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Migraine Prevention at the Tip of a Needle?

The science behind a new injectable drug for migraine prevention is compelling; the clinical evidence, however, less so.

Take-home message:
-A new injectable drug, Aimovig, has just been approved by Health Canada to prevent migraines.
-It costs USD 575 a month and it reduces the number of migraine days per month by an average of one or two.

When thinking of someone taking a medication for migraines, you may imagine them popping a pill. Now, there’s a syringe.

Injectable drugs are not so rare these days. Many drugs for psoriasis and arthritis are available in pre-filled syringes or injector pens. The reason is that the drug they carry would be destroyed by our stomach, so it can’t be taken by mouth. What’s special about this new migraine prevention drug called erenumab (brand name: Aimovig) is that it’s the first approved drug that was specifically designed for migraine prevention in a long, long time.

Before we explore if the drug works or not, let’s have a look at how it’s supposed to work.

Selective candy magnets

We naturally create antibodies to defend ourselves from viruses and bacteria. But these Y-shaped molecules can be produced to recognize something other than a virus and sequester it away.

Let’s say you had a deep-seated hatred of red M&Ms and wanted to remove them from your bowl of mixed candy. Imagine having a Y-shaped magnet for chocolates that would selectively bind the red M&Ms and none other. This is the power of an antibody. But an antibody needs a target.

Researchers discovered that a small protein called CGRP (which stands for “calcitonin gene-related peptide”) was produced by neurons and played a role in the perception of pain. They also saw that more of this CGRP molecule was made in patients with migraines. This made CGRP a target of interest.

First, so-called “small molecule” drugs were aimed at CGRP, but they caused liver toxicity. Then, researchers explored using antibodies to do the same (these drugs end in “-mab”). Because the process by which these antibodies are excreted from the body is different, they do not affect the liver in this way. One of these antibodies is erenumab.

The use of specific antibodies to treat or prevent disease is a form of immunotherapy and, in some cases (like with psoriasis), these injectable drugs have been quite effective.

When it comes to migraines, though, is erenumab—which has just been approved by the FDA and Health Canada—worth its price tag of USD 6,900 a year?

Are two days a month of relief worth it?

A small number of clinical trials have been conducted comparing erenumab to placebo. In the Sun et al. phase II trial (funded by the pharmaceutical company Amgen), participants who received the monthly erenumab injections at a very low dose had, on average, 1.1 fewer days of migraines per month than the participants who got a placebo. A phase III trial (funded by Amgen and Novartis) compared placebo to the now-standard dose (70 mg) and to a double dose, and they observed a reduction of 1.4 fewer days for 70 mg and 1.9 fewer days for 140 mg compared to placebo. This was in a population of patients who had, on average, 8.3 days of migraines each month.

The most recent human study to be published, also funded by Amgen, is the ARISE trial, which reported 1 fewer day of migraines a month when compared to placebo.

The drug was also tested in patients with chronic migraines, meaning people who experience at least 15 headache days per month. The result of this Amgen-funded trial? A reduction of 2.5 days per month for the erenumab group compared to placebo.

A small step for antibodies

We currently lack information about safety and efficacy of erenumab in the long term, with the longest human studies having monitored their patients for up to a year after the first injection. Given the fact that its target, CGRP, is not just involved in migraines but in the nervous system in general, some commentators have voiced concerns about erenumab’s effect on “hypertension, dementia, myocardial infarction, stroke, and sepsis.”

It is also fair to note that all human trials were funded and run by the pharmaceutical companies, Novartis and Amgen, that are selling the drug. No independent trial has been published so far. Importantly, erenumab has not been compared to current migraine medication, only to placebo. (See the collapsible box below for more information on this.)

There are other antibodies targeting CGRP on the final stretch of the drug development process, pronunciation challenges like eptinezumab, galcanezumab, and fremanezumab. When all considerations are added to the balance, it remains to be seen how many patients with migraines will find it tipping toward benefit. While the results quoted above were averages, a subset of patients may experience a much more significant reduction in symptoms. The problem is: we won’t know who without trying.

What is safe to say at this point is that erenumab, the first step toward harnessing the power of immunotherapy to prevent migraines, is no magic bullet.

For those who want to delve deeper into “Erenumab vs. Other Drugs”, click here

Comparing a new drug to a placebo is one thing, but what’s more instructive is to compare it to standard of care. None of the published trials did this comparison. It’s like comparing your red M&M magnet (which may or may not work all the time) to a foam magnet that does nothing, and not comparing it against sorting the M&Ms by hand.

Non-injectable drugs prescribed for migraine prevention are available as generics, which means they are much cheaper than erenumab. These drugs consist mainly of antihypertensives, antidepressants, and anticonvulsants. A systematic look at the literature on the subject revealed that, a year after patients started on these medications to prevent migraines, 35% to 56% of them were still taking them as prescribed or taking them at all. The most common reason for deviating from the prescription? It wasn’t that they weren’t working; it was side effects.

Antihypertensives and antidepressants can cause fatigue, sexual dysfunction, and depression. And valproate, an anticonvulsant, has been associated with tiredness, dizziness, tremors, hair loss, and nausea, for example. These side effects will vary from patient to patient and depend on the dose, but clearly, many migraine sufferers are not putting up with them.

By comparison, the most common side effects seen with erenumab so far were pain at the site of injection, upper respiratory tract infections, and nausea. Even if erenumab’s average efficacy is not superb, the very fact that it seems to be more tolerable might be appealing to many patients.


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