 90% of patients with WM. They are common enough that they can help with diagnosis.
CXCR4 Mutations Predict Worse Outcomes
The CXCR4 mutation occurs in an estimated 40% of patients with WM. When present, they are associated with worse outcomes, including a faster time to progression and a reduced overall survival, according to Stadtmauer.
The prognostic impact of less common mutations, such as TP53 and TERT or deletions in LYN, are less well characterized, but Stadtmauer said that most mutations associated with WM result in constitutive or continuous activation in BTK, which, in turn drives WM cell proliferation and survival.
The importance of BTK in WM progression is the reason targeted inhibitors have assumed such a key role in first-line treatment, but Stadtmauer cautioned that these drugs, like other therapies, should not be initiated in asymptomatic patients. This has been stated in past and current guidelines.
More accurately, therapy should be held until just prior to symptomatic manifestations of disease, Stadtmauer specified.
For an optimal response, “you want to start therapy about 3 or 4 months before the symptoms begin,” said Stadtmauer characterizing efforts to do so as “the art of medicine.” Starting therapy just prior to symptoms is advantageous, but it involves following patients closely. Any single biomarker might not be enough.
“In an asymptomatic patient, the level of monoclonal IgM is not an indication to start therapy,” he said, citing studies showing no effect on subsequent disease control from treating this biomarker alone.
However, he listed the development of moderate peripheral neuropathy (PN) as an exception. Essentially, anything greater than mild PN is “still bad” in Stadtmauer’s opinion, so treatment is warranted.
The growing number of second-line options relieves some of the concern when patients progress. Stadtmauer said he is now using BR more often in the second-line drug now that he is using BTK inhibitor more in the first line.
The Bcl-2 inhibitor venetoclax is highly effective and is another first- or second-line option even if this agent, like BTK inhibitors, also appears to require continuous dosing, said Stadtmauer, citing a study that showed patients relapsed relatively rapidly when the drug was stopped.
He now thinks of regimens with proteasome inhibitors as third line.
In selected patients who do not tolerate the non-covalent second-generation BTK inhibitors in the first or second line, he said, “I move quickly to the covalent BTKi pirtobrutinib,” based on data suggesting responses that are at least as good but with a better tolerability profile.
T-Cell Engager Data Are Limited
Without spending much time on the T-cell engagers, such as CAR T-cells or bispecific antibodies, Stadtmauer said that the advances he sees on the horizon “are tremendous,” and the “future is bright.” Such approaches could yield deep responses that could extend control or even provide cure, but these are speculations until more patients have been treated and followed long term.
Morton Coleman, MD, director of the Center for Lymphoma and Myeloma at Weill Cornell Medicine and the chairperson of the LLM Congress, called the talk a valuable and practical summary from a knowledgeable source. BTK inhibitors have represented a major evolution in WM management, but Coleman appreciated the underlying concept that treatment still has to be individualized.
“I think one of the most important take home messages is that the characterization of the mutational profile in patients with Waldenström should be considered a standard of care,” Coleman said. Helpful now, the mutational profile is likely to have a more valuable role as treatment is increasingly individualized.
Stadtmauer reported financial relationships with AbbVie, Bristol Myers Squibb, Celgene, Janssen, and Sorrento. Coleman disclosed ties with AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Gilead, Loxo Oncology, Janssen, and Pharmacyclics.
A version of this article appeared on Medscape.com.
Phase 2 Data on New Drug Class for Prurigo Nodularis Promising
AMSTERDAM — presented at the European Academy of Dermatology and Venereology (EADV) 2024 Congress are further validated.
“We now have a pipeline of clinical studies in PN. Who would have even thought that a few years ago,” said Shawn Kwatra, MD, professor and chair, Department of Dermatology, University of Maryland School of Medicine, Baltimore. That is a remarkable turn of events for a difficult disease, he added.
Dupilumab, a monoclonal antibody that inhibits the activity of interleukin (IL)–4 and IL-13, was the first treatment approved for PN by the Food and Drug Administration 2 years ago. Approval of nemolizumab, a monoclonal antibody that targets IL-31, a cytokine strongly implicated in the itch response, followed in August 2024. Povorcitinib, which targets Janus kinase 1 (JAK1), is on track to be the third.
New data on both nemolizumab and povorcitinib were presented in late breaking news sessions at EADV.
For povorcitinib, a JAK inhibitor, Dr. Kwatra presented extended phase 2 results through 40 weeks at a late-breaker session at the EADV meeting. They follow 16-week data from a randomized study presented earlier this year.
Of the 146 patients followed in the original 16-week randomized trial, which compared 15, 45, and 75 mg of oral povorcitinib once daily against placebo, 126 entered an extension in which all patients were treated with active therapy. In this single-blind phase, those who were responders at 16 weeks received 45 mg povorcitinib, and those who were nonresponders received 75 mg povorcitinib.
At 16 weeks, all doses were superior to placebo in achieving at least a 4-point reduction on the Itch Numerical Rating Scale (NRS4) and the Investigator Global Assessment (IGA) score 0 or 1 (clear or almost clear), as well as in a composite endpoint of both. However, even though the lowest dose of povorcitinib was active, there was a “very clear dose response” demonstrated in speed of response and proportion of responders, according to Dr. Kwatra.
On the 75-mg dose, the time to improvement was a median of 19 days, while the median times to improvement were 35 days on the 45-mg dose and 58 days on the 15-mg dose.
Among povorcitinib responders, 96% had met the NRS4 response at the time they entered the extension study. During the extension study, the proportion of responders who maintained this level of itch control hovered around 90% for the duration. The proportion was 89% at week 40.
The proportion of responders at 16 weeks achieving IGA 0/1, signifying clear or almost clear, was 93%. Again, the rate hovered around 90% for the full 40 weeks. At week 40, the proportion at this outcome was also 89%. The composite outcome among responders persisted at about 80% for most of the follow-up but fell to 63% at the last follow-up.
Among nonresponders who transitioned to 75 mg povorcitinib for the extension period, the NSR4 response rates climbed within 4 weeks to approximately 60% and reached 70% at week 40. For the endpoint of IGA 0/1, rates rose incrementally among the nonresponders over time, reaching 51% at week 40. The composite endpoint was reached at 40 weeks by 41% of nonresponders switched to 75 mg during the 24-week extension.
The results at 40 weeks were highly encouraging, according to Dr. Kwatra, who reported there were no surprises in regard to safety during the extension period. He reported some transient reductions in hemoglobin and infections that resolved, but there were no cardiac events or other more serious events that have been previously associated with JAK inhibitors during the 40-week study period.
When asked if there might be an advantage for povorcitinib relative to the monoclonal antibodies in regard to speed of onset, Dr. Kwatra said that there are no comparative data. Like previous experience with dupilumab, some patients responded rapidly with povorcitinib, but others took longer to achieve benefit.
This variability in response is consistent with the growing evidence that PN is a heterogeneous disease, according to Dr. Kwatra. With multiple up-regulated cytokines implicated in the pathogenesis of PN, he suggested that more treatment options would be useful. When it comes to the multiple molecular pathways involved in the pathogenesis of PN, he said, “patients can be at a different edge of a spectrum.”
In other evidence suggesting that more options are needed, another late-breaking news study at the 2024 EADV congress underlined the fact that PN is a chronic disease. Presented by Franz J. Legat, MD, professor of dermatology at the Medical University of Graz, Graz, Austria, the data involved a withdrawal evaluation nested in a long-term extension (LTE) of the OLYMPIA pivotal trials with nemolizumab.
