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CGRP inhibitors for Migraine

Timothy C. Hain, MD Page last modified: September 3, 2017

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Overview:

As of late 2017, there were 4 new CGRP drugs in phase II or phase III trials in the USA. These are calcitonin gene related peptide (CGRP) monoclonal antibodies. These drugs are a new generation of CGRP inhibitors -- previous versions failed due to liver toxicity (Edvinsson, 2015).

These are the ones in current trials:

How these drugs work on migraine:

CGRP is elevated in jugular vein blood during acute migraine and cluster headaches. According to Durham (2006), "Studies in cultured trigeminal neurons demonstrate that CGRP is released from trigeminal ganglia cells, that CGRP transcription is increased under conditions mimicking neurogenic inflammation, that migraine pharmacotherapies can both reduce CGRP release and inhibit CGRP transcription, and that tumor necrosis factor-alpha (TNF-alpha), an endogenous inflammatory mediator implicated in migraine, can stimulate CGRP transcription. Together, the results suggest that, in migraine, activation of trigeminal nerves release CGRP and other peptides that cause the release of proinflammatory mediators. These mediators further increase CGRP synthesis and release over hours to days in correspondence with the 4- to 72-hour duration of a typical migraine episode. The increased CGRP synthesis and release might be mediated by activation of mitogen-activated protein kinase pathways, which, in turn, can be modulated by endogenous inflammatory substances such as TNF-alpha and affected by drugs such as sumatriptan."

Thus CGRP interacts with TNF-alpha, a cytokine, which is thought to modulate Meniere's disease. One would think that TNF-alpha inhibitors used for autoimmune disease, such as rheumatoid arthritis, might thus then reduce migraine as well. It is well known that migraine and Meniere's disease are associated with each other. Perhaps these drugs also work in a subset of Meniere's disease. Time will tell. The triptans do not appear to work in Meniere's disease, so this conjecture may fail.

Again from Durham (2016), " Our findings provide evidence that proton regulated release of CGRP from trigeminal neurons utilizes a different mechanism than the calcium and synaptosomal-associated protein 25-dependent pathways that are inhibited by the antimigraine therapies, rizatriptan and onabotulinum toxin A. " This might thus provide a reason that onabotulinum toxin works (modestly) in migraine.

Expectations for CGRP inhibitors.

The CGRP drugs will all compete with a very large number of other migraine prevention drugs. Hopefully as they are working on a different mechanism than other drugs, they will be effective in situations where these other drugs have failed. As noted above, these drugs may share a mechanism with Botox treatment. It will be interesting to see if the effect of Botox and CGRP drugs are additive or not.

In the author's view, these drugs are over-hyped. This is because Migraine is not a homogeneous condition, as it is defined by symptoms rather than molecular biology or imaging. This means it is a "wastebasket condition" resembling many other conditions defined by symptoms -- including most os psychiatry. Because of it's "wastebasket status", meaning we are not treating a disease but rather a menagerie of disorders, we expect that these drugs will be far less effective than reported in these pre-marketing trials, as well as be in the "nose bleed" range for price. We also expect that patients will develop blocking antibodies to these proteins, and even if they work for a while, their efficacy will eventually wane.

Nevertheless, we look forward to trying them out in patients with refractory and severe migraine.

Eptinezumab (Alder BioPharmaceuticals, ALD403)

Eptinezumab has an IV mode of delivery. About 33% of patients taking the 300 mg dose reached the primary endpoint of a 75% reduction in migraine days, compared to 21% of those taking a placebo. So in other words, out of 100 patients, there were about 10 more patients that had a 75% reduction, than patients with placebo. Viewed from this perspective, this drug is not that different in efficacy than all of the other migraine prevention drugs, but of course, the advantage is that it may "pick off" another 10% of the refractory migraine patients.

Erenumab -- a CGRP receptor antibody

Unlike the other three drugs, erenumab is an anti-CGRP receptor antibody. It is not directed against CGRP, but against the receptor for CGRP. Compared to placebo, this drug was reported to reduce mean headache days by 6.6 (from 18), compared to a 4.2 day reduction in placebo. Converting this to percentages (not the same as the above calculation), the difference in days between active drug and placebo is 2.4, and that divided by 18, is again about a 10% difference.

Fremanezumab (Teva)

Results were similar -- a mean reduction of 4.6 headache days, which differed from placebo (2.5 headache days). Thus drug was injected quarterly.

Galcanezumab (Lily)

This drug is another CGRP antibody. Again, good results were reported, although the placebo response was not compared to the active response. As the placebo response makes up about 2/3 of the response in other trials, one wonders why this study left out this critical information.

 

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Copyright September 3, 2017 , Timothy C. Hain, M.D. All rights reserved. Last saved on September 3, 2017