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Esketamine nasal spray may get expanded indication
COPENHAGEN – Esketamine nasal spray achieved rapid reduction of major depressive disorder symptoms in patients at imminent risk for suicide in a pair of pivotal phase 3 clinical trials known as ASPIRE-1 and ASPIRE-2, Carla M. Canuso, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
These were groundbreaking studies, which addressed a major unmet need familiar to every mental health professional, given that more than 800,000 suicides per year occur worldwide. Standard antidepressants are of only limited value during the period of acute suicidal crisis because they take 4-6 weeks to work. Moreover, this population of seriously depressed and suicidal patients has been understudied.
“Patients with active suicidal ideation and intent are routinely excluded from antidepressant trials,” observed Dr. Canuso, a psychiatrist who serves as senior director of neuroscience clinical development at Janssen Research and Development in Titusville, N.J.
It’s very important for the field to know that we can actually study these patients safely and effectively in clinical trials,” she said.
ASPIRE-1 and -2 were identically designed, randomized, double-blind, placebo-controlled, multinational studies conducted in patients with moderate to severe major depressive disorder as evidenced by a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score of about 40, along with moderate to extreme active suicidal ideation and intent as assessed using the Clinical Global Impression-Severity of Suicidality-Revised (CGI-SS-R).
“These were all patients in psychiatric crisis seeking clinical care,” according to Dr. Canuso.
All 456 participants in the two phase 3 studies underwent an initial 5-14 days of psychiatric hospitalization, during which they began treatment with esketamine nasal spray at 84 mg twice weekly or placebo coupled with comprehensive standard of care, which included a newly initiated and/or optimized oral antidepressant regimen.
The primary endpoint in the two clinical trials was the change in MADRS total score 24 hours after the first dose of study medication. The esketamine-treated patients demonstrated a mean reduction of 16.4 and 15.7 points, respectively, in the two trials, which was 3.82 points greater than in the pooled placebo group. This represents a clinically meaningful and statistically significant between-group difference.
The treatment effect size was even larger in some of the prespecified patient subgroups. Dr. Canuso drew attention to two key groups: In the roughly 60% of ASPIRE participants with a prior suicide attempt, esketamine resulted in a mean 4.81-point greater reduction in MADRS total score than placebo, and in the nearly 30% of participants with a suicide attempt during the past month, the difference was 5.22 points.
A word on the study design: Patients received intranasal esketamine at 84 mg per dose or placebo in double-blind fashion twice weekly for 4 weeks, thereby giving time for their oral antidepressant therapy to kick in, and were then followed on the conventional therapy out to 90 days.
A between-group difference in MADRS total score in favor of the esketamine group was evident as early as 4 hours after the first dose and continued through day 25, the end of the double-blind treatment period, at which point 54% and 47% of the esketamine-plus-conventional-antidepressant groups in the two trials had achieved remission as defined by a MADRS score of 12 or less, as had about one-third of the control group.
The prespecified key secondary efficacy endpoint in ASPIRE-1 and -2 was change in the CGI-SS-R 24 hours after the first dose. Both the esketamine and placebo-treated patients experienced significant improvement in this domain, with a disappointing absence of between-group statistical significance.
“We think that this may be due to the effect of acute hospitalization in diffusing the suicidal crisis,” Dr. Canuso said.
She noted, however, that other suicidality indices did show significant improvement in the esketamine-treated group during assessments at 4 hours, 24 hours, and 25 days after the first dose. For example, the double-blind esketamine-treated patients were 2.62-fold more likely than controls to show a significant improvement in MADRS Suicidal Thoughts at 4 hours after dose number one, and 6.15 times more likely to do so 4 hours after their day-25 dose. The CGI structured physician assessments of suicide risk and frequency of suicidal thinking, as well as patient-reported frequency of suicidal thinking, showed consistent favorable numeric trends for improvement with esketamine, with odds ratios of 1.46-2.11 from 4 hours through 25 days, although those results generally failed to achieve statistical significance.
