CGRP and migraine 2: rise of the mAbs

In the last blog, I took the CGRP story from the 1980s to the 2000s, from the fortuitous discovery of triptans to advent of monoclonal antibody technology, and the first inklings that it could be applied to the treatment of migraine.

Useful drugs do not always start out as such. One transformation, seen time and time again in the modern history of medicine, is the evolution from laboratory tool to pharmaceutical phenomenon. Classic examples include penicillin, which was initially used by Alexander Fleming to get rid of fast-growing bacteria so he could study the more fastidious types in which he was interested; and physostigmine, the first effective treatment for myasthenia gravis, which was developed by the physiologist Otto Loewi to make it easier to detect the neurotransmitter acetylcholine. It was the remarkable female physician Mary Walker who first applied it in 1934 to the treatment of patients with what had previously been an incurable neurological disorder.

The same transition can be found in the early history of CGRP antibodies. The first sighting of a monoclonal antibody (mAb) against CGRP in the literature comes in 2007, where it is a laboratory tool: a CGRP ‘scavenger’ used to investigate the distribution and function of the molecule in the brain and peripheral nervous system. This first mAb was made by a company called Rinat Neuroscience, based in Palo Alto, California. It was subsequently acquired by Pfizer, and licensed on to TEVA Pharmaceuticals.

The penny dropped quickly. By 2013 the journal Nature Review Drug Discovery was trumpeting the “comeback” of the “flagging migraine target” CGRP, as mAbs advanced into Phase II clinical trials. Within a year the headline was “Anti-CGRP antibodies for migraine turn industry heads”, as the first Phase II studies of ALD403 and LY2951742 appeared in Lancet Neurology. TEV-48125 and AMG334 quickly followed. By 2015, it was “CGRP antibodies: the Holy Grail for migraine prevention?”

After the publication of Phase III trials of erenumab (AMG334), fremanezumab (TEV-48125), and galcanezumab (LY2951742) in 2018, applications were quickly made to the FDA in the United States and to the EMA in Europe for the mAbs to be licensed. Marketing authorisation has since been granted in Europe for erenumab (Aimovig, 26th July 2018), galcanezumab (Emgality, 14th November 2018) and fremanezumab (Ajovy, 28th March 2019).

The names of mAbs may seem a mouthful, but they follow established rules of nomenclature. The -umab ending of erenumab indicates that it is a human antibody, whereas the -zumab endings of the other antibodies indicate that they are humanised. The original Rinat Neuroscience mAb, for example, was created in rabbits, parts of the variable regions being modified to prevent the antibodies being rejected by the human immune system. In practice, this makes little difference, as does the fact that erenumab binds to the CGRP receptor, while the other mAbs bind to the molecule itself. The results of the Phase III studies are pretty consistent across the board: the mAbs have the potential to reduce the frequency and severity of migraines in anyone who is having >4 migraine days each month.

In the third blog in this sequence I will go into a little more detail on the evidence for the effectiveness of the mAbs, their safety and side effect profiles, and where we stand at present on their use in the United Kingdom.