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SAN FRANCISCO – Galcanezumab, the investigational calcitonin gene-related peptide inhibitor under development as preventive therapy for migraine, looks like a triple threat: Multiple phase 3 randomized trials have not only demonstrated safety and efficacy of the monoclonal antibody for prevention of both episodic and chronic migraine but for prevention of episodic cluster headache as well.
Galcanezumab’s demonstrated preventive benefit in patients with episodic cluster headache, if confirmed, would be a big deal. This type of headache is far less common than migraine, but often characterized as not merely debilitating but devastating. Phase 3 evidence of galcanezumab’s safety and efficacy for prevention of episodic cluster headache constitutes a unique advantage over fremanezumab and eptinezumab, the other two monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) for which new phase 3 data were presented at the annual meeting of the American Headache Society. But the latter two novel agents showed advantages of their own.
While the efficacy of the CGRP inhibitors isn’t light-years ahead of the long-standard preventive therapies for migraine, such as topiramate, beta-blockers, antidepressants, and valproate, the new agents offer far greater tolerability and safety – side effect profiles are essentially the same as for placebo except for a modest increase in mild injection site reactions – along with documented substantial quality of life improvements using validated measures. And onset of benefit is far more rapid than with the long-time standard oral preventive medications.
Here are the highlights from the AHS annual meeting:
Galcanezumab
Sheena K. Aurora, MD, presented the results of the GCAL study, a phase 3 randomized, double-blind, 8-week study of subcutaneous galcanezumab at 300 mg once monthly or placebo administered for 2 months in 106 patients with ongoing episodic cluster headache attacks at baseline.
“This is really uncharted territory. The American Headache Society, in its 2016 cluster headache guidelines, reported that there was no high-quality evidence for prophylactic therapy,” noted Dr. Aurora of Eli Lilly in Indianapolis.
After the GCAL study, that’s no longer true. Study participants were a typical population of episodic cluster headache patients: that is, mostly middle-aged men. They averaged more than 17 cluster headache attacks per week during the baseline period, or 2-3 daily, with roughly a 16-year history of episodic cluster headaches, which typically occur in bursts lasting 6-8 weeks before temporarily fading. Of note, 14 of the 106 patients reported a history of prior suicidal ideation; while disturbing, that’s actually a lower rate than in some epidemiologic studies examining patients with this excruciating form of head pain.
The primary endpoint was the mean change in weekly cluster headache attack frequency during weeks 1-3. The difference was significant: a reduction of 8.7 attacks per week in the galcanezumab group, compared with 5.2 fewer in controls. The key secondary endpoint was the proportion of patients with at least a 50% reduction in weekly cluster attack frequency from baseline at week 3: This was achieved in 76% in the galcanezumab arm, versus 57% for placebo, again a significant difference.
At week 4, 73% of patients on galcanezumab rated themselves as very much or much better on the Patient Global Impression of Improvement, significantly greater than the 46% rate in controls. By week 8, this difference – while trending favorably – was no longer statistically significant, but it must be noted that by then 8 of the original 57 patients randomized to placebo had discontinued treatment because of the lack of efficacy, compared with just 1 of 49 in the galcanezumab group.
Adverse events in the two treatment arms were essentially the same as placebo except for an 8% rate of mild injection site reactions in the active treatment group.
Another double-blind, placebo-controlled phase 3 trial known as the CGAM study was conducted in 237 patients with chronic rather than episodic cluster headache. However, it proved negative for the same endpoints, Dr. Aurora said.
Separately, she presented a new post hoc analysis of the recently published EVOLVE-1 (JAMA Neurol. 2018 May 29. doi: 10.1001/jamaneurol.2018.1212) and EVOLVE-2 (Cephalalgia. 2018 Jul;38[8]:1442-54) trials. These two mirror-image pivotal phase 3, double-blind, placebo-controlled, 6-month studies of galcanezumab at 120 or 240 mg once monthly included a collective 1,773 episodic migraine patients with a baseline mean of 9.1 migraine headache days per month. Her analysis focused on the rapidity of onset of the humanized monoclonal antibody’s preventive effect.