In terms of safety, the rate of serious adverse events was just under 12% in both the esketamine and placebo arms. As in earlier studies, the most common adverse events associated with the novel antidepressant were dizziness, dissociation, nausea, and sleepiness, all several-fold more frequent than with placebo.
Esketamine is the S-enantiomer of racemic ketamine. It’s a noncompetitive N-methyl-D-aspartate receptor antagonist.
Janssen, which already markets intranasal esketamine as Spravato in the United States for treatment-resistant depression, plans to file for an expanded indication on the basis of the ASPIRE-1 and -2 results. The Food and Drug Administration already has granted Breakthrough Therapy designation for research on esketamine for reduction of major depression symptoms in patients with active suicidal ideation.
The ASPIRE studies were funded by Janssen.
COPENHAGEN – Esketamine nasal spray achieved rapid reduction of major depressive disorder symptoms in patients at imminent risk for suicide in a pair of pivotal phase 3 clinical trials known as ASPIRE-1 and ASPIRE-2, Carla M. Canuso, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
These were groundbreaking studies, which addressed a major unmet need familiar to every mental health professional, given that more than 800,000 suicides per year occur worldwide. Standard antidepressants are of only limited value during the period of acute suicidal crisis because they take 4-6 weeks to work. Moreover, this population of seriously depressed and suicidal patients has been understudied.
“Patients with active suicidal ideation and intent are routinely excluded from antidepressant trials,” observed Dr. Canuso, a psychiatrist who serves as senior director of neuroscience clinical development at Janssen Research and Development in Titusville, N.J.
It’s very important for the field to know that we can actually study these patients safely and effectively in clinical trials,” she said.
ASPIRE-1 and -2 were identically designed, randomized, double-blind, placebo-controlled, multinational studies conducted in patients with moderate to severe major depressive disorder as evidenced by a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score of about 40, along with moderate to extreme active suicidal ideation and intent as assessed using the Clinical Global Impression-Severity of Suicidality-Revised (CGI-SS-R).
“These were all patients in psychiatric crisis seeking clinical care,” according to Dr. Canuso.
All 456 participants in the two phase 3 studies underwent an initial 5-14 days of psychiatric hospitalization, during which they began treatment with esketamine nasal spray at 84 mg twice weekly or placebo coupled with comprehensive standard of care, which included a newly initiated and/or optimized oral antidepressant regimen.
The primary endpoint in the two clinical trials was the change in MADRS total score 24 hours after the first dose of study medication. The esketamine-treated patients demonstrated a mean reduction of 16.4 and 15.7 points, respectively, in the two trials, which was 3.82 points greater than in the pooled placebo group. This represents a clinically meaningful and statistically significant between-group difference.
The treatment effect size was even larger in some of the prespecified patient subgroups. Dr. Canuso drew attention to two key groups: In the roughly 60% of ASPIRE participants with a prior suicide attempt, esketamine resulted in a mean 4.81-point greater reduction in MADRS total score than placebo, and in the nearly 30% of participants with a suicide attempt during the past month, the difference was 5.22 points.
A word on the study design: Patients received intranasal esketamine at 84 mg per dose or placebo in double-blind fashion twice weekly for 4 weeks, thereby giving time for their oral antidepressant therapy to kick in, and were then followed on the conventional therapy out to 90 days.
A between-group difference in MADRS total score in favor of the esketamine group was evident as early as 4 hours after the first dose and continued through day 25, the end of the double-blind treatment period, at which point 54% and 47% of the esketamine-plus-conventional-antidepressant groups in the two trials had achieved remission as defined by a MADRS score of 12 or less, as had about one-third of the control group.
The prespecified key secondary efficacy endpoint in ASPIRE-1 and -2 was change in the CGI-SS-R 24 hours after the first dose. Both the esketamine and placebo-treated patients experienced significant improvement in this domain, with a disappointing absence of between-group statistical significance.
“We think that this may be due to the effect of acute hospitalization in diffusing the suicidal crisis,” Dr. Canuso said.
