Some interesting updates on migraine drugs related to CGRP were published in the latest review published in Curr Treat Options Neurol. Here are the highlights and a few of my thoughts.
It is well known that for the most part, current drug therapies for migraine were not designed specifically for migraine therapy; instead they were therapies borrowed from other diseases. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is important in the pathophysiology of migraine. Monoclonal antibodies antagonizing the CGRP pathway are a new approach to migraine prevention. The first couple attempts to target this pathway in migraine were effective; however, drug trials had to be stopped due to issues with liver toxicity etc.
The CGRP pathway can be interrupted by targeting CGRP itself or by targeting its receptor with either antagonists2 or monoclonal antibodies3. There are four drugs related to the CGRP pathway that are currently being tested for used in migraine patients.
RESULTS OF STUDIES ON THE FOUR DRUGS
There are four monoclonal antibodies in development for migraine prevention. Three of them are against CGRP, one is against the CGRP receptor.
Galcanezumab from Eli-Lilly was first to publish phase II1 clinical trial results. Patients in this study had episodic migraine (4-14 days with headache during the baseline period of 4 weeks). Patients were randomized to receive either 150mg of galcanezumab or placebo subcutaneously every two weeks for 12 weeks. Their endpoint was change in number of migraine days during weeks 9-12 compared to baseline. The mean decrease in migraine days was significantly higher in the galcanezumab group (-4.2 days) when compared to the placebo group (-3.0 days).
Eptinezumab from Alder Biopharmaceuticals was administered once a month intravenously in trials to patients with episodic migraine. This resulted in a decrease from 5.6 migraine days to 4.6 migraine days during weeks 5-8, a significant difference.
Fremanezumab was investigated by Teva pharmaceuticals in two types of patients: those with episodic migraine and those with chronic migraine. Both groups were given subcutaneous injections every four weeks for twelve weeks. This study is different because patients were not excluded for use of preventive medications. Both a high dose (675mg) and a lower dose (225mg) were tested in the episodic group every 4 weeks for 12 weeks. Their efficacy endpoint was a significant decrease in number of migraines at weeks 9-12. The low dose group had a decrease of 2.8 days, high dose a decrease of 2.6 days.
For the chronic migraine group, patients were given a 675mg loading dose followed by either two 225mg doses or three 900mg doses. For this group the efficacy endpoint was change in hours of headache of any severity during weeks 9-12. The first group had a decrease of 23 hours, the second 30 hours.
Erenumab was developed by Amgen, and is the only drug whose target is the CGRP receptor instead of the CGRP molecule itself. Their study was carried out in patients with episodic migraine. Three subcutaneous doses were tested (7, 14, and 70mg) and given every 4 weeks for 12 weeks. The efficacy endpoint was a significant change in the number of migraine days during weeks 9-12. Only the highest dose of 70mg led to a significant decrease in migraines by 1.1 days.
CONCLUSION AND MY COMMENTS: Safety data for all four of these drugs has been encouraging so far. Adverse events were similar in placebo and drug groups. Having recognized that many patients simply do not respond to migraine drug therapies, an analysis was carried out that determined that significantly more patients responded than did not respond. This is interesting but it left me curious about how many did not respond and who they were. Are the non-responders the more chronic patients with more severe migraines? I’m very curious to see which of these drugs will make it to the market first. But most of all, I’m interested in the one that might help us the most.
1Phase I Clinical trials are carried out to establish safety and determine dosage of a drug
Phase II Clinical trials determine efficacy – does the drug work?
Phase III compare safety and efficacy against current treatments
2Receptor antagonists are molecules (usually a drug) that blocks a receptor entirely or decreases the response at that receptor instead of causing a response by binding like an agonist would
3Monoclonal antibodies are molecules designed in a laboratory to bind specific molecules in the body and render them ineffective