After 52 weeks in the LTE, 34 patients entered the OLYMPIA DURABILITY study, in which they were randomized to withdrawal or to continue on nemolizumab on an every 4-week dosing schedule.
The relapse rate over 24 weeks was 16.7% (3 of 18 patients) in the continuous nemolizumab arm and 75% (12 of 16 patients) in the withdrawal arm. The median time to relapse was 112.5 days for those in the withdrawal arm and was not reached during follow-up in the nemolizumab arm.
Praising the patients who were willing to risk PN relapse by entering this randomized trial, Dr. Legat said that the study shows a relatively high risk for relapse within months of treatment withdrawal even after good PN control over a period of 52 weeks.
“These data clearly support continuous nemolizumab beyond 52 weeks,” he said.
Dr. Kwatra reported financial relationships with AbbVie, Arcutis, Biotherapeutics, Aslan, Celldex, Galderma, Genzada, Johnson & Johnson, Novartis, Pfizer, Regeneron, Sanofi, and Incyte, which is developing povorcitinib for PN. Dr. Legat reported financial relationships with Almirall, Celgene, Eli Lilly, Menlo Therapeutics, Novartis, Pfizer, Trevi, Vifor, and Galderma, which provided funding for the nemolizumab studies.
A version of this article appeared on Medscape.com.
AMSTERDAM — presented at the European Academy of Dermatology and Venereology (EADV) 2024 Congress are further validated.
“We now have a pipeline of clinical studies in PN. Who would have even thought that a few years ago,” said Shawn Kwatra, MD, professor and chair, Department of Dermatology, University of Maryland School of Medicine, Baltimore. That is a remarkable turn of events for a difficult disease, he added.
Dupilumab, a monoclonal antibody that inhibits the activity of interleukin (IL)–4 and IL-13, was the first treatment approved for PN by the Food and Drug Administration 2 years ago. Approval of nemolizumab, a monoclonal antibody that targets IL-31, a cytokine strongly implicated in the itch response, followed in August 2024. Povorcitinib, which targets Janus kinase 1 (JAK1), is on track to be the third.
New data on both nemolizumab and povorcitinib were presented in late breaking news sessions at EADV.
For povorcitinib, a JAK inhibitor, Dr. Kwatra presented extended phase 2 results through 40 weeks at a late-breaker session at the EADV meeting. They follow 16-week data from a randomized study presented earlier this year.
Of the 146 patients followed in the original 16-week randomized trial, which compared 15, 45, and 75 mg of oral povorcitinib once daily against placebo, 126 entered an extension in which all patients were treated with active therapy. In this single-blind phase, those who were responders at 16 weeks received 45 mg povorcitinib, and those who were nonresponders received 75 mg povorcitinib.
At 16 weeks, all doses were superior to placebo in achieving at least a 4-point reduction on the Itch Numerical Rating Scale (NRS4) and the Investigator Global Assessment (IGA) score 0 or 1 (clear or almost clear), as well as in a composite endpoint of both. However, even though the lowest dose of povorcitinib was active, there was a “very clear dose response” demonstrated in speed of response and proportion of responders, according to Dr. Kwatra.
On the 75-mg dose, the time to improvement was a median of 19 days, while the median times to improvement were 35 days on the 45-mg dose and 58 days on the 15-mg dose.
Among povorcitinib responders, 96% had met the NRS4 response at the time they entered the extension study. During the extension study, the proportion of responders who maintained this level of itch control hovered around 90% for the duration. The proportion was 89% at week 40.
The proportion of responders at 16 weeks achieving IGA 0/1, signifying clear or almost clear, was 93%. Again, the rate hovered around 90% for the full 40 weeks. At week 40, the proportion at this outcome was also 89%. The composite outcome among responders persisted at about 80% for most of the follow-up but fell to 63% at the last follow-up.
Among nonresponders who transitioned to 75 mg povorcitinib for the extension period, the NSR4 response rates climbed within 4 weeks to approximately 60% and reached 70% at week 40. For the endpoint of IGA 0/1, rates rose incrementally among the nonresponders over time, reaching 51% at week 40. The composite endpoint was reached at 40 weeks by 41% of nonresponders switched to 75 mg during the 24-week extension.
The results at 40 weeks were highly encouraging, according to Dr. Kwatra, who reported there were no surprises in regard to safety during the extension period. He reported some transient reductions in hemoglobin and infections that resolved, but there were no cardiac events or other more serious events that have been previously associated with JAK inhibitors during the 40-week study period.
When asked if there might be an advantage for povorcitinib relative to the monoclonal antibodies in regard to speed of onset, Dr. Kwatra said that there are no comparative data. Like previous experience with dupilumab, some patients responded rapidly with povorcitinib, but others took longer to achieve benefit.
This variability in response is consistent with the growing evidence that PN is a heterogeneous disease, according to Dr. Kwatra. With multiple up-regulated cytokines implicated in the pathogenesis of PN, he suggested that more treatment options would be useful. When it comes to the multiple molecular pathways involved in the pathogenesis of PN, he said, “patients can be at a different edge of a spectrum.”
In other evidence suggesting that more options are needed, another late-breaking news study at the 2024 EADV congress underlined the fact that PN is a chronic disease. Presented by Franz J. Legat, MD, professor of dermatology at the Medical University of Graz, Graz, Austria, the data involved a withdrawal evaluation nested in a long-term extension (LTE) of the OLYMPIA pivotal trials with nemolizumab.
After 52 weeks in the LTE, 34 patients entered the OLYMPIA DURABILITY study, in which they were randomized to withdrawal or to continue on nemolizumab on an every 4-week dosing schedule.
The relapse rate over 24 weeks was 16.7% (3 of 18 patients) in the continuous nemolizumab arm and 75% (12 of 16 patients) in the withdrawal arm. The median time to relapse was 112.5 days for those in the withdrawal arm and was not reached during follow-up in the nemolizumab arm.
Praising the patients who were willing to risk PN relapse by entering this randomized trial, Dr. Legat said that the study shows a relatively high risk for relapse within months of treatment withdrawal even after good PN control over a period of 52 weeks.
“These data clearly support continuous nemolizumab beyond 52 weeks,” he said.
Dr. Kwatra reported financial relationships with AbbVie, Arcutis, Biotherapeutics, Aslan, Celldex, Galderma, Genzada, Johnson & Johnson, Novartis, Pfizer, Regeneron, Sanofi, and Incyte, which is developing povorcitinib for PN. Dr. Legat reported financial relationships with Almirall, Celgene, Eli Lilly, Menlo Therapeutics, Novartis, Pfizer, Trevi, Vifor, and Galderma, which provided funding for the nemolizumab studies.
A version of this article appeared on Medscape.com.
AMSTERDAM — presented at the European Academy of Dermatology and Venereology (EADV) 2024 Congress are further validated.
“We now have a pipeline of clinical studies in PN. Who would have even thought that a few years ago,” said Shawn Kwatra, MD, professor and chair, Department of Dermatology, University of Maryland School of Medicine, Baltimore. That is a remarkable turn of events for a difficult disease, he added.