She noted, however, that other suicidality indices did show significant improvement in the esketamine-treated group during assessments at 4 hours, 24 hours, and 25 days after the first dose. For example, the double-blind esketamine-treated patients were 2.62-fold more likely than controls to show a significant improvement in MADRS Suicidal Thoughts at 4 hours after dose number one, and 6.15 times more likely to do so 4 hours after their day-25 dose. The CGI structured physician assessments of suicide risk and frequency of suicidal thinking, as well as patient-reported frequency of suicidal thinking, showed consistent favorable numeric trends for improvement with esketamine, with odds ratios of 1.46-2.11 from 4 hours through 25 days, although those results generally failed to achieve statistical significance.
In terms of safety, the rate of serious adverse events was just under 12% in both the esketamine and placebo arms. As in earlier studies, the most common adverse events associated with the novel antidepressant were dizziness, dissociation, nausea, and sleepiness, all several-fold more frequent than with placebo.
Esketamine is the S-enantiomer of racemic ketamine. It’s a noncompetitive N-methyl-D-aspartate receptor antagonist.
Janssen, which already markets intranasal esketamine as Spravato in the United States for treatment-resistant depression, plans to file for an expanded indication on the basis of the ASPIRE-1 and -2 results. The Food and Drug Administration already has granted Breakthrough Therapy designation for research on esketamine for reduction of major depression symptoms in patients with active suicidal ideation.
The ASPIRE studies were funded by Janssen.
COPENHAGEN – Esketamine nasal spray achieved rapid reduction of major depressive disorder symptoms in patients at imminent risk for suicide in a pair of pivotal phase 3 clinical trials known as ASPIRE-1 and ASPIRE-2, Carla M. Canuso, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
These were groundbreaking studies, which addressed a major unmet need familiar to every mental health professional, given that more than 800,000 suicides per year occur worldwide. Standard antidepressants are of only limited value during the period of acute suicidal crisis because they take 4-6 weeks to work. Moreover, this population of seriously depressed and suicidal patients has been understudied.
“Patients with active suicidal ideation and intent are routinely excluded from antidepressant trials,” observed Dr. Canuso, a psychiatrist who serves as senior director of neuroscience clinical development at Janssen Research and Development in Titusville, N.J.
It’s very important for the field to know that we can actually study these patients safely and effectively in clinical trials,” she said.
ASPIRE-1 and -2 were identically designed, randomized, double-blind, placebo-controlled, multinational studies conducted in patients with moderate to severe major depressive disorder as evidenced by a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score of about 40, along with moderate to extreme active suicidal ideation and intent as assessed using the Clinical Global Impression-Severity of Suicidality-Revised (CGI-SS-R).
“These were all patients in psychiatric crisis seeking clinical care,” according to Dr. Canuso.
All 456 participants in the two phase 3 studies underwent an initial 5-14 days of psychiatric hospitalization, during which they began treatment with esketamine nasal spray at 84 mg twice weekly or placebo coupled with comprehensive standard of care, which included a newly initiated and/or optimized oral antidepressant regimen.
The primary endpoint in the two clinical trials was the change in MADRS total score 24 hours after the first dose of study medication. The esketamine-treated patients demonstrated a mean reduction of 16.4 and 15.7 points, respectively, in the two trials, which was 3.82 points greater than in the pooled placebo group. This represents a clinically meaningful and statistically significant between-group difference.
The treatment effect size was even larger in some of the prespecified patient subgroups. Dr. Canuso drew attention to two key groups: In the roughly 60% of ASPIRE participants with a prior suicide attempt, esketamine resulted in a mean 4.81-point greater reduction in MADRS total score than placebo, and in the nearly 30% of participants with a suicide attempt during the past month, the difference was 5.22 points.
A word on the study design: Patients received intranasal esketamine at 84 mg per dose or placebo in double-blind fashion twice weekly for 4 weeks, thereby giving time for their oral antidepressant therapy to kick in, and were then followed on the conventional therapy out to 90 days.
