CGRP-targeted migraine prevention drugs succeed in phase II

Two investigational migraine prevention drugs that target a vasodilating peptide significantly decreased the number of migraine days per month, compared with placebo, during a pair of phase II studies.

Both drugs reduced mean migraine headache days per month by more than 4 days overall, and one even eliminated migraine in up to 30% of patients.

Each is a monoclonal antibody that inhibits calcitonin gene–related peptide (CGRP). Activated trigeminal sensory nerves release the peptide, which dilates intra- and extracranial blood vessels and modulates vascular nociception.

The antibodies could be game changers for migraine patients, Dr. Peter Goadsby said in an interview.

"Here are the first mechanism-based preventive treatments for migraine," said Dr. Goadsby of the University of California, San Francisco. "They are easy to use, biweekly or even monthly injections, which are effective and well tolerated. For neurologists it means the first major addition to the preventive armamentarium for a generation or more, and for patients, a tangible advance that they can look forward to enjoying soon."

During the annual meeting of the American Academy of Neurology, Dr. Goadsby will present the findings on ALD403, developed by Alder Biopharmaceuticals. His colleague Dr. David W. Dodick of the Mayo Clinic, Rochester, Minn., will present findings on LY2951742, which is being developed by Arteaus Therapeutics in conjunction with Eli Lily. Both presentations are scheduled for May 1.

The trial of ALD403 comprised 163 patients who experienced 5-14 migraine headache days per month; 81 were randomized to receive a single infusion of 1,000 mg ALD403 and the rest received placebo. Patients were followed for 24 weeks. The primary outcome was the mean change in migraine days between weeks 5-8 and baseline.

Patients in the active treatment group fared significantly better than those in the placebo group, with a mean reduction in migraine headache days of –5.6, compared to –4.6 for the placebo group (66% vs. 52% decrease).

Most patients taking the study drug had at least a 50% reduction in migraine headache days at 12 weeks (60% vs. 30%); the proportions of those with at least a 75% reduction were 32% vs. 9%. A 100% reduction occurred in 16% of the active group and in none of the placebo group. These differences were all statistically significant.

There were no differences in the type or frequency of adverse events, vital signs, or laboratory safety data between the two treatment groups.

The LY2951742 study was similarly successful. It comprised 217 patients who experienced 4-14 migraine headache days per month, said Dr. Dodick. They were randomized to placebo or to biweekly subcutaneous injections of LY2951742 150 mg for 12 weeks. The primary end point was the mean change in number of migraine days per month. Secondary end points were the change in headache days, migraine attacks, and responder rate.

Patients in the active treatment group experienced a significantly greater reduction in migraine days than those taking placebo (–4.2 vs. –3 days; 63% vs. 42% decrease).

LY2951742 was significantly better than placebo in all secondary end points including headache days (–4.9 vs. –3.7), migraine attacks (–3 vs. –2.3), and overall response rate (70% vs. 45%).

In an exploratory analysis, 33% of those in the active treatment group were complete responders, with a 100% reduction in migraine headache days, compared with 17% of the placebo group,

Adverse events seen more frequently with LY2951742 than placebo included injection site pain, upper respiratory tract infections, and abdominal pain.

Both drugs will advance to phase III studies, Dr. Dodick said in an interview. "If they are ultimately confirmed to be effective and safe, this will represent a new era in mechanism-based migraine prevention – in other words, treatment directed at a molecule now known to be very important in generating a migraine attack. This would provide a highly effective treatment option that is delivered intermittently by subcutaneous injection or infusion rather than requiring patients to consume oral medications 1-3 times daily."

And, he said, because the antibodies act on the very specific target of CGRP, they exhibit a very favorable side effect profile.

"This would be a major advantage over currently available medications, which have a high rate of side effects [weight gain, sedation, altered concentration, fatigue, etc]. The lack of efficacy and the side effect profile of currently available preventive migraine medications account in large part for the lack of adherence to these medications. We recently showed that even in patients with chronic migraine who experience headaches every other day, about 86% have discontinued their oral migraine preventive drug within 1 year."

Drugs that hit CGRP may even help other headache types, Dr. Dodick added.

"There is some evidence that CGRP is also important in other serious headache disorders such as chronic migraine, medication overuse headache, and cluster headache – disorders that are currently very difficult to manage."

The ALD403 study was supported by Alder Biopharmaceuticals. The LY2951742 study was supported by Arteaus Therapeutics in conjunction with Eli Lily. Both Dr. Goadsby and Dr. Dodick have financial relationships with numerous pharmaceutical companies, including receiving research monies, and participating as officers or speakers.

msullivan@frontlinemedcom.com

Two investigational migraine prevention drugs that target a vasodilating peptide significantly decreased the number of migraine days per month, compared with placebo, during a pair of phase II studies.