“As most clinicians are aware, the current oral preventive treatments that we use require titration, and we don’t really see a good effect for maybe 2-3 months,” she observed.
In an ordinal logistic regression analysis, she and her coinvestigators first determined that the galcanezumab group separated from placebo in terms of reduced migraine headache days as early as 1 month in both studies. Next, they drilled down deeper into the participants’ daily headache diaries and determined that the onset of effect was seen at week 1, at which point the odds of a significant reduction in weekly migraine headache days were 2.71-fold greater with galcanezumab than placebo in EVOLVE-1 and 2.88-fold greater in EVOLVE-2.
“Patients would like to know how quickly they might see an effect, so the fact that we start seeing it for patients who’ve had migraine for 20 years with an average of 9.1 migraine headache days per month as early as week 1 is gratifying, even though the absolute numbers who benefit at that point are small,” Dr. Aurora said.
Fremanezumab
Fremanezumab is a fully humanized monoclonal antibody selectively targeting CGRP. Like galcanezumab and eptinezumab, it is now supported by phase 3 data from short-term, double-blind, placebo-controlled trials backed up by reassuring results from long-term, open-label studies.
During the 28 days prior to the start of the long-term, double-blind study, the chronic migraine patients averaged 16.4 migraine days, while the episodic migraine patients averaged 9.2. After 6 months on their assigned dosing regimen, the episodic migraine patients in the 225 mg monthly group had a mean 4.9 fewer monthly migraine days than at baseline, and the 675 mg quarterly group averaged 5.0 fewer days. The chronic migraine patients on 225 mg monthly had a mean 7.9-day reduction, while the 675 mg quarterly group averaged a 6.5-day reduction in monthly migraine days.
The key point in this interim analysis is that these clinically meaningful reductions in monthly number of migraine days at 6 months were of the same magnitude as at month 1, demonstrating solid maintenance of efficacy over time, noted Dr. Goadsby, professor of neurology at the University of California, San Francisco, and AHS president-elect.
Jessica Ailani, MD, presented evidence that fremanezumab is not only an effective migraine preventive therapy, it also shows potential as a medication for reversion from chronic migraine to episodic migraine.
She presented a post hoc analysis of the 1,130 chronic migraine patients who participated in the 12-week, placebo-controlled HALO CM trial. Thirty-two percent of them who were randomized to 675 mg of fremanezumab quarterly reverted from chronic to episodic migraine, meaning they had fewer than 15 headache days per month during all 3 months of the treatment period. So did 35% of patients who received 225 mg monthly. Both results were significantly better than the 23% placebo reversion rate, which is consistent with the effect of placebo in other studies.
The mean number of monthly headache days of at least moderate severity fell by 4.3 days from baseline in the fremanezumab quarterly group and by 4.6 with monthly therapy, significantly outperforming the 2.5-day reduction with placebo. And the patients who did well did very well indeed: those who reverted from chronic to episodic migraine went from a mean of 18-19 headache days per month at baseline to about 7 days during any month in the treatment period, she reported.
Two patients on 675 mg of fremanezumab quarterly developed antidrug antibodies.
Patients with MOH at baseline experienced a mean reduction of 4.7 headache days of at least moderate severity per month on fremanezumab at 675 mg quarterly and a 5.2-day reduction with monthly fremanezumab, both significantly better than the 2.5-day reduction with placebo. A total of 35% of the fremanezumab quarterly group achieved a 50% or greater reduction in the monthly average number of at least moderately severe headaches, as did 39% of patients on monthly fremanezumab and 14% on placebo.
Moreover, during the 12-week study period, 55% of patients with MOH at baseline who were on fremanezumab quarterly reported no medication overuse, as did 61% of those on 225 mg of fremanezumab once monthly and 46% of controls, according to Dr. Silberstein, professor of neurology and director of the headache center at Thomas Jefferson University in Philadelphia.
For the 1,034 participants who completed testing, the average baseline HIT-6 score was 64 points on a test that can range from 36-78, with higher scores indicating greater adverse impact. At repeat testing 4 weeks after the last dose, the quarterly dosing group showed a statistically significant and clinically meaningful 6.4-point reduction from baseline, and the monthly fremanezumab group had a 6.8-point reduction. Both of those outcomes were significantly better than the placebo group’s 4.5-point decrease, reported Dr. Winner, director of Palm Beach Neurology in West Palm Beach, Fla.