Dupilumab, a monoclonal antibody that inhibits the activity of interleukin (IL)–4 and IL-13, was the first treatment approved for PN by the Food and Drug Administration 2 years ago. Approval of nemolizumab, a monoclonal antibody that targets IL-31, a cytokine strongly implicated in the itch response, followed in August 2024. Povorcitinib, which targets Janus kinase 1 (JAK1), is on track to be the third.
New data on both nemolizumab and povorcitinib were presented in late breaking news sessions at EADV.
For povorcitinib, a JAK inhibitor, Dr. Kwatra presented extended phase 2 results through 40 weeks at a late-breaker session at the EADV meeting. They follow 16-week data from a randomized study presented earlier this year.
Of the 146 patients followed in the original 16-week randomized trial, which compared 15, 45, and 75 mg of oral povorcitinib once daily against placebo, 126 entered an extension in which all patients were treated with active therapy. In this single-blind phase, those who were responders at 16 weeks received 45 mg povorcitinib, and those who were nonresponders received 75 mg povorcitinib.
At 16 weeks, all doses were superior to placebo in achieving at least a 4-point reduction on the Itch Numerical Rating Scale (NRS4) and the Investigator Global Assessment (IGA) score 0 or 1 (clear or almost clear), as well as in a composite endpoint of both. However, even though the lowest dose of povorcitinib was active, there was a “very clear dose response” demonstrated in speed of response and proportion of responders, according to Dr. Kwatra.
On the 75-mg dose, the time to improvement was a median of 19 days, while the median times to improvement were 35 days on the 45-mg dose and 58 days on the 15-mg dose.
Among povorcitinib responders, 96% had met the NRS4 response at the time they entered the extension study. During the extension study, the proportion of responders who maintained this level of itch control hovered around 90% for the duration. The proportion was 89% at week 40.
The proportion of responders at 16 weeks achieving IGA 0/1, signifying clear or almost clear, was 93%. Again, the rate hovered around 90% for the full 40 weeks. At week 40, the proportion at this outcome was also 89%. The composite outcome among responders persisted at about 80% for most of the follow-up but fell to 63% at the last follow-up.
Among nonresponders who transitioned to 75 mg povorcitinib for the extension period, the NSR4 response rates climbed within 4 weeks to approximately 60% and reached 70% at week 40. For the endpoint of IGA 0/1, rates rose incrementally among the nonresponders over time, reaching 51% at week 40. The composite endpoint was reached at 40 weeks by 41% of nonresponders switched to 75 mg during the 24-week extension.
The results at 40 weeks were highly encouraging, according to Dr. Kwatra, who reported there were no surprises in regard to safety during the extension period. He reported some transient reductions in hemoglobin and infections that resolved, but there were no cardiac events or other more serious events that have been previously associated with JAK inhibitors during the 40-week study period.
When asked if there might be an advantage for povorcitinib relative to the monoclonal antibodies in regard to speed of onset, Dr. Kwatra said that there are no comparative data. Like previous experience with dupilumab, some patients responded rapidly with povorcitinib, but others took longer to achieve benefit.
This variability in response is consistent with the growing evidence that PN is a heterogeneous disease, according to Dr. Kwatra. With multiple up-regulated cytokines implicated in the pathogenesis of PN, he suggested that more treatment options would be useful. When it comes to the multiple molecular pathways involved in the pathogenesis of PN, he said, “patients can be at a different edge of a spectrum.”
In other evidence suggesting that more options are needed, another late-breaking news study at the 2024 EADV congress underlined the fact that PN is a chronic disease. Presented by Franz J. Legat, MD, professor of dermatology at the Medical University of Graz, Graz, Austria, the data involved a withdrawal evaluation nested in a long-term extension (LTE) of the OLYMPIA pivotal trials with nemolizumab.
After 52 weeks in the LTE, 34 patients entered the OLYMPIA DURABILITY study, in which they were randomized to withdrawal or to continue on nemolizumab on an every 4-week dosing schedule.
The relapse rate over 24 weeks was 16.7% (3 of 18 patients) in the continuous nemolizumab arm and 75% (12 of 16 patients) in the withdrawal arm. The median time to relapse was 112.5 days for those in the withdrawal arm and was not reached during follow-up in the nemolizumab arm.
Praising the patients who were willing to risk PN relapse by entering this randomized trial, Dr. Legat said that the study shows a relatively high risk for relapse within months of treatment withdrawal even after good PN control over a period of 52 weeks.
“These data clearly support continuous nemolizumab beyond 52 weeks,” he said.
Dr. Kwatra reported financial relationships with AbbVie, Arcutis, Biotherapeutics, Aslan, Celldex, Galderma, Genzada, Johnson & Johnson, Novartis, Pfizer, Regeneron, Sanofi, and Incyte, which is developing povorcitinib for PN. Dr. Legat reported financial relationships with Almirall, Celgene, Eli Lilly, Menlo Therapeutics, Novartis, Pfizer, Trevi, Vifor, and Galderma, which provided funding for the nemolizumab studies.
A version of this article appeared on Medscape.com.
FROM EADV 2024
Over 3 Years, Atopic Dermatitis Well-Controlled with Lebrikizumab
AMSTERDAM — among those followed up for an additional 2 years, according to the latest data from an extension study.
At the end of the maintenance phase of the pivotal trials at 12 months, 84% of the patients enrolled into the extension had clear or almost clear skin, as per the Investigator Global Assessment (IGA). This overall figure as well as the proportion with even better responses have persisted unchanged, reported Diamant Thaçi, MD, PhD, professor and head of the Comprehensive Center for Inflammatory Medicine, University of Lübeck in Germany.
Responses at 3 Years Maintained
“This is really quite remarkable,” Dr. Thaçi said. “Roughly all the patients maintained their response.” These results became even more remarkable when patients were assessed for their use of adjunctive therapy to control flares.
“Over the whole follow-up, 90% had no need for topical corticosteroids or any other rescue therapy,” Dr. Thaçi reported, providing data from the ADjoin lebrikizumab extension study during a late-breaking news session at the annual meeting of the European Academy of Dermatology and Venereology.
The patients in ADjoin were enrolled from the pivotal phase 3 ADvocate 1 and 2 trials completed almost 2 years ago and published together in March 2023. Lebrikizumab was approved in the United States in September 2024 for moderate to severe AD in patients aged ≥ 12 years, following previous approvals in Europe in 2023 and in Japan in January 2024.
In these two identical trials with a total of 564 patients, the primary endpoint was an IGA of 0 or 1, signifying clear or almost clear skin. At nearly 40%, the proportion of patients reaching this outcome at 16 weeks was about threefold greater (P < .001) on lebrikizumab than on placebo. The benefit was similar on secondary endpoints, such as 75% improvement in the Eczema Area and Severity Index (EASI75) score.
At the end of the double-blind, placebo-controlled 16-week phase of the ADvocate 1 and 2 trials, which enrolled adults and adolescents aged ≥ 12 years, responders were enrolled into a maintenance phase in which they were rerandomized to 250 mg lebrikizumab every 2 weeks (Q2W) or every 4 weeks (Q4W). The latter is the approved maintenance dose.
At the end of the maintenance phase, which lasted another 32 weeks (total exposure of 52 weeks for those initially randomized to lebrikizumab), patients were invited into the ADjoin extension. The only exclusions from the extension were serious adverse events related to lebrikizumab and noncompliance.
