Protein makes sensory nerves very sensitive

Expanded blood vessels used to be considered the cause of migraine. But new studies suggest a protein is the culprit.

possible. When a light touch of the scalp activates a sensory nerve, it will, under normal circumstances, send a weak electric nerve signal to the brain, which will hence register a light touch. But particular nerve cells that originate from a hub near the ear contain large quantities of CGRP, and for reasons that scientists do not yet quite understand, they can suddenly open the gates, so the protein flows across the surrounding sensory nerves.

If that happens, the sensory nerves become extra sensitive, and the weak nerve signal will be amplified very much. When, fractions of a second later, it hits the brain, it will hence no longer communicate the message of a light touch, rather one of intense pain. Other small influences on the head’s sensory nerves – such as a muscle contraction in the face or just the blood flow through the vessels – are also much amplified, and all the false pain sensations gradually place the brain in a state of alarm, also reacting to light, smells, and sounds.

The situation quickly develops into a very painful experience, and a migraine attack is coming up. However, the newly-developed erenumab antibody can slow the escalating pain, because it invalidates the CGRP protein, before the sensory nerves have time to react. So, the treatment is preventive, and as antibodies, which are large proteins, have long durability in the body, the patient only needs to take one dose a month to avoid new migraine attacks.

Antibody halved migraine attacks

Doctor Peter Goadsby from the King’s College Hospital in London is the man behind the development of the antibody, and in December 2017, he introduced the promising results of a major clinical trial. A total of 955 migraine victims participated, and they were randomly divided into three groups who were given montly injections of 70 or 140 mg of the antibody over a period of six months.

The patients experienced 4-14 days of migraine a month, but after six months of treatment, the number of monthly migraine days had fallen by 3.2 and 3.7 among the test subjects who had had the low and high dose, respectively. Among the patients who were treated with the low dose, 43.3 % experienced at least a halving of the number of days with migraine, whereas the similar percentage for those who had the high dose was 50.

The positive effect of erenumab is achieved, because the antibody prevents CGRP from sticking to the sensory nerves, making them extra sensitive. In order to carry out its normal job, CGRP is to bind to a receptor on the surface of the sensory nerve, but the antibody "beats" CGRP, locating itself solidly on the receptor. In other words, the antibody takes up the place on the receptor, so CGRP has no opportunity to bind to it and trigger the painful experience.

However, Peter Goadsby has also developed another antibody, which gets stuck to the CGRP protein, preventing it from binding to the receptor. Known as fremanezumab, this antibody has also been tested in a similar clinical trial of 1,130 migraine patients, of whom some were only given an injection every three months. That was enough to reduce the number of monthly migraine days by an average of 4.3 among all test subjects, and 38 % of the participants had the number of migraine days halved.

Several other antibodies that invalidate CGRP have been tested in clinical trials with similarly positive results. Common to all of them is that they do not have the same effect on all the test subjects and that the effect is markedly better in a few patients. In another clinical trial involving the new erenumab drug, whose results were published in 2017, one in four patients became migrainefree, whereas an experiment with another antibody, galcanezumab, demonstrated that 16 % of the patients were fully cured.

Researcher caused headaches

Scientists do not yet know why the patients reacted so differently to the antibodies, but the key to the answer is probably to be found in how their sensory nerves are affected by CGRP. All humans produce the protein that regulates the blood flow by making blood vessels expand. But for some reason, migraine patients react differently.

Already in 2002, neurologist Jes Olesen from the University of Copenhagen showed that an injection with CGRP quickly triggered an attack in migraine patients, whereas people who did not suffer from migraines got a light headache or no effect due to the protein injection. So, migraine patients are much more sensible to CGRP than healthy people, in whom the sensory nerves only react by becoming extra sensitive. However, the migraine patients’ reaction to CGRP is probably also different, and so, the antibodies are not equally efficient.

New drug eases acute attacks

Until scientists learn to understand why some patients react differently to the treatment than others, and will be able to develop even better antibodies, they will instead try to identify the patients who benefit the most from the antibodies beforehand. The treatment is rather expensive, and as it only has a limited effect on about half of the patients, it makes sense to use

the treatment for people who benefit the most. Apart from antibodies, scientists are also developing a series of small molecules that can ease their way into the CGRP protein’s receptors and hence prevent that the sensory nerves are affected. The small molecules are known as gepants, and unlike the antibodies, they are not preventive, rather they can ease the pain of an ongoing migraine attack. Consequently, doctors can influence the migraine-causing CGRP protein in two ways: the antibodies reduce the number of attacks, and when an attack develops anyway, the pain can be relieved with other substances.

Already by the end of 2019, European doctors are expected to begin writing prescriptions for the new erenumab antibody, and more antibodies and other treatments will probably follow quickly. At that time, many migraine patients will be able to draw their curtains without getting the feeling that the light is drilling its way into their brains.