Those HIT-6 changes in fremanezumab-treated patients moved them from the severe disability category to moderate disability, he noted.
“We also evaluated other disability components in this study. The MSQ – the Migraine Specific Quality-of-Life Questionnaire – also showed significant improvement by patient assessment, and on a patient global assessment measure, over 50% of patients who got fremanezumab noted improvement in that 12-week study, getting back to work, functioning normally, etc.,” the neurologist added.
Eptinezumab
Unlike other anti-CGRP antibodies, eptinezumab is administered intravenously, once every 3 months, rather than by subcutaneous injection. This IgG1 anti-CGRP monoclonal antibody was engineered for reduced immune activation and a 30-day half-life. It’s onset of action is extremely rapid, with 100% of the agent being bioavailable within a few hours after administration.
The positive 12-week outcomes of the phase 3 randomized, double-blind, placebo-controlled PROMISE-2 trial of eptinezumab for prophylaxis against chronic migraine have previously been presented, as have the 1-year results in episodic migraine patients in PROMISE-1.
Of those on the higher dose of eptinezumab, 33% had at least a 75% reduction in monthly migraine days from baseline, a figure that climbed to 43% after the second infusion; and of those who received eptinezumab at the 300-mg dose, 61% experienced a 50% or greater reduction in monthly migraine days from baseline during weeks 1-12, as did 64% during weeks 13-24 following a second infusion.
A key secondary endpoint in PROMISE-2 was the proportion of patients having a migraine on any given day. During the 28-day baseline period, that figure was 58%. But the day after the first infusion that proportion dropped to 28% in both the eptinezumab 100- and 300-mg groups, and that rate held through the next 12 weeks. In contrast, roughly 45% of placebo-treated controls had a migraine on any given day during the 12 weeks.
“The key thing is on the day following infusion you have established pretty much the full preventive value of eptinezumab, and it is maintained stable all the way through 12 weeks,” according to Dr. Cady, vice president of neurology at Alder BioPharmaceuticals, which is developing the biologic.
When an audience member remarked on the placebo response rates in the CRGP inhibitor studies and indeed in clinical trials in migraine generally, Dr. Cady responded with one of the meeting’s more memorable comments: “If placebo brought you to the dance, you’re still at the party.”
Dr. Winner reported serving as a consultant to Alder BioPharmaceuticals, which sponsored the HALO trials and is developing eptinezumab, as well as to numerous other pharmaceutical companies. Similarly, Dr. Goadsby, Dr. Ailani, and Dr. Silberstein are consultants to many companies, including Teva Pharmaceuticals, which is developing fremanezumab.
SAN FRANCISCO – Galcanezumab, the investigational calcitonin gene-related peptide inhibitor under development as preventive therapy for migraine, looks like a triple threat: Multiple phase 3 randomized trials have not only demonstrated safety and efficacy of the monoclonal antibody for prevention of both episodic and chronic migraine but for prevention of episodic cluster headache as well.
Galcanezumab’s demonstrated preventive benefit in patients with episodic cluster headache, if confirmed, would be a big deal. This type of headache is far less common than migraine, but often characterized as not merely debilitating but devastating. Phase 3 evidence of galcanezumab’s safety and efficacy for prevention of episodic cluster headache constitutes a unique advantage over fremanezumab and eptinezumab, the other two monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) for which new phase 3 data were presented at the annual meeting of the American Headache Society. But the latter two novel agents showed advantages of their own.
While the efficacy of the CGRP inhibitors isn’t light-years ahead of the long-standard preventive therapies for migraine, such as topiramate, beta-blockers, antidepressants, and valproate, the new agents offer far greater tolerability and safety – side effect profiles are essentially the same as for placebo except for a modest increase in mild injection site reactions – along with documented substantial quality of life improvements using validated measures. And onset of benefit is far more rapid than with the long-time standard oral preventive medications.
