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SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
REPORTING FROM THE AHS ANNUAL MEETING