Response Curves Appear as Straight Lines
Over the next 2 years of ADjoin, response curves appeared as straight lines not only for the overall response but when patients were stratified for different levels of response at the extension study entry. Specifically, 81.5% and 83.3% had an IGA score of 0 or 1 in the Q2W and Q4W arms at completion of the ADvocate 16-week double-blind phase. At 3 years, the rates were 84.0% and 82.9%, respectively.
For the subgroup who entered ADjoin with an EASI75 or an EASI90 response, the persistence of this level of response over 2 years was similar, although there was some gain observed among those who entered the trial with an EASI75 response.
“Not only did these patients maintain their response, but the response on average slowly improved, so that there were more patients with an EASI90 response at the 3-year timepoint,” Dr. Thaçi said.
Of the 181 patients in the ADjoin extension, 82 patients were maintained on Q2W dosing and 99 were maintained on Q4W lebrikizumab. Their mean age was about 35 years, more than half were women, and nearly 40% had severe AD at the time they enrolled in the ADvocate trials. There was essentially no difference in response rates among those in the Q2W and Q4W arms over time in ADjoin.
Side Effect Profile Essentially Unchanged
The side effect and tolerability profiles, which were favorable in the original 16-week placebo-controlled study, have remained unchanged over the subsequent maintenance phase and through the additional 2 years of the ADjoin extension.
“There continued to be reports of conjunctivitis, which is very specific for anti–IL-13 therapies,” Dr. Thaçi said. However, he said that the incidence did not increase over time, and because it was easy to treat, “most patients do not discontinue lebrikizumab for this reason.” Moreover, he said the impression was that “the number of patients experiencing adverse effects has been decreasing over time.”
Calling these long-term results “very exciting,” Dr. Thaçi called lebrikizumab “a very valuable option for long-term AD care.”
Asked for his perspective on the results, Jonathan I. Silverberg, MD, PhD, Director of Clinical Research, Department of Dermatology, George Washington University, Washington, DC, said that it is important to study long-term efficacy, and these results are positive. Without direct comparisons to other biologics available for AD, nothing can be implied about the relative efficacy of monoclonal antibodies approved for AD.
“These data are important both from an efficacy and safety perspective” for those advising patients who need chronic AD treatment, said Dr. Silverberg, who was the principal investigator of the ADvocate trials.
Earlier this year, 5-year follow-up data were published for dupilumab. Of 326 patients who remained on therapy this long, 220 (67%) maintained an IGA of 0 or 1 at the end of the study. There were no unexpected adverse events, which were generally stable or declined throughout the study.
Dr. Thaçi has financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Galderma, Leo Pharma, L’Oreal, Janssen-Cilag, New Bridge, Novartis, Pfizer, Regeneron, Roche, Sanofi, Sun Pharma, UCB, and Vichy. Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies including those that make drugs for AD.
A version of this article appeared on Medscape.com.
AMSTERDAM — among those followed up for an additional 2 years, according to the latest data from an extension study.
At the end of the maintenance phase of the pivotal trials at 12 months, 84% of the patients enrolled into the extension had clear or almost clear skin, as per the Investigator Global Assessment (IGA). This overall figure as well as the proportion with even better responses have persisted unchanged, reported Diamant Thaçi, MD, PhD, professor and head of the Comprehensive Center for Inflammatory Medicine, University of Lübeck in Germany.
Responses at 3 Years Maintained
“This is really quite remarkable,” Dr. Thaçi said. “Roughly all the patients maintained their response.” These results became even more remarkable when patients were assessed for their use of adjunctive therapy to control flares.
“Over the whole follow-up, 90% had no need for topical corticosteroids or any other rescue therapy,” Dr. Thaçi reported, providing data from the ADjoin lebrikizumab extension study during a late-breaking news session at the annual meeting of the European Academy of Dermatology and Venereology.
The patients in ADjoin were enrolled from the pivotal phase 3 ADvocate 1 and 2 trials completed almost 2 years ago and published together in March 2023. Lebrikizumab was approved in the United States in September 2024 for moderate to severe AD in patients aged ≥ 12 years, following previous approvals in Europe in 2023 and in Japan in January 2024.
In these two identical trials with a total of 564 patients, the primary endpoint was an IGA of 0 or 1, signifying clear or almost clear skin. At nearly 40%, the proportion of patients reaching this outcome at 16 weeks was about threefold greater (P < .001) on lebrikizumab than on placebo. The benefit was similar on secondary endpoints, such as 75% improvement in the Eczema Area and Severity Index (EASI75) score.
At the end of the double-blind, placebo-controlled 16-week phase of the ADvocate 1 and 2 trials, which enrolled adults and adolescents aged ≥ 12 years, responders were enrolled into a maintenance phase in which they were rerandomized to 250 mg lebrikizumab every 2 weeks (Q2W) or every 4 weeks (Q4W). The latter is the approved maintenance dose.
At the end of the maintenance phase, which lasted another 32 weeks (total exposure of 52 weeks for those initially randomized to lebrikizumab), patients were invited into the ADjoin extension. The only exclusions from the extension were serious adverse events related to lebrikizumab and noncompliance.
Response Curves Appear as Straight Lines
Over the next 2 years of ADjoin, response curves appeared as straight lines not only for the overall response but when patients were stratified for different levels of response at the extension study entry. Specifically, 81.5% and 83.3% had an IGA score of 0 or 1 in the Q2W and Q4W arms at completion of the ADvocate 16-week double-blind phase. At 3 years, the rates were 84.0% and 82.9%, respectively.
For the subgroup who entered ADjoin with an EASI75 or an EASI90 response, the persistence of this level of response over 2 years was similar, although there was some gain observed among those who entered the trial with an EASI75 response.
“Not only did these patients maintain their response, but the response on average slowly improved, so that there were more patients with an EASI90 response at the 3-year timepoint,” Dr. Thaçi said.
Of the 181 patients in the ADjoin extension, 82 patients were maintained on Q2W dosing and 99 were maintained on Q4W lebrikizumab. Their mean age was about 35 years, more than half were women, and nearly 40% had severe AD at the time they enrolled in the ADvocate trials. There was essentially no difference in response rates among those in the Q2W and Q4W arms over time in ADjoin.
Side Effect Profile Essentially Unchanged
The side effect and tolerability profiles, which were favorable in the original 16-week placebo-controlled study, have remained unchanged over the subsequent maintenance phase and through the additional 2 years of the ADjoin extension.
“There continued to be reports of conjunctivitis, which is very specific for anti–IL-13 therapies,” Dr. Thaçi said. However, he said that the incidence did not increase over time, and because it was easy to treat, “most patients do not discontinue lebrikizumab for this reason.” Moreover, he said the impression was that “the number of patients experiencing adverse effects has been decreasing over time.”
Calling these long-term results “very exciting,” Dr. Thaçi called lebrikizumab “a very valuable option for long-term AD care.”
Asked for his perspective on the results, Jonathan I. Silverberg, MD, PhD, Director of Clinical Research, Department of Dermatology, George Washington University, Washington, DC, said that it is important to study long-term efficacy, and these results are positive. Without direct comparisons to other biologics available for AD, nothing can be implied about the relative efficacy of monoclonal antibodies approved for AD.
“These data are important both from an efficacy and safety perspective” for those advising patients who need chronic AD treatment, said Dr. Silverberg, who was the principal investigator of the ADvocate trials.
Earlier this year, 5-year follow-up data were published for dupilumab. Of 326 patients who remained on therapy this long, 220 (67%) maintained an IGA of 0 or 1 at the end of the study. There were no unexpected adverse events, which were generally stable or declined throughout the study.
