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CGRP inhibitors for Migraine

Timothy C. Hain, MD Page last modified: June 6, 2018

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Overview:

CGRP is a 37 amino acid peptide first described in 1983. It plays a role in pain transmission. CGRP infusion can trigger migraine. The primary site of action for CGRP is thought to be the trigeminovascular system, located outside the blood-brain barrier, where CGRP interacts with trigeminal afferents and the meningeal blood vessels to release nitric acid and more CGRP. It is hoped that monoclonal antibodies to CGRP will disrupt this cycle, and reduce head pain mediated through this circuit. (Parikh and Silberstein, 2018).

As of late 2017, there were 4 new CGRP drugs in phase II or phase III trials in the USA. These are mainly 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).

From emerging data in 2018, these drugs appear to be basically just another weakly effective prevention medication --they are not "magic bullet" drugs, but add-on prevention drugs. It appears, at least right now (in 2018), that these drugs may be somewhat "over-hyped". This makes sense in as much as migraine is not a homogeneous condition, and it would be hard to imagine that a single approach could make a big difference. This is the usual problem with disorders that are defined by symptoms.

These are the CGRP drugs 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.

Why these drugs have side effects

CGRP receptors are found in other places than the head, including peripheral, enteric, and central nervous system, as well as the cardiovascular system, and they are also active in wound healing and other physiologic functions.

There is no evidence for hepatotoxicity (which was the problem with previous types of CGRP receptor antagonists).

CGRP is a vasodilator. Blocking CGRP may block the protective role of CGRP in preventing stroke and heart attack. As small stroke like lesions are more common in persons with migraine, this may turn out to be a long term issue.

We probably will not discover the rarer or long term side effects of CGRP inhibitors until a few 10,000 people try these new drugs.

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.

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. The most common adverse effects in trials were URI and UTI -- i.e. infections. This drug does not appear to be especially effective as results suggest a 1 day/month reduction in migraine frequency.

Erenumab -- a CGRP receptor antibody (Aimovig)

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. The safety profile of this drug is similar to placebo. An open label trial (i.e. not controlled) suggested roughly a 50% reduction in migraine days/month, for a dose of 70 mg subcutaneous every 4 weeks. Another phase-2 trial suggested a mean reduction of 2.5 headache days/month compared to placebo.

Although Erunamab was approved by the FDA in May of 2018, it is not yet in pharmacies, and how insurance is going to handle this drug is not certain either. It appears to be priced at about $575/month (if you pay out of pocket). It can be injected at home. There are two dose sizes -- 70 mg and 140 mg.

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 in a rather large amount -- 225 or 675 mg. It is also subcutaneous. The most common adverse effect was injection site pain.

Galcanezumab (Lilly)

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.

In a phase 2b trial, there was a mean reduction of 1.1 headache days per month with 120 mg of this drug.

In a recent study reported in 2018, there was approximately a decrease of 4 migraine headache days, compared to pre-treatment (Sklijarevski et al, 2018). These patients were not very sick and only were experiencing (on average) about 7 migraine headache days with no treatment. Both the placebo and the active treatment had a large effect -- about 3 of the 4 headache days were placebo response. So this is really a study of persons with relatively mild migraine headaches. I would not say that a 1 day/month change in the # of headaches (compared to placebo), was very large.

Concerns about these new CGRP drugs

As summarized above, we have a new class of migraine drugs, that seem to be rather weak, like nearly every other prevention drug.

Dr. Cowan, Chief of the division of headache medicine at Stanford, recently wrote a commentary about CGRP antagonists. As Cowan pointed out (2018), these drugs will likely be "priced in the range of the currently available onabotulinumtoxin A" -- In other words, rather high, and also require a diagnosis of chronic migraine, and also require trials of 3 other medications. Dr. Cowan suggested that these drugs will be a $4.5 billion product.

In the author's view, these drugs are worth trying in severe patients, but not in most people whose headaches can be managed. We also expect that it will not work in everybody with "migraine". 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 of psychiatry.

Because of its "wastebasket status", meaning we are not treating a disease but rather a menagerie of disorders, we expect that these drugs will be less effective than reported in these pre-marketing trials. 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. We are not sure whether or not these drugs will affect the propensity of migraine patients to develop white matter lesions -- as CGRP is a vasodilator, blocking CGRP might lead to more white matter lesions.

Long term trials are in progress but take .. a long time. Still, there is always risk in trying new things.

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Copyright June 6, 2018 , Timothy C. Hain, M.D. All rights reserved. Last saved on June 6, 2018