Here are the highlights from the AHS annual meeting:
Galcanezumab
Sheena K. Aurora, MD, presented the results of the GCAL study, a phase 3 randomized, double-blind, 8-week study of subcutaneous galcanezumab at 300 mg once monthly or placebo administered for 2 months in 106 patients with ongoing episodic cluster headache attacks at baseline.
“This is really uncharted territory. The American Headache Society, in its 2016 cluster headache guidelines, reported that there was no high-quality evidence for prophylactic therapy,” noted Dr. Aurora of Eli Lilly in Indianapolis.
After the GCAL study, that’s no longer true. Study participants were a typical population of episodic cluster headache patients: that is, mostly middle-aged men. They averaged more than 17 cluster headache attacks per week during the baseline period, or 2-3 daily, with roughly a 16-year history of episodic cluster headaches, which typically occur in bursts lasting 6-8 weeks before temporarily fading. Of note, 14 of the 106 patients reported a history of prior suicidal ideation; while disturbing, that’s actually a lower rate than in some epidemiologic studies examining patients with this excruciating form of head pain.
The primary endpoint was the mean change in weekly cluster headache attack frequency during weeks 1-3. The difference was significant: a reduction of 8.7 attacks per week in the galcanezumab group, compared with 5.2 fewer in controls. The key secondary endpoint was the proportion of patients with at least a 50% reduction in weekly cluster attack frequency from baseline at week 3: This was achieved in 76% in the galcanezumab arm, versus 57% for placebo, again a significant difference.
At week 4, 73% of patients on galcanezumab rated themselves as very much or much better on the Patient Global Impression of Improvement, significantly greater than the 46% rate in controls. By week 8, this difference – while trending favorably – was no longer statistically significant, but it must be noted that by then 8 of the original 57 patients randomized to placebo had discontinued treatment because of the lack of efficacy, compared with just 1 of 49 in the galcanezumab group.
Adverse events in the two treatment arms were essentially the same as placebo except for an 8% rate of mild injection site reactions in the active treatment group.
Another double-blind, placebo-controlled phase 3 trial known as the CGAM study was conducted in 237 patients with chronic rather than episodic cluster headache. However, it proved negative for the same endpoints, Dr. Aurora said.
Separately, she presented a new post hoc analysis of the recently published EVOLVE-1 (JAMA Neurol. 2018 May 29. doi: 10.1001/jamaneurol.2018.1212) and EVOLVE-2 (Cephalalgia. 2018 Jul;38[8]:1442-54) trials. These two mirror-image pivotal phase 3, double-blind, placebo-controlled, 6-month studies of galcanezumab at 120 or 240 mg once monthly included a collective 1,773 episodic migraine patients with a baseline mean of 9.1 migraine headache days per month. Her analysis focused on the rapidity of onset of the humanized monoclonal antibody’s preventive effect.
“As most clinicians are aware, the current oral preventive treatments that we use require titration, and we don’t really see a good effect for maybe 2-3 months,” she observed.
In an ordinal logistic regression analysis, she and her coinvestigators first determined that the galcanezumab group separated from placebo in terms of reduced migraine headache days as early as 1 month in both studies. Next, they drilled down deeper into the participants’ daily headache diaries and determined that the onset of effect was seen at week 1, at which point the odds of a significant reduction in weekly migraine headache days were 2.71-fold greater with galcanezumab than placebo in EVOLVE-1 and 2.88-fold greater in EVOLVE-2.
“Patients would like to know how quickly they might see an effect, so the fact that we start seeing it for patients who’ve had migraine for 20 years with an average of 9.1 migraine headache days per month as early as week 1 is gratifying, even though the absolute numbers who benefit at that point are small,” Dr. Aurora said.
Fremanezumab
Fremanezumab is a fully humanized monoclonal antibody selectively targeting CGRP. Like galcanezumab and eptinezumab, it is now supported by phase 3 data from short-term, double-blind, placebo-controlled trials backed up by reassuring results from long-term, open-label studies.
During the 28 days prior to the start of the long-term, double-blind study, the chronic migraine patients averaged 16.4 migraine days, while the episodic migraine patients averaged 9.2. After 6 months on their assigned dosing regimen, the episodic migraine patients in the 225 mg monthly group had a mean 4.9 fewer monthly migraine days than at baseline, and the 675 mg quarterly group averaged 5.0 fewer days. The chronic migraine patients on 225 mg monthly had a mean 7.9-day reduction, while the 675 mg quarterly group averaged a 6.5-day reduction in monthly migraine days.