Dr. Thaçi has financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Galderma, Leo Pharma, L’Oreal, Janssen-Cilag, New Bridge, Novartis, Pfizer, Regeneron, Roche, Sanofi, Sun Pharma, UCB, and Vichy. Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies including those that make drugs for AD.
A version of this article appeared on Medscape.com.
AMSTERDAM — among those followed up for an additional 2 years, according to the latest data from an extension study.
At the end of the maintenance phase of the pivotal trials at 12 months, 84% of the patients enrolled into the extension had clear or almost clear skin, as per the Investigator Global Assessment (IGA). This overall figure as well as the proportion with even better responses have persisted unchanged, reported Diamant Thaçi, MD, PhD, professor and head of the Comprehensive Center for Inflammatory Medicine, University of Lübeck in Germany.
Responses at 3 Years Maintained
“This is really quite remarkable,” Dr. Thaçi said. “Roughly all the patients maintained their response.” These results became even more remarkable when patients were assessed for their use of adjunctive therapy to control flares.
“Over the whole follow-up, 90% had no need for topical corticosteroids or any other rescue therapy,” Dr. Thaçi reported, providing data from the ADjoin lebrikizumab extension study during a late-breaking news session at the annual meeting of the European Academy of Dermatology and Venereology.
The patients in ADjoin were enrolled from the pivotal phase 3 ADvocate 1 and 2 trials completed almost 2 years ago and published together in March 2023. Lebrikizumab was approved in the United States in September 2024 for moderate to severe AD in patients aged ≥ 12 years, following previous approvals in Europe in 2023 and in Japan in January 2024.
In these two identical trials with a total of 564 patients, the primary endpoint was an IGA of 0 or 1, signifying clear or almost clear skin. At nearly 40%, the proportion of patients reaching this outcome at 16 weeks was about threefold greater (P < .001) on lebrikizumab than on placebo. The benefit was similar on secondary endpoints, such as 75% improvement in the Eczema Area and Severity Index (EASI75) score.
At the end of the double-blind, placebo-controlled 16-week phase of the ADvocate 1 and 2 trials, which enrolled adults and adolescents aged ≥ 12 years, responders were enrolled into a maintenance phase in which they were rerandomized to 250 mg lebrikizumab every 2 weeks (Q2W) or every 4 weeks (Q4W). The latter is the approved maintenance dose.
At the end of the maintenance phase, which lasted another 32 weeks (total exposure of 52 weeks for those initially randomized to lebrikizumab), patients were invited into the ADjoin extension. The only exclusions from the extension were serious adverse events related to lebrikizumab and noncompliance.
Response Curves Appear as Straight Lines
Over the next 2 years of ADjoin, response curves appeared as straight lines not only for the overall response but when patients were stratified for different levels of response at the extension study entry. Specifically, 81.5% and 83.3% had an IGA score of 0 or 1 in the Q2W and Q4W arms at completion of the ADvocate 16-week double-blind phase. At 3 years, the rates were 84.0% and 82.9%, respectively.
For the subgroup who entered ADjoin with an EASI75 or an EASI90 response, the persistence of this level of response over 2 years was similar, although there was some gain observed among those who entered the trial with an EASI75 response.
“Not only did these patients maintain their response, but the response on average slowly improved, so that there were more patients with an EASI90 response at the 3-year timepoint,” Dr. Thaçi said.
Of the 181 patients in the ADjoin extension, 82 patients were maintained on Q2W dosing and 99 were maintained on Q4W lebrikizumab. Their mean age was about 35 years, more than half were women, and nearly 40% had severe AD at the time they enrolled in the ADvocate trials. There was essentially no difference in response rates among those in the Q2W and Q4W arms over time in ADjoin.
Side Effect Profile Essentially Unchanged
The side effect and tolerability profiles, which were favorable in the original 16-week placebo-controlled study, have remained unchanged over the subsequent maintenance phase and through the additional 2 years of the ADjoin extension.
“There continued to be reports of conjunctivitis, which is very specific for anti–IL-13 therapies,” Dr. Thaçi said. However, he said that the incidence did not increase over time, and because it was easy to treat, “most patients do not discontinue lebrikizumab for this reason.” Moreover, he said the impression was that “the number of patients experiencing adverse effects has been decreasing over time.”
Calling these long-term results “very exciting,” Dr. Thaçi called lebrikizumab “a very valuable option for long-term AD care.”
Asked for his perspective on the results, Jonathan I. Silverberg, MD, PhD, Director of Clinical Research, Department of Dermatology, George Washington University, Washington, DC, said that it is important to study long-term efficacy, and these results are positive. Without direct comparisons to other biologics available for AD, nothing can be implied about the relative efficacy of monoclonal antibodies approved for AD.
“These data are important both from an efficacy and safety perspective” for those advising patients who need chronic AD treatment, said Dr. Silverberg, who was the principal investigator of the ADvocate trials.
Earlier this year, 5-year follow-up data were published for dupilumab. Of 326 patients who remained on therapy this long, 220 (67%) maintained an IGA of 0 or 1 at the end of the study. There were no unexpected adverse events, which were generally stable or declined throughout the study.
Dr. Thaçi has financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Galderma, Leo Pharma, L’Oreal, Janssen-Cilag, New Bridge, Novartis, Pfizer, Regeneron, Roche, Sanofi, Sun Pharma, UCB, and Vichy. Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies including those that make drugs for AD.
A version of this article appeared on Medscape.com.
FROM EADV 2024
Topical JAK Inhibitor Shows Benefits in Small Frontal Fibrosing Alopecia Study
AMSTERDAM —
“This is an exciting avenue for FFA if the data are recapitulated in a larger population. It could be an important new treatment option,” said Maryanne Senna, MD, director at Lahey Hospital & Medical Center’s Hair Loss Center of Excellence, Burlington, Massachusetts, and assistant dermatology professor at Harvard Medical School, Boston, Massachusetts.
In a design characterized as “exploratory,” the trial had two parts: a randomized, double-blind, vehicle-controlled intervention for 12 weeks, followed by an open-label extension of topical delgocitinib for all participants for another 12 weeks.
The primary efficacy endpoint was change in the molecular signature of FFA inflammation at 12 weeks. Clinical improvement was monitored with both trichoscopic images capturing the numbers of hairs and follicular units at 12 weeks and clinical severity scores through week 24. In a topical cream formulation, the Janus kinase inhibitor (JAKi) delgocitinib was associated with favorable activity for both.
Some Hair Regrowth for All
“At 24 weeks, all patients achieved some degree of hair regrowth and a stabilization of disease based on hairline measurements,” Senna reported in a late-breaking news session at the 2024 European Academy of Dermatology and Venereology (EADV) Congress.
On the clinical endpoints, Senna noted an upward trajectory in clinical improvement at the completion of the study.
The 30 participants were randomly assigned in a 1:1 ratio to receive delgocitinib cream in a concentration of 20 mg/g or vehicle cream applied twice daily for 12 weeks. At the end of this double-blind period, patients on vehicle were crossed over to the active therapy, and all patients were monitored for another 12 weeks in an open-label extension.
The change from baseline in FFA biomarkers was selected as the primary endpoint based on previous work showing up-regulation in the expression of the Th1 biomarkers CXCL9, CXCL10, and interferon gamma in lesional vs nonlesional scalp in patients with FFA.