Both drugs reduced mean migraine headache days per month by more than 4 days overall, and one even eliminated migraine in up to 30% of patients.

Each is a monoclonal antibody that inhibits calcitonin gene–related peptide (CGRP). Activated trigeminal sensory nerves release the peptide, which dilates intra- and extracranial blood vessels and modulates vascular nociception.

The antibodies could be game changers for migraine patients, Dr. Peter Goadsby said in an interview.

"Here are the first mechanism-based preventive treatments for migraine," said Dr. Goadsby of the University of California, San Francisco. "They are easy to use, biweekly or even monthly injections, which are effective and well tolerated. For neurologists it means the first major addition to the preventive armamentarium for a generation or more, and for patients, a tangible advance that they can look forward to enjoying soon."

During the annual meeting of the American Academy of Neurology, Dr. Goadsby will present the findings on ALD403, developed by Alder Biopharmaceuticals. His colleague Dr. David W. Dodick of the Mayo Clinic, Rochester, Minn., will present findings on LY2951742, which is being developed by Arteaus Therapeutics in conjunction with Eli Lily. Both presentations are scheduled for May 1.

The trial of ALD403 comprised 163 patients who experienced 5-14 migraine headache days per month; 81 were randomized to receive a single infusion of 1,000 mg ALD403 and the rest received placebo. Patients were followed for 24 weeks. The primary outcome was the mean change in migraine days between weeks 5-8 and baseline.

Patients in the active treatment group fared significantly better than those in the placebo group, with a mean reduction in migraine headache days of –5.6, compared to –4.6 for the placebo group (66% vs. 52% decrease).

Most patients taking the study drug had at least a 50% reduction in migraine headache days at 12 weeks (60% vs. 30%); the proportions of those with at least a 75% reduction were 32% vs. 9%. A 100% reduction occurred in 16% of the active group and in none of the placebo group. These differences were all statistically significant.

There were no differences in the type or frequency of adverse events, vital signs, or laboratory safety data between the two treatment groups.

The LY2951742 study was similarly successful. It comprised 217 patients who experienced 4-14 migraine headache days per month, said Dr. Dodick. They were randomized to placebo or to biweekly subcutaneous injections of LY2951742 150 mg for 12 weeks. The primary end point was the mean change in number of migraine days per month. Secondary end points were the change in headache days, migraine attacks, and responder rate.

Patients in the active treatment group experienced a significantly greater reduction in migraine days than those taking placebo (–4.2 vs. –3 days; 63% vs. 42% decrease).

LY2951742 was significantly better than placebo in all secondary end points including headache days (–4.9 vs. –3.7), migraine attacks (–3 vs. –2.3), and overall response rate (70% vs. 45%).

In an exploratory analysis, 33% of those in the active treatment group were complete responders, with a 100% reduction in migraine headache days, compared with 17% of the placebo group,

Adverse events seen more frequently with LY2951742 than placebo included injection site pain, upper respiratory tract infections, and abdominal pain.

Both drugs will advance to phase III studies, Dr. Dodick said in an interview. "If they are ultimately confirmed to be effective and safe, this will represent a new era in mechanism-based migraine prevention – in other words, treatment directed at a molecule now known to be very important in generating a migraine attack. This would provide a highly effective treatment option that is delivered intermittently by subcutaneous injection or infusion rather than requiring patients to consume oral medications 1-3 times daily."

And, he said, because the antibodies act on the very specific target of CGRP, they exhibit a very favorable side effect profile.

"This would be a major advantage over currently available medications, which have a high rate of side effects [weight gain, sedation, altered concentration, fatigue, etc]. The lack of efficacy and the side effect profile of currently available preventive migraine medications account in large part for the lack of adherence to these medications. We recently showed that even in patients with chronic migraine who experience headaches every other day, about 86% have discontinued their oral migraine preventive drug within 1 year."

Drugs that hit CGRP may even help other headache types, Dr. Dodick added.

"There is some evidence that CGRP is also important in other serious headache disorders such as chronic migraine, medication overuse headache, and cluster headache – disorders that are currently very difficult to manage."

The ALD403 study was supported by Alder Biopharmaceuticals. The LY2951742 study was supported by Arteaus Therapeutics in conjunction with Eli Lily. Both Dr. Goadsby and Dr. Dodick have financial relationships with numerous pharmaceutical companies, including receiving research monies, and participating as officers or speakers.

msullivan@frontlinemedcom.com

Two investigational migraine prevention drugs that target a vasodilating peptide significantly decreased the number of migraine days per month, compared with placebo, during a pair of phase II studies.