The key point in this interim analysis is that these clinically meaningful reductions in monthly number of migraine days at 6 months were of the same magnitude as at month 1, demonstrating solid maintenance of efficacy over time, noted Dr. Goadsby, professor of neurology at the University of California, San Francisco, and AHS president-elect.
Jessica Ailani, MD, presented evidence that fremanezumab is not only an effective migraine preventive therapy, it also shows potential as a medication for reversion from chronic migraine to episodic migraine.
She presented a post hoc analysis of the 1,130 chronic migraine patients who participated in the 12-week, placebo-controlled HALO CM trial. Thirty-two percent of them who were randomized to 675 mg of fremanezumab quarterly reverted from chronic to episodic migraine, meaning they had fewer than 15 headache days per month during all 3 months of the treatment period. So did 35% of patients who received 225 mg monthly. Both results were significantly better than the 23% placebo reversion rate, which is consistent with the effect of placebo in other studies.
The mean number of monthly headache days of at least moderate severity fell by 4.3 days from baseline in the fremanezumab quarterly group and by 4.6 with monthly therapy, significantly outperforming the 2.5-day reduction with placebo. And the patients who did well did very well indeed: those who reverted from chronic to episodic migraine went from a mean of 18-19 headache days per month at baseline to about 7 days during any month in the treatment period, she reported.
Two patients on 675 mg of fremanezumab quarterly developed antidrug antibodies.
Patients with MOH at baseline experienced a mean reduction of 4.7 headache days of at least moderate severity per month on fremanezumab at 675 mg quarterly and a 5.2-day reduction with monthly fremanezumab, both significantly better than the 2.5-day reduction with placebo. A total of 35% of the fremanezumab quarterly group achieved a 50% or greater reduction in the monthly average number of at least moderately severe headaches, as did 39% of patients on monthly fremanezumab and 14% on placebo.
Moreover, during the 12-week study period, 55% of patients with MOH at baseline who were on fremanezumab quarterly reported no medication overuse, as did 61% of those on 225 mg of fremanezumab once monthly and 46% of controls, according to Dr. Silberstein, professor of neurology and director of the headache center at Thomas Jefferson University in Philadelphia.
For the 1,034 participants who completed testing, the average baseline HIT-6 score was 64 points on a test that can range from 36-78, with higher scores indicating greater adverse impact. At repeat testing 4 weeks after the last dose, the quarterly dosing group showed a statistically significant and clinically meaningful 6.4-point reduction from baseline, and the monthly fremanezumab group had a 6.8-point reduction. Both of those outcomes were significantly better than the placebo group’s 4.5-point decrease, reported Dr. Winner, director of Palm Beach Neurology in West Palm Beach, Fla.
Those HIT-6 changes in fremanezumab-treated patients moved them from the severe disability category to moderate disability, he noted.
“We also evaluated other disability components in this study. The MSQ – the Migraine Specific Quality-of-Life Questionnaire – also showed significant improvement by patient assessment, and on a patient global assessment measure, over 50% of patients who got fremanezumab noted improvement in that 12-week study, getting back to work, functioning normally, etc.,” the neurologist added.
Eptinezumab
Unlike other anti-CGRP antibodies, eptinezumab is administered intravenously, once every 3 months, rather than by subcutaneous injection. This IgG1 anti-CGRP monoclonal antibody was engineered for reduced immune activation and a 30-day half-life. It’s onset of action is extremely rapid, with 100% of the agent being bioavailable within a few hours after administration.
The positive 12-week outcomes of the phase 3 randomized, double-blind, placebo-controlled PROMISE-2 trial of eptinezumab for prophylaxis against chronic migraine have previously been presented, as have the 1-year results in episodic migraine patients in PROMISE-1.
Of those on the higher dose of eptinezumab, 33% had at least a 75% reduction in monthly migraine days from baseline, a figure that climbed to 43% after the second infusion; and of those who received eptinezumab at the 300-mg dose, 61% experienced a 50% or greater reduction in monthly migraine days from baseline during weeks 1-12, as did 64% during weeks 13-24 following a second infusion.