When biopsies at the end of 12 weeks in the double-blind phase of the study were compared with the baseline biopsies, researchers found a decrease in expression of the three local inflammation markers in all patients receiving the JAKi, but not in those receiving the vehicle cream. In this small patient sample, only the reduction in expression of CXCL9, a cytokine known for differentiation and promotion of leukocytes, reached statistical significance (P < .05).
But in an analysis involving the expression of multiple genes, “lesions treated with delgocitinib had a 4% improvement in normalization toward a nonlesional transcriptomic profile, while patients treated with vehicle had a 33% worsening,” Senna reported. The difference was highly significant (P < .001).
Furthermore, the decrease in total Lichen Planopilaris Activity Index and FFA severity scores were numerically and statistically greater (P = .023) in the active-treatment arm than in the vehicle arm by the end of the double-blind part of the trial, she said.
On trichoscopy, there was an increased number of hairs and follicular units at 12 weeks relative to baseline among those treated with topical delgocitinib but a reduction in those treated with vehicle.
JAKi Patients Gained Hair, Vehicle Patients Lost Hair
On the basis of hair count per square centimeter from baseline, delgocitinib-treated patients gained on average of seven hairs whereas vehicle recipients lost an average of 11 hairs at 24 weeks, Senna reported.
Patients originally treated with vehicle did improve in most outcome measures in the open-label extension of the experimental treatment after crossover, but they did not catch up to those initially randomized to delgocitinib because of further accrual of favorable changes in the active-treatment group over time.
“There were no adverse events associated with active therapy or vehicle, including application-site reactions,” Senna said. The one between-group difference was a higher rate of COVID-19, but this was greater in the control arm.
All 30 of the participants in this study were women, and all had moderate to severe disease at enrollment. The median age was 64 years. Because of the predominant population at the hair loss center, all but one of the participants were White, and one participant was Asian.
Characterizing FFA as “devastating and disfiguring,” Senna, who specializes in the care of alopecia, noted that this a difficult disease to control with the off-label strategies that are now used. The slow progress to identify treatments for FFA is illustrated by the fact that only one other double-blind and randomized trial has ever been conducted in FFA, she said.
Exploratory Study Supports Anecdotal Experience
On the basis of prior anecdotal experience with JAKi treatment for FFA, Senna said, “I do think that it is possible to get largely clear skin with this therapy.” However, she is now hoping for definitive trials to better characterize the efficacy and safety of oral and topical therapies, perhaps used sequentially to maintain clinical improvement.
In light of the limited current options, Menno de Rie, MD, PhD, professor of dermatology at the University of Amsterdam in the Netherlands, called these data “very inspiring and hopeful.” He suggested the promise of this therapy was reinforced by the upward trajectory of the biomarkers and clinical improvement over the study period.
“Any improvement in treatment options would be welcome, because we do not [have] any reliable therapies for this condition,” de Rie, who was not an investigator, said in an interview after the presentation.
Ultimately, Senna said, once effective therapy is established, the goal will be to start as early as possible in the disease process. She noted that there is evidence that prompt therapy can reverse the disorder, not just prevent progression.
“If you can get to the hair follicles before the point of no return, there is [a] chance [of] follicular rescue,” she said.
Delgocitinib cream (Anzupgo) was approved in Europe for treating chronic hand eczema in late September and is under review for the same indication in the United States.
Senna has financial relationships with Arena, Concert, Eli Lilly, Pfizer, and Leo Pharma, which provided funding for this study. de Rie reported no potential conflicts of interest.
A version of this article appeared on Medscape.com.
AMSTERDAM —
“This is an exciting avenue for FFA if the data are recapitulated in a larger population. It could be an important new treatment option,” said Maryanne Senna, MD, director at Lahey Hospital & Medical Center’s Hair Loss Center of Excellence, Burlington, Massachusetts, and assistant dermatology professor at Harvard Medical School, Boston, Massachusetts.
In a design characterized as “exploratory,” the trial had two parts: a randomized, double-blind, vehicle-controlled intervention for 12 weeks, followed by an open-label extension of topical delgocitinib for all participants for another 12 weeks.
The primary efficacy endpoint was change in the molecular signature of FFA inflammation at 12 weeks. Clinical improvement was monitored with both trichoscopic images capturing the numbers of hairs and follicular units at 12 weeks and clinical severity scores through week 24. In a topical cream formulation, the Janus kinase inhibitor (JAKi) delgocitinib was associated with favorable activity for both.
Some Hair Regrowth for All
“At 24 weeks, all patients achieved some degree of hair regrowth and a stabilization of disease based on hairline measurements,” Senna reported in a late-breaking news session at the 2024 European Academy of Dermatology and Venereology (EADV) Congress.
On the clinical endpoints, Senna noted an upward trajectory in clinical improvement at the completion of the study.
The 30 participants were randomly assigned in a 1:1 ratio to receive delgocitinib cream in a concentration of 20 mg/g or vehicle cream applied twice daily for 12 weeks. At the end of this double-blind period, patients on vehicle were crossed over to the active therapy, and all patients were monitored for another 12 weeks in an open-label extension.
The change from baseline in FFA biomarkers was selected as the primary endpoint based on previous work showing up-regulation in the expression of the Th1 biomarkers CXCL9, CXCL10, and interferon gamma in lesional vs nonlesional scalp in patients with FFA.
When biopsies at the end of 12 weeks in the double-blind phase of the study were compared with the baseline biopsies, researchers found a decrease in expression of the three local inflammation markers in all patients receiving the JAKi, but not in those receiving the vehicle cream. In this small patient sample, only the reduction in expression of CXCL9, a cytokine known for differentiation and promotion of leukocytes, reached statistical significance (P < .05).
But in an analysis involving the expression of multiple genes, “lesions treated with delgocitinib had a 4% improvement in normalization toward a nonlesional transcriptomic profile, while patients treated with vehicle had a 33% worsening,” Senna reported. The difference was highly significant (P < .001).
Furthermore, the decrease in total Lichen Planopilaris Activity Index and FFA severity scores were numerically and statistically greater (P = .023) in the active-treatment arm than in the vehicle arm by the end of the double-blind part of the trial, she said.
On trichoscopy, there was an increased number of hairs and follicular units at 12 weeks relative to baseline among those treated with topical delgocitinib but a reduction in those treated with vehicle.
JAKi Patients Gained Hair, Vehicle Patients Lost Hair
On the basis of hair count per square centimeter from baseline, delgocitinib-treated patients gained on average of seven hairs whereas vehicle recipients lost an average of 11 hairs at 24 weeks, Senna reported.
Patients originally treated with vehicle did improve in most outcome measures in the open-label extension of the experimental treatment after crossover, but they did not catch up to those initially randomized to delgocitinib because of further accrual of favorable changes in the active-treatment group over time.
“There were no adverse events associated with active therapy or vehicle, including application-site reactions,” Senna said. The one between-group difference was a higher rate of COVID-19, but this was greater in the control arm.
All 30 of the participants in this study were women, and all had moderate to severe disease at enrollment. The median age was 64 years. Because of the predominant population at the hair loss center, all but one of the participants were White, and one participant was Asian.
Characterizing FFA as “devastating and disfiguring,” Senna, who specializes in the care of alopecia, noted that this a difficult disease to control with the off-label strategies that are now used. The slow progress to identify treatments for FFA is illustrated by the fact that only one other double-blind and randomized trial has ever been conducted in FFA, she said.
