In one of the most recent developments, a new phase 2 trial of ALD403, a humanized monoclonal antibody directed against calcitonin gene-related peptide (CGRO) showed that the drug was safe and effective.
Results also showed that adverse events associated with the drug were transient and mild to moderate in severity. The study also suggests the agent significantly reduced the mean number of migraine headache days, with some patients experiencing no migraines at all.
Although preliminary, the results are promising, said lead author, David W. Dodick, professor, neurology, Mayo Clinic, Phoenix, Arizona.
“In 30 years of preclinical work in animals, and clinical work in humans, this is the most validated target in migraine,” Dr Dodick told Medscape Medical News.
The study was published online October 6 in The Lancet.
Dr. David W. Dodick
Fast and effective preventive treatments for migraine, which is the third most prevalent and seventh most disabling disease in the world, are lacking, said Dr Dodick.
“If you spent a day in my clinic, this would become obvious. There is an absolutely desperate need for preventative medications which dramatically reduce, if not eliminate, migraine attacks. The drugs we have now are fraught with side effects and they work in 50% or less of patients.”
ALD403 is a monoclonal antibody that selectively binds to CGRP, which is crucial in the pathophysiology of migraine headaches. It was designed specifically to prevent migraine.
In contrast, triptans which are used in the acute treatment of migraine may reduce circulating CGRP concentrations, but this is not their primary effect.
Triptans also have a number of drawbacks, said Dr Dodick. As agonists, they may cause overuse headaches in patients taking them frequently. Four of 5 patients taking triptans “don’t get the pain-free response that we’d like to see” in an acute medication. He added that triptans are also linked to numerous adverse effects.
The new analysis included 163 adults (mean age about 39 years) at 26 centers in the united States. Patients had experienced migraines for more than 12 months and had 5 to 14 migraine days in each of the 3 months before screening. The mean Headache Impact Test 6 (HIT-6) score was about 64.
Patients were randomly assigned to receive ALD403, 1000 mg, or placebo by intravenous injection. The 1000-mg drug dose was chosen because it had fully suppressed peripheral CGRP responses in healthy persons for at least 12 weeks in a previous trial.
The study sponsor (Alder Biopharmaceuticals) designed the trial and was responsible for data collection, processing, and management; statistical analysis; and reporting of results. The sponsor wrote the first draft of the results, which the authors reviewed and approved.
New Drug Class
During the study, site investigators, patients, and the sponsor were masked to treatment allocation.
No patient withdrew from the study because of adverse events of lack of efficacy, although two patients in the placebo group and five in the ALD403 group were lost to follow-up in the 12 weeks after receipt of the dose.
During these 12 weeks, adverse events occurred in 52% of the placebo group and 57% of the treatment group. The most frequent adverse events in both groups were upper respiratory tract and urinary tract infections, fatigue, back pain, nausea and vomiting, and arthralgia. Most adverse events were transient and mild to moderate in severity.
The groups were similar in terms of vital signs and laboratory safety data.
During the study, patients completed an electronic headache diary. According to these diaries, the mean change in migraine days between baseline and weeks 5 to 8 was –5.6 for the ALD403 group and –4.6 for the placebo group (difference, –1.0; 95% confidence interval, –2.0 to 0.1; P = .0306).
Dr Dodick attributed the high placebo response to heightened expectations.
“It’s one thing to take a tablet at home as part of study, but it’s another to come to the hospital, get hooked up to IV [intravenous line] and get an infusion. There’s a whole sort of medical theater created around the administration of the drug. This increases the expectations that whatever is being infused is going to be powerful and it’s going to work.”
He added that in this age of social media, prospective participants were likely well aware that the scientific community was developing targeted antibodies to treat migraine. “There was a lot of excitement and enthusiasm around this; we were finally getting a new drug class that was designed specifically to treat migraine.”
A secondary analysis showed that at all times points (weeks 4, 8, and 12), more patients in the ALD403 than in the placebo group had a 50%, 75%, and 100% reduction in migraine days; the treatment group rate was generally about 20% higher. Of the 143 patients who consistently completed their diary, 11 had no migraine attacks — all of these were treated with ALD403.
Researchers noted a reduction at week 8 in both study groups for scores on the HIT-6 (change, –9.9 for ALD403 and –8.1 for placebo) and on the Migraine Specific Quality of Life Instrument. Although the study wasn’t powered to detect differences for these patient-reported outcomes, “these findings are promising and provide justification to undertake future studies that are appropriately powered,” the authors write.
ALD403 doesn’t work in everyone because in some patients, other neuropeptides, such as glutamate, may be triggering migraines, said Dr Dodick. “While CGRP is important, and for some patients it appears to be crucially important, for other patients it may not be important at all.”
The next step is likely to carry out studies to determine the optimal and best-tolerated dose, said Dr Dodick. He said he hopes that a phase 3 study will be launched within a year.
ALD403 is among 4 CGRP antibodies being tested in migraine.
Commenting for Medscape Medical News, Noah Rosen, MD, a headache specialist and associate professor, Hofstra North Shore, Long Island Jewish Medical Center, New York, said he’s excited about the advent of a novel class of drugs to prevent migraine.
“Everything we use now preventively for migraine has been adapted for that purpose, or found separately to be effective for migraine prevention. This new class of medications is the first to be tailored to the treatment or designed for the treatment of migraines. That’s what really makes it exciting.”
Current migraine preventive treatments include β-blockers (propranolol, timolol), anticonvulsants (sodium valproate, topiramate), and botulinum toxin type A (Botox). There is also good evidence for some antidepressants, including amitriptyline, said Dr Rosen.
Dr Rosen’s patients are also anxiously awaiting the new drugs.
“They’re tired of trial after trial of nonspecific treatments,” he said. “My patient population is highly educated and is greatly anticipating this, but they know that they need to be patient because you’re still talking years from being on the market.”
Alder Biopharmaceuticals supported the study. Dr Dodick reports he has served on advisory boards or has consulted, or both, for Allergan, Amgen, Alder, Arteaus, Pfizer, Colucid, Merck, ENeura, NuPathe, Eli Lilly, Autonomic Technologies, Ethicon Johnson & Johnson, Zogenix, Supernus, Labrys, Boston Scientific, Medtronic, St Jude, Bristol-Myers Squibb, Lundbeck, Impax, MAP, and Electrocore; has received funding for travel, speaking, editorial activities, or royalty payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, American Academy of Neurology, West Virginia University Foundation, Canadian Headache Society, Healthlogix, Wiley, Universal Meeting Management, WebMD, UptoDate, Oregon Health Science Center, Starr Clinical, Decision Resources, and Synergy.
Lancet. Published online October 6, 2014
Source: Medscape article by P. Anderson