A key secondary endpoint in PROMISE-2 was the proportion of patients having a migraine on any given day. During the 28-day baseline period, that figure was 58%. But the day after the first infusion that proportion dropped to 28% in both the eptinezumab 100- and 300-mg groups, and that rate held through the next 12 weeks. In contrast, roughly 45% of placebo-treated controls had a migraine on any given day during the 12 weeks.
“The key thing is on the day following infusion you have established pretty much the full preventive value of eptinezumab, and it is maintained stable all the way through 12 weeks,” according to Dr. Cady, vice president of neurology at Alder BioPharmaceuticals, which is developing the biologic.
When an audience member remarked on the placebo response rates in the CRGP inhibitor studies and indeed in clinical trials in migraine generally, Dr. Cady responded with one of the meeting’s more memorable comments: “If placebo brought you to the dance, you’re still at the party.”
Dr. Winner reported serving as a consultant to Alder BioPharmaceuticals, which sponsored the HALO trials and is developing eptinezumab, as well as to numerous other pharmaceutical companies. Similarly, Dr. Goadsby, Dr. Ailani, and Dr. Silberstein are consultants to many companies, including Teva Pharmaceuticals, which is developing fremanezumab.
SAN FRANCISCO – Galcanezumab, the investigational calcitonin gene-related peptide inhibitor under development as preventive therapy for migraine, looks like a triple threat: Multiple phase 3 randomized trials have not only demonstrated safety and efficacy of the monoclonal antibody for prevention of both episodic and chronic migraine but for prevention of episodic cluster headache as well.
Galcanezumab’s demonstrated preventive benefit in patients with episodic cluster headache, if confirmed, would be a big deal. This type of headache is far less common than migraine, but often characterized as not merely debilitating but devastating. Phase 3 evidence of galcanezumab’s safety and efficacy for prevention of episodic cluster headache constitutes a unique advantage over fremanezumab and eptinezumab, the other two monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) for which new phase 3 data were presented at the annual meeting of the American Headache Society. But the latter two novel agents showed advantages of their own.
While the efficacy of the CGRP inhibitors isn’t light-years ahead of the long-standard preventive therapies for migraine, such as topiramate, beta-blockers, antidepressants, and valproate, the new agents offer far greater tolerability and safety – side effect profiles are essentially the same as for placebo except for a modest increase in mild injection site reactions – along with documented substantial quality of life improvements using validated measures. And onset of benefit is far more rapid than with the long-time standard oral preventive medications.
Here are the highlights from the AHS annual meeting:
Galcanezumab
Sheena K. Aurora, MD, presented the results of the GCAL study, a phase 3 randomized, double-blind, 8-week study of subcutaneous galcanezumab at 300 mg once monthly or placebo administered for 2 months in 106 patients with ongoing episodic cluster headache attacks at baseline.
“This is really uncharted territory. The American Headache Society, in its 2016 cluster headache guidelines, reported that there was no high-quality evidence for prophylactic therapy,” noted Dr. Aurora of Eli Lilly in Indianapolis.
After the GCAL study, that’s no longer true. Study participants were a typical population of episodic cluster headache patients: that is, mostly middle-aged men. They averaged more than 17 cluster headache attacks per week during the baseline period, or 2-3 daily, with roughly a 16-year history of episodic cluster headaches, which typically occur in bursts lasting 6-8 weeks before temporarily fading. Of note, 14 of the 106 patients reported a history of prior suicidal ideation; while disturbing, that’s actually a lower rate than in some epidemiologic studies examining patients with this excruciating form of head pain.
The primary endpoint was the mean change in weekly cluster headache attack frequency during weeks 1-3. The difference was significant: a reduction of 8.7 attacks per week in the galcanezumab group, compared with 5.2 fewer in controls. The key secondary endpoint was the proportion of patients with at least a 50% reduction in weekly cluster attack frequency from baseline at week 3: This was achieved in 76% in the galcanezumab arm, versus 57% for placebo, again a significant difference.
