For the last 150 years, the understanding of migraine has oscillated between two poles: the vascular theory (that migraine is a disease of blood vessels and blood flow), and the neural theory (that migraine is first and foremost a brain disease). The first generation of truly effective acute migraine treatments – ergotamine and DHE – were known to cause changes in the calibre of blood vessels as they settled down migraine pain, and for many decades the vascular theory held the upper hand. This started to change in the 1970s and 1980s, as increasing evidence of brain activation in migraine accumulated from early PET studies. As the neural theory took control, the vascular theorists had one last throw of the dice: the triptans.
The first member of the triptan family was discovered by Pat Humphry at the Glaxo site in Ware, Hertfordshire, in the 1980s. The technique used in Humphry’s lab to identify molecules with the potential to be effective treatments for migraine in humans was their effect on the isolated dog saphenous vein, which was thought to be a good model for the human intracranial vasculature. Humphry found a good candidate in GR43175 (patented in 1982), which was over the next five years developed into the drug we now know as sumatriptan.
By the time sumatriptan was licensed in 1991, it was already clear that the model used to identify it was almost completely wrong. Work done by Lars Edvinsson and Peter Goadsby showed that the effect of sumatriptan was mediated through its effect on the levels of a substance called CGRP (calcitonin gene-related peptide). Prior to this work Edvinsson had been a member of a research group based in Edinburgh with an interest in the peptide control of cerebral blood vessels.
Six further triptans were released in the 1990s and early 2000s. Through this period there was intense interest both in the science of CGRP, and in the development of new drugs targeting it. In the early 2000s a new class of drug – the gepants – was launched: these drugs blocked CGRP, but were unexpectedly found to have adverse effects on liver function, and had to be withdrawn. (The gepants are making a comeback, but that’s a story for a different blog.)
Around the time the gepants were falling at the final hurdle, a series of patents were taken out on monoclonal antibodies (mAbs) against CGRP or its receptor. Naturally occurring antibodies are proteins that the immune system uses to recognise and remember specific harmful substances such as bacteria, viruses, toxins and so on. Monoclonal antibodies – invented by César Milstein in Cambridge in 1975 – can be engineered to recognise anything of interest. Milstein received the Nobel Prize in 1984 for this work.
In the last 20 years increasing numbers of mAbs have found their place in medicine: mAbs can slow down the course of cancers; they can modify the immune system in conditions such as rheumatoid arthritis and multiple sclerosis; and by the mid-2010s evidence was emerging that mAbs against the CGRP system could be effective in the preventive treatment of migraine.