Exploratory Study Supports Anecdotal Experience
On the basis of prior anecdotal experience with JAKi treatment for FFA, Senna said, “I do think that it is possible to get largely clear skin with this therapy.” However, she is now hoping for definitive trials to better characterize the efficacy and safety of oral and topical therapies, perhaps used sequentially to maintain clinical improvement.
In light of the limited current options, Menno de Rie, MD, PhD, professor of dermatology at the University of Amsterdam in the Netherlands, called these data “very inspiring and hopeful.” He suggested the promise of this therapy was reinforced by the upward trajectory of the biomarkers and clinical improvement over the study period.
“Any improvement in treatment options would be welcome, because we do not [have] any reliable therapies for this condition,” de Rie, who was not an investigator, said in an interview after the presentation.
Ultimately, Senna said, once effective therapy is established, the goal will be to start as early as possible in the disease process. She noted that there is evidence that prompt therapy can reverse the disorder, not just prevent progression.
“If you can get to the hair follicles before the point of no return, there is [a] chance [of] follicular rescue,” she said.
Delgocitinib cream (Anzupgo) was approved in Europe for treating chronic hand eczema in late September and is under review for the same indication in the United States.
Senna has financial relationships with Arena, Concert, Eli Lilly, Pfizer, and Leo Pharma, which provided funding for this study. de Rie reported no potential conflicts of interest.
A version of this article appeared on Medscape.com.
AMSTERDAM —
“This is an exciting avenue for FFA if the data are recapitulated in a larger population. It could be an important new treatment option,” said Maryanne Senna, MD, director at Lahey Hospital & Medical Center’s Hair Loss Center of Excellence, Burlington, Massachusetts, and assistant dermatology professor at Harvard Medical School, Boston, Massachusetts.
In a design characterized as “exploratory,” the trial had two parts: a randomized, double-blind, vehicle-controlled intervention for 12 weeks, followed by an open-label extension of topical delgocitinib for all participants for another 12 weeks.
The primary efficacy endpoint was change in the molecular signature of FFA inflammation at 12 weeks. Clinical improvement was monitored with both trichoscopic images capturing the numbers of hairs and follicular units at 12 weeks and clinical severity scores through week 24. In a topical cream formulation, the Janus kinase inhibitor (JAKi) delgocitinib was associated with favorable activity for both.
Some Hair Regrowth for All
“At 24 weeks, all patients achieved some degree of hair regrowth and a stabilization of disease based on hairline measurements,” Senna reported in a late-breaking news session at the 2024 European Academy of Dermatology and Venereology (EADV) Congress.
On the clinical endpoints, Senna noted an upward trajectory in clinical improvement at the completion of the study.
The 30 participants were randomly assigned in a 1:1 ratio to receive delgocitinib cream in a concentration of 20 mg/g or vehicle cream applied twice daily for 12 weeks. At the end of this double-blind period, patients on vehicle were crossed over to the active therapy, and all patients were monitored for another 12 weeks in an open-label extension.
The change from baseline in FFA biomarkers was selected as the primary endpoint based on previous work showing up-regulation in the expression of the Th1 biomarkers CXCL9, CXCL10, and interferon gamma in lesional vs nonlesional scalp in patients with FFA.
When biopsies at the end of 12 weeks in the double-blind phase of the study were compared with the baseline biopsies, researchers found a decrease in expression of the three local inflammation markers in all patients receiving the JAKi, but not in those receiving the vehicle cream. In this small patient sample, only the reduction in expression of CXCL9, a cytokine known for differentiation and promotion of leukocytes, reached statistical significance (P < .05).
But in an analysis involving the expression of multiple genes, “lesions treated with delgocitinib had a 4% improvement in normalization toward a nonlesional transcriptomic profile, while patients treated with vehicle had a 33% worsening,” Senna reported. The difference was highly significant (P < .001).
Furthermore, the decrease in total Lichen Planopilaris Activity Index and FFA severity scores were numerically and statistically greater (P = .023) in the active-treatment arm than in the vehicle arm by the end of the double-blind part of the trial, she said.
On trichoscopy, there was an increased number of hairs and follicular units at 12 weeks relative to baseline among those treated with topical delgocitinib but a reduction in those treated with vehicle.
JAKi Patients Gained Hair, Vehicle Patients Lost Hair
On the basis of hair count per square centimeter from baseline, delgocitinib-treated patients gained on average of seven hairs whereas vehicle recipients lost an average of 11 hairs at 24 weeks, Senna reported.
Patients originally treated with vehicle did improve in most outcome measures in the open-label extension of the experimental treatment after crossover, but they did not catch up to those initially randomized to delgocitinib because of further accrual of favorable changes in the active-treatment group over time.
“There were no adverse events associated with active therapy or vehicle, including application-site reactions,” Senna said. The one between-group difference was a higher rate of COVID-19, but this was greater in the control arm.
All 30 of the participants in this study were women, and all had moderate to severe disease at enrollment. The median age was 64 years. Because of the predominant population at the hair loss center, all but one of the participants were White, and one participant was Asian.
Characterizing FFA as “devastating and disfiguring,” Senna, who specializes in the care of alopecia, noted that this a difficult disease to control with the off-label strategies that are now used. The slow progress to identify treatments for FFA is illustrated by the fact that only one other double-blind and randomized trial has ever been conducted in FFA, she said.
Exploratory Study Supports Anecdotal Experience
On the basis of prior anecdotal experience with JAKi treatment for FFA, Senna said, “I do think that it is possible to get largely clear skin with this therapy.” However, she is now hoping for definitive trials to better characterize the efficacy and safety of oral and topical therapies, perhaps used sequentially to maintain clinical improvement.
In light of the limited current options, Menno de Rie, MD, PhD, professor of dermatology at the University of Amsterdam in the Netherlands, called these data “very inspiring and hopeful.” He suggested the promise of this therapy was reinforced by the upward trajectory of the biomarkers and clinical improvement over the study period.
“Any improvement in treatment options would be welcome, because we do not [have] any reliable therapies for this condition,” de Rie, who was not an investigator, said in an interview after the presentation.
Ultimately, Senna said, once effective therapy is established, the goal will be to start as early as possible in the disease process. She noted that there is evidence that prompt therapy can reverse the disorder, not just prevent progression.
“If you can get to the hair follicles before the point of no return, there is [a] chance [of] follicular rescue,” she said.
Delgocitinib cream (Anzupgo) was approved in Europe for treating chronic hand eczema in late September and is under review for the same indication in the United States.
Senna has financial relationships with Arena, Concert, Eli Lilly, Pfizer, and Leo Pharma, which provided funding for this study. de Rie reported no potential conflicts of interest.
A version of this article appeared on Medscape.com.
FROM EADV 2024
Different Biomarker Profiles Identified in Study of Late Dupilumab Responders
AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.
A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.
The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.
The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.
“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.
For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.
In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.
In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.
“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.
To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.
When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.
“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.
Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.
The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.
This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.
When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.
This is an important missing piece of this investigation, according to Dréno.
“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”
This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.
The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.
A version of this article appeared on Medscape.com.
AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.
A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.
The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.
The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.
“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.
For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.
In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.
In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.
“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.
To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.
When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.
“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.
Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.
The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.
This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.
When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.