At week 4, 73% of patients on galcanezumab rated themselves as very much or much better on the Patient Global Impression of Improvement, significantly greater than the 46% rate in controls. By week 8, this difference – while trending favorably – was no longer statistically significant, but it must be noted that by then 8 of the original 57 patients randomized to placebo had discontinued treatment because of the lack of efficacy, compared with just 1 of 49 in the galcanezumab group.
Adverse events in the two treatment arms were essentially the same as placebo except for an 8% rate of mild injection site reactions in the active treatment group.
Another double-blind, placebo-controlled phase 3 trial known as the CGAM study was conducted in 237 patients with chronic rather than episodic cluster headache. However, it proved negative for the same endpoints, Dr. Aurora said.
Separately, she presented a new post hoc analysis of the recently published EVOLVE-1 (JAMA Neurol. 2018 May 29. doi: 10.1001/jamaneurol.2018.1212) and EVOLVE-2 (Cephalalgia. 2018 Jul;38[8]:1442-54) trials. These two mirror-image pivotal phase 3, double-blind, placebo-controlled, 6-month studies of galcanezumab at 120 or 240 mg once monthly included a collective 1,773 episodic migraine patients with a baseline mean of 9.1 migraine headache days per month. Her analysis focused on the rapidity of onset of the humanized monoclonal antibody’s preventive effect.
“As most clinicians are aware, the current oral preventive treatments that we use require titration, and we don’t really see a good effect for maybe 2-3 months,” she observed.
In an ordinal logistic regression analysis, she and her coinvestigators first determined that the galcanezumab group separated from placebo in terms of reduced migraine headache days as early as 1 month in both studies. Next, they drilled down deeper into the participants’ daily headache diaries and determined that the onset of effect was seen at week 1, at which point the odds of a significant reduction in weekly migraine headache days were 2.71-fold greater with galcanezumab than placebo in EVOLVE-1 and 2.88-fold greater in EVOLVE-2.
“Patients would like to know how quickly they might see an effect, so the fact that we start seeing it for patients who’ve had migraine for 20 years with an average of 9.1 migraine headache days per month as early as week 1 is gratifying, even though the absolute numbers who benefit at that point are small,” Dr. Aurora said.
Fremanezumab
Fremanezumab is a fully humanized monoclonal antibody selectively targeting CGRP. Like galcanezumab and eptinezumab, it is now supported by phase 3 data from short-term, double-blind, placebo-controlled trials backed up by reassuring results from long-term, open-label studies.
During the 28 days prior to the start of the long-term, double-blind study, the chronic migraine patients averaged 16.4 migraine days, while the episodic migraine patients averaged 9.2. After 6 months on their assigned dosing regimen, the episodic migraine patients in the 225 mg monthly group had a mean 4.9 fewer monthly migraine days than at baseline, and the 675 mg quarterly group averaged 5.0 fewer days. The chronic migraine patients on 225 mg monthly had a mean 7.9-day reduction, while the 675 mg quarterly group averaged a 6.5-day reduction in monthly migraine days.
The key point in this interim analysis is that these clinically meaningful reductions in monthly number of migraine days at 6 months were of the same magnitude as at month 1, demonstrating solid maintenance of efficacy over time, noted Dr. Goadsby, professor of neurology at the University of California, San Francisco, and AHS president-elect.
Jessica Ailani, MD, presented evidence that fremanezumab is not only an effective migraine preventive therapy, it also shows potential as a medication for reversion from chronic migraine to episodic migraine.
She presented a post hoc analysis of the 1,130 chronic migraine patients who participated in the 12-week, placebo-controlled HALO CM trial. Thirty-two percent of them who were randomized to 675 mg of fremanezumab quarterly reverted from chronic to episodic migraine, meaning they had fewer than 15 headache days per month during all 3 months of the treatment period. So did 35% of patients who received 225 mg monthly. Both results were significantly better than the 23% placebo reversion rate, which is consistent with the effect of placebo in other studies.
The mean number of monthly headache days of at least moderate severity fell by 4.3 days from baseline in the fremanezumab quarterly group and by 4.6 with monthly therapy, significantly outperforming the 2.5-day reduction with placebo. And the patients who did well did very well indeed: those who reverted from chronic to episodic migraine went from a mean of 18-19 headache days per month at baseline to about 7 days during any month in the treatment period, she reported.
