Two Emerging Migraine-Preventive Drugs That Target CGRP

Two Emerging CGRP-Targeted Migraine Medications
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The purpose of preventive migraine therapy is to reduce the number and severity of migraine headaches.

Yet the currently utilized migraine-preventive medications, like Topamax (topiramate), Inderal (propranolol), and Elavil (amitriptyline), are often not as effective as people would like. In addition, these medications have side effects that commonly lead to discontinuation.

The good news is that researchers are now focusing much effort on developing novel migraine preventive medications.

One specific protein they are targeting with these medications is the calcitonin gene-related peptide (CGRP), which has been found to be elevated in people during migraine attacks.

More specifically, two drugs, fremanezumab and erenumab, have shown promise in phase 3 trials—a truly exciting time for migraineurs and their doctors and loved ones.

Let's take a closer look at these emerging CGRP-targeted drugs.

Erenumab for Preventing Episodic Migraine

Erenumab is a humanized monoclonal antibody, and it binds to the CGRP receptor (the protein's docking site).

While erenumab's precise mechanism of action is not fully understood, experts know that CGRP is released from trigeminal nerve fibers during a migraine attack. Once released, CGRP is not only involved in the transmission of pain signals, but it also acts to dilate the blood vessels outside and inside the skull.

With that, by erenumab blocking CGRP's normal docking site, researchers speculate that a migraine attack can be thwarted—and now there is good data to support this theory.

In a phase 3 trial in the New England Journal of Medicine, over 900 participants with episodic migraine (defined as less than 15 migraines per month), were randomized to receive one of the following three therapies every month for six months:

  • A 70-mg subcutaneous (beneath the skin into your fatty issue) injection of erenumab
  • A 140-mg subcutaneous injection of erenumab
  • A placebo subcutaneous injection

The participants nor the investigators knew who was receiving erenumab versus the placebo injection, which is why this study is labeled a double-blind study.

Results

Results of the study revealed that the number of migraine days per month reduced by 3.2 days in the 70-mg treatment group and 3.7 days in the 140-mg treatment group, as compared with 1.8 days in the placebo group.

After a statistical analysis, the investigators determined that this result was significant. This means that the higher reduction in the treatment group was real (due to the effect of the drug) and not a random study error.

Results also revealed that about half of the participants receiving erenumab experienced a 50 percent or greater reduction in their average number of migraine days per month compared to about a quarter of those in the placebo group—again, this result was significant.

The treatment groups also had a significant reduction in the number of days they needed to use acute migraine medications, as compared to the placebo group.

Lastly, the participants in the study completed a scale called the Migraine Physical Function Impact Diary, of which a higher score indicates a greater migraine burden on functioning.

Scores in physical-impairment and everyday-activities significantly improved for the treatment groups when compared to the placebo group.

Adverse Effects

The rates of adverse events were similar between the participants who received erenumab and the participants who received placebo. Overall, less than 3 percent of all the participants withdrew from the trial because of adverse effects.

Conclusion

These results suggest that erenumab is effective (in both doses) for preventing episodic migraine in some people. Erenumab also appears to have a good safety profile. This is welcoming news as current migraine-preventive medications are often discontinued due to undesirable side effects.

Fremanezumab for Preventing Chronic Migraine

Fremanezumab is a humanized monoclonal antibody that binds to and inhibits the actual protein CGRP, as opposed to its receptor (like erenumab).

In a phase 3 trial in the New England Journal of Medicine, over one thousand people with chronic migraine (defined as more than 15 migraines per month for at least three months), were randomized to receive one of the following three regimens over a 12 week period:

  • A single subcutaneous injection of fremanezumab at baseline, followed by a placebo subcutaneous injection at week 4 and week 8 (called a quarterly injection)
  • Three subcutaneous injections of fremanezumab with one at baseline, one at week 4, and one at week 8 (called a monthly injection)
  • A placebo subcutaneous injection at baseline, week 4, and week 8

Like the erenumab trial, the participants and the investigators were both blind to who was receiving the medication versus who was receiving the placebo.

While the participants were scheduled for five visits (at screening, baseline, week four, week eight, and then week 12), all of their headache data was recorded on a daily basis through an electronic headache-diary device. Example of the headache data included whether a headache occurred, its duration, and its pain severity.

Results

Results of this study revealed that those participants receiving either the single injection of fremanezumab or the three monthly injections of fremanezumab had a significant reduction in the average number of migraine days per month, as compared to the placebo group.

More specifically, the participants receiving the placebo had an average of 10.4 migraine days versus those receiving fremanezumab quarterly (8.5 days) and monthly (8.0 days).

In addition, there was also a larger reduction in the average number of days participants needed to use acute migraine medications in the treatment group versus the placebo group.

Lastly, there was a greater reduction in headache-related disability (as measured by a scale called the Headache Impact Test) for the treatment group versus the placebo group.

Adverse Effects

The most common adverse effect in the study was pain at the injection site, which occurred more commonly in the participants receiving fremanezumab than the participants receiving placebo. However, the severity of the reactions did not differ among the groups, occurring at nearly the same rate in all three groups.

Additionally, there were some mild elevations of liver enzyme levels in eight of the participants taking fremanezumab. The levels, however, went back to normal, so the participants were not discontinued from the study.

In fact, per the investigators of the study, all of these participants had used medications like nonsteroidal anti-inflammatory (NSAIDs) or Tylenol (acetaminophen) frequently or antidepressants daily. The intake of these medications could explain these transient liver enzyme elevations, especially since fremanezumab is not metabolized in the liver.

Conclusion

In this phase 3 trial, fremanezumab given either quarterly or monthly was beneficial in preventing chronic migraine. It not only reduced the number of migraine days per month (about two less), but it reduced migraine-related disability.

A Word From Verywell

The bottom line here is that these medications, which specifically target migraines (prior preventive medications were designed to treat other conditions, like seizures and depression), give hope and another option for people. They are not perfect, though, supporting the mindset that a trial and error process is still needed when sorting out your preventive migraine plan.

In addition to being effective in preventing migraines in some people, these two CGRP-targeted drugs were well-tolerated—a double bonus. That said, more studies are needed to examine the long-term safety and effectiveness of these drugs.

Moreover, migraineurs in both these studies were excluded if they had not responded to two prior classes of migraine preventive medications. So, it's hard to say whether erenumab, fremanezumab, or other CGRP-targeted drugs in the pipeline will be effective options for people with refractory migraine.

Additionally, the studies examined only adults, so trials that study children and teens with migraine are also needed.

Sources:

Bigal ME, Walter S, Rapoport AM. Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache. 2013 Sep;53(8):1230-44.

Buse DC et al. Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache. 2012 Nov-Dec;52(10):1456-70.

Goadsby PJ et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 2017;377:2123-32.

Schuster NM, Rapoport AM. Calcitonin gene-related peptide-targeted therapies for migraine and cluster headaches: A review. Clin Neuropharmacol. 2017 Jul/Aug;40(4):169-74.

Silberstein SD et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017;377:2113-22.