Both drugs reduced mean migraine headache days per month by more than 4 days overall, and one even eliminated migraine in up to 30% of patients.

Each is a monoclonal antibody that inhibits calcitonin gene–related peptide (CGRP). Activated trigeminal sensory nerves release the peptide, which dilates intra- and extracranial blood vessels and modulates vascular nociception.

The antibodies could be game changers for migraine patients, Dr. Peter Goadsby said in an interview.

"Here are the first mechanism-based preventive treatments for migraine," said Dr. Goadsby of the University of California, San Francisco. "They are easy to use, biweekly or even monthly injections, which are effective and well tolerated. For neurologists it means the first major addition to the preventive armamentarium for a generation or more, and for patients, a tangible advance that they can look forward to enjoying soon."

During the annual meeting of the American Academy of Neurology, Dr. Goadsby will present the findings on ALD403, developed by Alder Biopharmaceuticals. His colleague Dr. David W. Dodick of the Mayo Clinic, Rochester, Minn., will present findings on LY2951742, which is being developed by Arteaus Therapeutics in conjunction with Eli Lily. Both presentations are scheduled for May 1.

The trial of ALD403 comprised 163 patients who experienced 5-14 migraine headache days per month; 81 were randomized to receive a single infusion of 1,000 mg ALD403 and the rest received placebo. Patients were followed for 24 weeks. The primary outcome was the mean change in migraine days between weeks 5-8 and baseline.

Patients in the active treatment group fared significantly better than those in the placebo group, with a mean reduction in migraine headache days of –5.6, compared to –4.6 for the placebo group (66% vs. 52% decrease).

Most patients taking the study drug had at least a 50% reduction in migraine headache days at 12 weeks (60% vs. 30%); the proportions of those with at least a 75% reduction were 32% vs. 9%. A 100% reduction occurred in 16% of the active group and in none of the placebo group. These differences were all statistically significant.

There were no differences in the type or frequency of adverse events, vital signs, or laboratory safety data between the two treatment groups.

The LY2951742 study was similarly successful. It comprised 217 patients who experienced 4-14 migraine headache days per month, said Dr. Dodick. They were randomized to placebo or to biweekly subcutaneous injections of LY2951742 150 mg for 12 weeks. The primary end point was the mean change in number of migraine days per month. Secondary end points were the change in headache days, migraine attacks, and responder rate.

Patients in the active treatment group experienced a significantly greater reduction in migraine days than those taking placebo (–4.2 vs. –3 days; 63% vs. 42% decrease).

LY2951742 was significantly better than placebo in all secondary end points including headache days (–4.9 vs. –3.7), migraine attacks (–3 vs. –2.3), and overall response rate (70% vs. 45%).

In an exploratory analysis, 33% of those in the active treatment group were complete responders, with a 100% reduction in migraine headache days, compared with 17% of the placebo group,

Adverse events seen more frequently with LY2951742 than placebo included injection site pain, upper respiratory tract infections, and abdominal pain.

Both drugs will advance to phase III studies, Dr. Dodick said in an interview. "If they are ultimately confirmed to be effective and safe, this will represent a new era in mechanism-based migraine prevention – in other words, treatment directed at a molecule now known to be very important in generating a migraine attack. This would provide a highly effective treatment option that is delivered intermittently by subcutaneous injection or infusion rather than requiring patients to consume oral medications 1-3 times daily."

And, he said, because the antibodies act on the very specific target of CGRP, they exhibit a very favorable side effect profile.

"This would be a major advantage over currently available medications, which have a high rate of side effects [weight gain, sedation, altered concentration, fatigue, etc]. The lack of efficacy and the side effect profile of currently available preventive migraine medications account in large part for the lack of adherence to these medications. We recently showed that even in patients with chronic migraine who experience headaches every other day, about 86% have discontinued their oral migraine preventive drug within 1 year."

Drugs that hit CGRP may even help other headache types, Dr. Dodick added.

"There is some evidence that CGRP is also important in other serious headache disorders such as chronic migraine, medication overuse headache, and cluster headache – disorders that are currently very difficult to manage."

The ALD403 study was supported by Alder Biopharmaceuticals. The LY2951742 study was supported by Arteaus Therapeutics in conjunction with Eli Lily. Both Dr. Goadsby and Dr. Dodick have financial relationships with numerous pharmaceutical companies, including receiving research monies, and participating as officers or speakers.

msullivan@frontlinemedcom.com