In previous blogs, I have described how calcitonin gene related peptide (CGRP) was found to be a lynchpin molecule in migraine, and how this led to the development of the new class of monoclonal antibody migraine treatments. I mentioned in passing that, in the early 2000s a new class of drug – the gepants – was created, which blocked CGRP. The first generation gepants were unexpectedly found to have adverse effects on liver function, and had to be withdrawn. In the last few years, however, the gepants are making a comeback, with a second generation of CGRP antagonists making it all the way through the clinical trial process to licensing in the United States, providing the first new acute treatment option for migraine since the introduction of the triptans in the 1990. Ubrogepant (Ubrelvy) 50 mg or 100 mg was approved by the FDA on 23rd December 2019 for the acute treatment of migraine. Rimegepant 75 mg (Nurtec ODT) was approved on 27th February 2020.(1)
Other gepants are in development. One of these is vazegepant, which differs from the other members of the class in that it is delivered intranasally. Phase II trials of vazegepant have been completed, but not yet published, and Phase III trials are planned. Biohaven, the manufacturers of vazegepant, have announced that it will be tested in a double blind, randomized clinical trial as a potential treatment option for COVID-19-related pulmonary complications in hospitalized patients with COVID-19 who require supplemental oxygen.(2)
That a drug developed for migraine might be beneficial in mitigating the adverse effect of a viral infection reminds us how ubiquitous CGRP is in the human body, and how complex (and as yet incompletely understood) is its physiology. Amongst other roles, it is involved in cardiovascular homoeostasis, mucosal integrity in the gut, wound healing, and immunity in the skin. It is found in sensory nerve fibres throughout the respiratory tract, and it is here that its potential role in combatting the effects of SARS-Cov-2 may lie.
Lung infections activate transient receptor potential (TRP) channels in sensory nerves, causing CGRP release into the airways. CGRP promotes vasodilation and enhanced vascular permeability (which may worsen pulmonary oedema); and may alter immune responses towards a pro-inflammatory state (thus causing more damage to lung tissues). Previous laboratory studies have shown that blocking CGRP may improve survival outcomes in MRSA-infected mice, and CGRP antagonism has been considered a potential method for clinical studies in pneumonia. It is hypothesised that CGRP antagonism may potentially blunt the severe inflammatory response seen in Covid-19 at the alveolar level, delaying or reversing the path towards oxygen desaturation, ARDS, requirement for supplemental oxygenation, artificial ventilation or death.
Whether or not it proves a helpful drug in the treatment of Covid-19, vazegepant is one of a number of exciting new additions to our treatment options in migraine.
References
- Moreno-Ajona D, Pérez-Rodriguez A, Goadsby P. Gepants, calcitonin-gene-related peptide antagonists: what could be their role in migraine treatment? Curr Opin Neurol 2020. DOI:10.1097/WCO.0000000000000806
- Biohaven receives FDA may proceed letter to begin phase 2 trial of intranasal vazegepant to treat lung inflammation after COVID-19 infection. https://www.biohavenpharma.com/investors/news-events/press-releases/04-09-2020