This is an important missing piece of this investigation, according to Dréno.
“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”
This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.
The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.
A version of this article appeared on Medscape.com.
AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.
A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.
The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.
The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.
“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.
For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.
In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.
In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.
“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.
To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.
When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.
“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.
Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.
The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.
This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.
When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.
This is an important missing piece of this investigation, according to Dréno.
“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”
This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.
The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.
A version of this article appeared on Medscape.com.
FROM EADV 2024
Hidradenitis Suppurativa: Nodules Respond to As Needed Topical JAK Inhibitor
AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in
“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.
In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
Over 80% Meet Primary Endpoint at 32 Weeks
Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4.
In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.
The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.
The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.
This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said.
For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).
AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.
One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively.
The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively.
Patients in the Study Mostly Women, 42% Black Individuals
Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m2. A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.
“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.
The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low.
Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.
Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.
Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.
“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment.
Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years.
Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.
A version of this article appeared on Medscape.com.
AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in
“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.
In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
Over 80% Meet Primary Endpoint at 32 Weeks
Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4.
In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.
The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.
The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.
This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said.
For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).
AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.
One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively.
The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively.
Patients in the Study Mostly Women, 42% Black Individuals
Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m2. A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.
“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.
The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low.
Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.
Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.
Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.
“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment.
Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years.
Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.
A version of this article appeared on Medscape.com.
AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in
“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.
In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
Over 80% Meet Primary Endpoint at 32 Weeks
Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4.
In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.
The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.
The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.
This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said.
For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).
AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.
One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively.
The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively.
Patients in the Study Mostly Women, 42% Black Individuals
Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m2. A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.
“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.
The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low.
Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.
Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.
Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.
“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment.
Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years.
Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.
A version of this article appeared on Medscape.com.
FROM EADV 2024
sNFl and sGFAP Predict MS Disability in Unique Ways
COPENHAGEN — , according to multiple independent studies.
The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.
This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
A New Biomarker for MS Disability Progression
Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.
In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.
On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.
Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.
It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.
The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.
Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.
Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).
Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
Comparing sGFAP and sNFl
This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.
The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.
However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.
Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”
So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.
Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.
“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.
Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.
COPENHAGEN — , according to multiple independent studies.
The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.
This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
A New Biomarker for MS Disability Progression
Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.
In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.
On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.
Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.
It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.
The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.
Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.
Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).
Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
Comparing sGFAP and sNFl
This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.
The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.
However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.
Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”
So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.
Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.
“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.
Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.
COPENHAGEN — , according to multiple independent studies.
The basic consensus is that “elevated sNFl levels predict inflammatory-associated worsening, while sGFAP values correlate with progression independent of inflammation,” said Enric Monreal, MD, Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.
This key message was repeated by several researchers presenting data at the 2024 ECTRIMS 2004 meeting, including one delivered as a latebreaker. There was also general agreement that sGFAP will eventually be a routine prognostic tool even if more data are needed to validate how it will be used in routine MS management.
A New Biomarker for MS Disability Progression
Although apparently reliable for predicting MS disability, “sGFAP is about 5 years behind where we are with sNFl,” said Evan Madill, MD, a clinical research fellow at the Brigham Multiple Sclerosis Research Center, Harvard Medical School, Boston. He does think, however, that it is coming to clinical practice.
In the study he presented, 744 patients from the Brigham MS Research Center database were evaluated retrospectively for sGFAP levels and subsequent disability progression. Among this cohort, for which sGFAP levels were collected at baseline and over time, 46.5% had 6-month confirmed disability progression (CDP) over follow-up.
On univariate analysis, sGFAP levels correlated with and predicted CDP, need for a new ambulatory aid, and conversion to secondary progressive MS (SPMS). For patients less than 60 years of age, all of these correlations were highly significant (P ≤ .002). On multivariate analysis, the significance was preserved for CDP (P = .032) and for need of a new ambulatory aid (P = .007), but it was lost for SPMS conversion.
Notably, his data suggest that a one-time baseline measurement of sGFAP was more useful than change in sGFAP as a predictor.
It is unclear why sGFAP is less predictive in older individuals, but Dr. Madill speculated that non-MS phenomena might play a role at older ages. Treatment did not influence sGFAP levels in this study, but Dr. Madill said most of the data were collected before anti-CD20 monoclonal antibodies were widely available.
The observational study data presented by Dr. Monreal involved 725 patients drawn from 13 European hospitals. sGFAP and sNFl levels were evaluated from blood drawn within 12 months of MS onset. Over time these biomarkers had overlapping but different predictive strengths.
Consistent with previously published studies, which link elevations in sNFl to neuronal damage and elevations in sGFAP to astrogliosis, sGFAP was found to be more useful for predicting progression independent of relapse activity (PIRA), particularly in patients with low sNFl levels.
Increases in sNFl were associated with an increased risk of both PIRA and relapse-associated worsening (RAW), but sNFl was more closely associated with RAW in untreated patients. The risk of PIRA and RAW were similar across GFAP and sNFl levels in those patients treated with high-efficacy disease-modifying therapies (DMT).
Overall, when stratifying the cohort into three groups, those with both low sNFl and low GFAP, those with high sNFl with low GFAP, and those with high GFAP and low sNFl, the relative risks of disability associated with PIRA and RAW diverged, suggesting these biomarkers correlate with different processes of progression.
Comparing sGFAP and sNFl
This same principle was explored further in the latebreaking presentation by Ahmed Abdelhak, MD, a clinical instructor, Weill Institute for Neurosciences, University of California, San Francisco. The objective of his study was to compare sGFAP and sNFl for predicting PIRA in patients on treatment.
The study included 212 patients from the Swiss Multiple Sclerosis Cohort who were started on fingolimod or on B-cell depleting therapies like rituximab. After correcting for sex, age at onset, baseline Expanded Disability Status Scale (EDSS) scores, and other variables, Dr. Abdelhak also reported that the predictive values for PIRA were different for sGFAP relative to sNFl at least on the group level.
However, in this study, unlike the analysis of the Brigham MS Research Center data, changes in sGFAP over time when on treatment did have prognostic value, and there was a relationship between sGFAP levels and treatment. Although reductions in GFAP predicted less disability progression whether patients were treated with fingolimod B-cell depleting therapies, that patterns were different. Dr. Abdelhak, like the other investigators speaking at ECTRIMS, also said the data so far favor sGFAP over sNFl for predicting PIRA.
Each z-score unit change in sGFAP corresponded to a 47% lower risk of PIRA in follow-up over 6.8 years, Dr. Abdelhak reported, adding that the predictive value of sGFAP was “numerically stronger than the corresponding relation for sNFl.”
So far, clinical utility of sGFAP remains speculative. Most of the correlations he presented were on a group rather than the individual level. Moreover, Dr. Abdelhak cautioned that these correlations, based on observational data, do not necessarily reflect causation.
Nonetheless, remarking on the parallels of his data on sGFAP and sNFl with other studies presented at the ECTRIMS meeting, Dr. Abdelhak foresees a time when GFAP will be a prognostic tool, offering relative simplicity and lower cost than the current standard of imaging. He also sees a role in clinical research.
“Monitoring of sGFAP dynamics following DMT initiation could be used to prognosticate long-term PIRA risk and provide insights valuable for design and interpretation of trial outcomes,” he said.
Dr. Monreal reported financial relationships with Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Dr. Madill and Dr. Abdelhak reported no potential conflicts of interest.
FROM ECTRIMS 2024