4 Novel Drugs in Development to Get Rid of Headache (Migraine)
Calcitonin Gene-Related Peptides (CGRPs) – Major culprit in migraine
Migraine is a common neurovascular primary headache disorder with typical clinical features (with an estimated global prevalence of 14.7%). In the Global Burden of Disease Study, updated in 2013, migraine on its own was found to be the sixth highest cause worldwide of years lost due to disability.
Activation of trigeminovascular system in the brain that leads to the release of neuropeptides like CGRP are thought to be the major culprits involved in pain transmission during a migraine attack. So, targeting them for migraine treatment is an obvious choice. Non-peptide CGRP receptor antagonists like olcegepant and telcagepant have been shown to be effective in the acute treatment of migraine but are associated with liver toxicity. Current interventions in clinical development involves monoclonal antibodies that target CGRP and may prevent migraine from occurring (prophylaxis). These mAbs which binds to either the peptide or its receptor have led to several successful clinical trials which could finally lead to approval of an efficient drug.
Anti-CGRP mAbs in advanced stages of clinical development:
- Erenumab (developed by Amgen & Novartis): This intervention has recently completed Phase 3 trials in episodic migraine and expected to file for regulatory approval in 2017. Results from Phase 3 trials for episodic migraine prevention shows that depending on dosage of 70mg and 140mg, patients experienced a statistically significant 3.2-day and 3.7-day reduction from baseline in mean monthly migraine days, respectively, as compared to a 1.8-day reduction in the placebo arm.
- Galcanezumab (developed by Eli Lilly): This intervention has completed Phase 3 trials for the prevention of both episodic and chronic migraine and expected to file for BLA to FDA by end of 2017. Two phase 3 trials are being run for episodic migraine (six-month placebo-controlled study)- EVOLVE-1 and EVOLVE-2. In EVOLVE-1, average reduction of 4.7 days for 120 mg and 4.6 days for 240 mg compared to an average reduction of 2.8 days for placebo, p < 0.001 were seen for both dosing groups. In EVOLVE-2, average reduction of 4.3 days for 120 mg and 4.2 days for 240 mg compared to an average reduction of 2.3 days for placebo, p < 0.001 were seen for both dosing groups.
Results from phase 3 trials for chronic migraine (three month placebo-controlled study) showed that there was an average reduction of 4.8 days for 120 mg and 4.6 days for 240 mg compared to an average reduction of 2.7 days for placebo, p < 0.001 for both dosing groups.
- Eptinezumab (developed by Alder Biopharmaceuticals): Having completed phase 2 trial with frequent episodic migraine patients and phase 2b study with chronic migraine patients, Alder has now initiated two phase 3 trials in patients for prevention of frequent episodic and chronic migraines respectively. This drug is expected to file for BLA in 2018. In the phase 2 studies, 27-41% of frequent episodic migraine patients experienced complete migraine-free relief i.e 100% suppression of migraine occurrence. Migraines were completely prevented in 16% of patients for the entire 12 week study period. In another trial, 33% and 31% of chronic migraine patients dosed with 300 mg and 100 mg, respectively, experienced a 75% decrease in their migraines over the 12 week study period.
- Fremanezumab (developed by Teva Pharmaceuticals): This intervention is undergoing late phase clinical development in Phase 3 (prevention) in patients with high frequency episodic migraine and chronic migraine. In these studies, in patients with chronic migraine, over half of the patients experienced a 50% or more decrease in headache frequency, nearly one third of patients had a 75% decrease in headache frequency and around 15% were totally free of headaches at month three. In patients with high frequency episodic migraine, a decrease of at least 50% of migraine days were seen in 53% and 59% patients given 225mg and 675mg correspondingly versus 28% of those receiving placebo. A decrease of at least 75% in episodic migraine days was observed in 11%, 34% and in 31% of patients given placebo, 225mg and 675mg respectively.
Till date triptans have been the drug of choice for pharmacologic treatment of migraines. Anti-CGRP mAbs are proving to be the next wave of revolution in this field on the basis of their ability to reduce number of headache days and daily analgesic intake, with a safety profile similar to that of placebo. Decision Resources recently predicted that the migraine market in seven key markets—the U.S., France, Germany, Italy, Spain, the U.K. and Japan—would rise from a value of around $3 billion in 2015 to more than $10 billion in 2025, with the CGRP inhibitors accounting for nearly half ($4.5 billion) of the latter figure. Despite the need for long term studies, these new class of molecules would offer more effective strategy for migraine prevention thereby reducing the global burden of disease.