Two patients on 675 mg of fremanezumab quarterly developed antidrug antibodies.
Patients with MOH at baseline experienced a mean reduction of 4.7 headache days of at least moderate severity per month on fremanezumab at 675 mg quarterly and a 5.2-day reduction with monthly fremanezumab, both significantly better than the 2.5-day reduction with placebo. A total of 35% of the fremanezumab quarterly group achieved a 50% or greater reduction in the monthly average number of at least moderately severe headaches, as did 39% of patients on monthly fremanezumab and 14% on placebo.
Moreover, during the 12-week study period, 55% of patients with MOH at baseline who were on fremanezumab quarterly reported no medication overuse, as did 61% of those on 225 mg of fremanezumab once monthly and 46% of controls, according to Dr. Silberstein, professor of neurology and director of the headache center at Thomas Jefferson University in Philadelphia.
For the 1,034 participants who completed testing, the average baseline HIT-6 score was 64 points on a test that can range from 36-78, with higher scores indicating greater adverse impact. At repeat testing 4 weeks after the last dose, the quarterly dosing group showed a statistically significant and clinically meaningful 6.4-point reduction from baseline, and the monthly fremanezumab group had a 6.8-point reduction. Both of those outcomes were significantly better than the placebo group’s 4.5-point decrease, reported Dr. Winner, director of Palm Beach Neurology in West Palm Beach, Fla.
Those HIT-6 changes in fremanezumab-treated patients moved them from the severe disability category to moderate disability, he noted.
“We also evaluated other disability components in this study. The MSQ – the Migraine Specific Quality-of-Life Questionnaire – also showed significant improvement by patient assessment, and on a patient global assessment measure, over 50% of patients who got fremanezumab noted improvement in that 12-week study, getting back to work, functioning normally, etc.,” the neurologist added.
Eptinezumab
Unlike other anti-CGRP antibodies, eptinezumab is administered intravenously, once every 3 months, rather than by subcutaneous injection. This IgG1 anti-CGRP monoclonal antibody was engineered for reduced immune activation and a 30-day half-life. It’s onset of action is extremely rapid, with 100% of the agent being bioavailable within a few hours after administration.
The positive 12-week outcomes of the phase 3 randomized, double-blind, placebo-controlled PROMISE-2 trial of eptinezumab for prophylaxis against chronic migraine have previously been presented, as have the 1-year results in episodic migraine patients in PROMISE-1.
Of those on the higher dose of eptinezumab, 33% had at least a 75% reduction in monthly migraine days from baseline, a figure that climbed to 43% after the second infusion; and of those who received eptinezumab at the 300-mg dose, 61% experienced a 50% or greater reduction in monthly migraine days from baseline during weeks 1-12, as did 64% during weeks 13-24 following a second infusion.
A key secondary endpoint in PROMISE-2 was the proportion of patients having a migraine on any given day. During the 28-day baseline period, that figure was 58%. But the day after the first infusion that proportion dropped to 28% in both the eptinezumab 100- and 300-mg groups, and that rate held through the next 12 weeks. In contrast, roughly 45% of placebo-treated controls had a migraine on any given day during the 12 weeks.
“The key thing is on the day following infusion you have established pretty much the full preventive value of eptinezumab, and it is maintained stable all the way through 12 weeks,” according to Dr. Cady, vice president of neurology at Alder BioPharmaceuticals, which is developing the biologic.
When an audience member remarked on the placebo response rates in the CRGP inhibitor studies and indeed in clinical trials in migraine generally, Dr. Cady responded with one of the meeting’s more memorable comments: “If placebo brought you to the dance, you’re still at the party.”
Dr. Winner reported serving as a consultant to Alder BioPharmaceuticals, which sponsored the HALO trials and is developing eptinezumab, as well as to numerous other pharmaceutical companies. Similarly, Dr. Goadsby, Dr. Ailani, and Dr. Silberstein are consultants to many companies, including Teva Pharmaceuticals, which is developing fremanezumab.
REPORTING FROM THE AHS ANNUAL MEETING