A between-group difference in MADRS total score in favor of the esketamine group was evident as early as 4 hours after the first dose and continued through day 25, the end of the double-blind treatment period, at which point 54% and 47% of the esketamine-plus-conventional-antidepressant groups in the two trials had achieved remission as defined by a MADRS score of 12 or less, as had about one-third of the control group.
The prespecified key secondary efficacy endpoint in ASPIRE-1 and -2 was change in the CGI-SS-R 24 hours after the first dose. Both the esketamine and placebo-treated patients experienced significant improvement in this domain, with a disappointing absence of between-group statistical significance.
“We think that this may be due to the effect of acute hospitalization in diffusing the suicidal crisis,” Dr. Canuso said.
She noted, however, that other suicidality indices did show significant improvement in the esketamine-treated group during assessments at 4 hours, 24 hours, and 25 days after the first dose. For example, the double-blind esketamine-treated patients were 2.62-fold more likely than controls to show a significant improvement in MADRS Suicidal Thoughts at 4 hours after dose number one, and 6.15 times more likely to do so 4 hours after their day-25 dose. The CGI structured physician assessments of suicide risk and frequency of suicidal thinking, as well as patient-reported frequency of suicidal thinking, showed consistent favorable numeric trends for improvement with esketamine, with odds ratios of 1.46-2.11 from 4 hours through 25 days, although those results generally failed to achieve statistical significance.
In terms of safety, the rate of serious adverse events was just under 12% in both the esketamine and placebo arms. As in earlier studies, the most common adverse events associated with the novel antidepressant were dizziness, dissociation, nausea, and sleepiness, all several-fold more frequent than with placebo.
Esketamine is the S-enantiomer of racemic ketamine. It’s a noncompetitive N-methyl-D-aspartate receptor antagonist.
Janssen, which already markets intranasal esketamine as Spravato in the United States for treatment-resistant depression, plans to file for an expanded indication on the basis of the ASPIRE-1 and -2 results. The Food and Drug Administration already has granted Breakthrough Therapy designation for research on esketamine for reduction of major depression symptoms in patients with active suicidal ideation.
The ASPIRE studies were funded by Janssen.
REPORTING FROM ECNP 2019
ISAR-REACT 5: Prasugrel superior to ticagrelor in ACS
PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.
The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.
The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.
“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.
“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”
ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.
The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.
Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.
Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.
The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.
Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”
In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.
The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.
The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.
“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.
Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.
Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).
PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.
The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.
The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.
“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.
“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”
ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.
The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.
Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.
Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.
The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.
Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”
In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.
The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.
The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.
“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.
Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.
Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).
PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.
The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.
The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.
“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.
“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”
ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.
The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.
Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.
Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.
The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.
Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”
In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.
The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.
The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.
“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.
Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.
Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).
REPORTING FROM THE ESC CONGRESS 2019
Plasma exchange in natalizumab-related PML shows no benefit, possible harm
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
REPORTING FROM ECTRIMS 2019
Key clinical point: Plasma exchange has no clinical benefit in natalizumab-associated progressive multifocal leukoencephalopathy (PML).
Major finding: The risk of composite endpoint of death or an Expanded Disability Status Scale of 7.0 or more at follow-up 2 years after a natalizumab-associated PML diagnosis was an adjusted 168% greater in multiple sclerosis patients who underwent plasma exchange than in those who did not.
Study details: A retrospective analysis of the records of 723 multiple sclerosis patients with confirmed natalizumab-associated PML.
Disclosures: The study was funded by Biogen. The presenter reported receiving research grants from and serving as an advisor to Biogen and several other pharmaceutical companies.
Source: McGuigan C et al. ECTRIMS 2019, Abstract 63.
Newer drugs provide superior disease activity control in pediatric MS
STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.
This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.
Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).
Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.
The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.
The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.
“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.
Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.
Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.
“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.
The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.
In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.
The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.
Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.
The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.
STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.
This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.
Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).
Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.
The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.
The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.
“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.
Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.
Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.
“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.
The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.
In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.
The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.
Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.
The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.
STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.
This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.
Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).
Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.
The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.
The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.
“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.
Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.
Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.
“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.
The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.
In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.
The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.
Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.
The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.
REPORTING FROM ECTRIMS 2019
Most patients with RIS develop MS within 10 years
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
REPORTING FROM ECTRIMS 2019
Neurologists need not discourage breastfeeding in women with MS
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
EXPERT ANALYSIS FROM ECTRIMS 2019
Statins may do double duty as antidepressants
COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.
Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.
SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.
For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).
His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).
All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.
Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.
Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).
He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.
The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.
Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).
Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).
“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.
All speakers reported having no financial conflicts of interest.
COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.
Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.
SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.
For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).
His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).
All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.
Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.
Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).
He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.
The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.
Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).
Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).
“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.
All speakers reported having no financial conflicts of interest.
COPENHAGEN – The tantalizing prospect that statins could be repurposed as adjunctive antidepressant drugs in a defined subgroup of patients with major depression is finally about to undergo rigorous testing.
Several lines of preliminary evidence, including large observational cohort studies as well as three small, short-duration randomized trials, suggest that this might indeed be the case. It’s an extremely attractive possibility, since patients and physicians wish that antidepressant therapy were more effective, statins are among the most widely prescribed drugs worldwide, and their safety profile is thoroughly established. The expectation is that a definitive answer as to whether repurposing of statins as antidepressants is worthwhile will be provided by the SIMCODE trial, recently approved for funding by the German Federal Ministry of Education and Research, Christian Otte, MD, announced at the annual congress of the European College of Neuropsychopharmacology.
SIMCODE is a multicenter, double-blind, placebo-controlled randomized trial to be conducted at eight German academic medical centers. Participants, all of whom must have major depressive disorder and comorbid obesity, will be randomized to simvastatin or placebo on top of standard antidepressant therapy with escitalopram, an SSRI which, like simvastatin, is available as a relatively inexpensive generic, explained Dr. Otte, professor and vice director of the department of psychiatry and psychotherapy at Charite University in Berlin.
For Dr. Otte, SIMCODE will close a circle he helped open with his 2012 report from the Heart and Soul Study, a prospective longitudinal study of nearly 1,000 San Francisco Bay Area patients with coronary heart disease who were assessed annually for depressive symptoms for 6 years. The 65% of patients who were on statin therapy, albeit in nonrandomized fashion, had an adjusted 38% lower risk of developing depression (J Clin Psychiatry. 2012 May;73[5]:610-5).
His was one of seven observational studies involving more than 9,000 patients included in a subsequent meta-analysis showing that statin users were 37% less likely to develop depression than were nonusers (J Affect Disord. 2014 May;160:62-7).
All agreed that the verdict isn’t in yet as to statins’ effectiveness as adjunctive antidepressants, and that the subgroup of patients with major depression who are most likely to gain added antidepressive effect from a statin are those with what the speakers variously described as comorbid cardiometabolic disease, immunometabolic disease, or simply, as in SIMCODE, obesity. These are patients with a high degree of systemic inflammation, which often makes their depression less responsive to standard antidepressant therapies. The working hypothesis is that the pleiotropic anti-inflammatory effects of statins will result in a greater response to conventional antidepressants.
Animal studies point to multiple potential mechanisms by which statins might have antidepressant efficacy in clinical practice, according to Dr. Otte. Beyond their anti-inflammatory effects, these include the drugs’ documented effects on glutamatergic N-methyl-D-aspartate (NMDA) receptors, dopamine receptors, brain-derived neurotrophic factor, glucocorticoid receptors, and hippocampal serotonin 2A receptors.
Ole Kohler, MD, a psychiatrist at Aarhus (Denmark) University, presented highlights of his eye-popping population-based study of more than 872,000 Danes on an SSRI in 1997-2012, more than 113,000 of whom were on a concomitant statin. The key finding: During roughly 3 years of follow-up, the risk of contact with a psychiatric hospital for depression was 36% lower in the group on concomitant SSRI/statin therapy than in those not on a statin (Am J Psychiatry. 2016 Aug 1;173[8]:807-15).
He was quick to observe that a study such as this is vulnerable to various forms of confounding. This risk can be mitigated to a considerable extent by careful propensity score matching. Of note, however, none of the three studies that have been conducted with propensity score matching, including his own recent study of nearly 194,000 statin users and an equal number of matched nonusers, showed a difference in risk of depression between statin users and nonusers. All three studies were performed in general populations without known depression, leading Dr. Kohler to conclude that it’s unlikely that statins have a role in preventing depression in nondepressed individuals.
The focus should instead be on the possible role of statins in reducing the risk of depression in patients with cardiometabolic disease – that is, heart disease, metabolic syndrome, or type 2 diabetes – where more than a half-dozen cohort studies, including the Heart and Soul Study, have found that statins have a favorable impact, he added.
Estela Salagre, MD, a psychiatrist at the University of Barcelona, has carried out a meta-analysis of the three randomized, double-blind, placebo-controlled trials of add-on statin therapy in patients on standard therapies for moderate to severe depression published to date. She found that statin therapy was associated with a 27% greater reduction in scores on the Hamilton Depression Rating Scale, compared with placebo (J Affect Disord. 2016 Aug;200:235-42). Those findings recently were confirmed in a separate meta-analysis by other investigators using different methodologies (J Affect Disord. 2019 Oct 1;257:55-63).
Femke Lamers, PhD, presented evidence based on the nearly 3,000-subject longitudinal Netherlands Study of Depression and Anxiety that roughly one-quarter of individuals with major depressive disorder have a distinct subtype of nonmelancholic depression characterized by a clustering of obesity, inflammation, increased appetite, fatigue, hypersomnia, and increased levels of insulin and leptin. She calls it immunometabolic depression. She and her coinvestigators in the international Psychiatric Genomics Consortium have demonstrated that this phenotypic clustering is associated with a shared genetic vulnerability between major depression and obesity (JAMA Psychiatry. 2017 Dec 1;74[12]:1214-25).
“Major depressive disorder is not a one-size-fits-all disorder. There is an immunometabolic form of depression,” declared Dr. Lamers, an epidemiologist at the University of Amsterdam.
All speakers reported having no financial conflicts of interest.
REPORTING FROM ECNP 2019
Oral drug for postpartum depression aces phase 3 trial
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
REPORTING FROM THE ECNP 2019
POP AGE shakes up DAPT in elderly
PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.
“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.
This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.
Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.
“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.
The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.
The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.
The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.
In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.
“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.
POP AGE is hailed as ‘a wake up call’
In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”
“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.
Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.
“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”
So is POP AGE a practice-changing study?
“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”
“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.
Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
SOURCE: Gimbel ME. ESC 2019, Abstract 84.
PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.
“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.
This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.
Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.
“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.
The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.
The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.
The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.
In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.
“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.
POP AGE is hailed as ‘a wake up call’
In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”
“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.
Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.
“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”
So is POP AGE a practice-changing study?
“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”
“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.
Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
SOURCE: Gimbel ME. ESC 2019, Abstract 84.
PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.
“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.
This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.
Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.
“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.
The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.
The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.
The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.
In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.
“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.
POP AGE is hailed as ‘a wake up call’
In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”
“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.
Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.
“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”
So is POP AGE a practice-changing study?
“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”
“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.
Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
SOURCE: Gimbel ME. ESC 2019, Abstract 84.
AT THE ESC CONGRESS 2019
Key clinical point:
Major finding: The rate of major and minor bleeding was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk.
Study details: POPular AGE, an 11-center Dutch RCT, included 1,003 patients age 70 or older with non-ST-elevation ACS.
Disclosures: The presenter reported having no financial conflicts regarding the study, funded by the Dutch government.
Source: Gimbel ME. ESC 2019, Abstract 84.
Cerliponase alfa continues to impress for CLN2 disease
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
REPORTING FROM IEC 2019