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Galcanezumab Appears Effective in Preventing Migraines

May 30, 2017
A new migraine therapy shows promise in reducing the frequency and duration of migraine-related pain symptoms in phase III clinical trials, and is the first of several monoclonal antibodies to successfully achieve clinical endpoints.

Interviews with Rachel Colman, MD, Duren Michael Ready, MD, and Lawrence Robbins, MD

The monoclonal antibody, galcanezumab, has shown promise in phase III trials as a preventative agent for at least some patients with chronic and episodic migraines, according to a statement by Eli Lilly and Company.1

Galcanezumab is 1 of 4 calcitonin gene-related peptide (CGRP) monoclonal antibodies currently under investigation for migraine prevention. The findings will be presented at scientific meetings later this year and will be submitted for publication in peer-reviewed journals.

The findings are “significant and important for migraine patients,” said Rachel Colman, MD, assistant professor of neurology at the Center for Headache and Pain Medicine, Icahn School of Medicine at Mount Sinai in New York City. “CGRP is a viable target for drug development for migraines, with a rational mechanism.”

“We have been waiting for these medications for a while,” Duren Michael Ready, MD, program director for the Headache Medicine Fellowship at Baylor Scott & White Healthcare in Temple, Texas, told Practical Pain Management, “[CGRP monoclonal antibodies] represent the first medications developed to specifically target the migraine pathway.”

“A 50% responder rate is the gold standard for treatment efficacy in migraines, and is at the upper limit of our current therapies,” Dr. Ready said. “However, a problem with many of our current treatment options is their associated adverse events.”

Based on these recent trials, Lilly plans to submit a Biologics License Application to the US Food and Drug Administration (FDA) for galcanezumab in the second half of 2017,1 according to a Lilly press statement. 

Galcanezumab, a once monthly monoclonal antibody injection, was effective in lessening migraine pain in 3 clinical trials.

Findings From 3 Clinical Trials

The findings come from the 6-month EVOLVE1 and EVOLVE2 trials, which included patients with episodic migraines (4-14 migraine headaches per month), and the 3-month REGAIN trial, which involved patients with chronic migraines (≥ 15 migraine headaches per month).

Key findings of the studies included:

  • EVOLVE1: galcanezumab reduced headache days by an average of 4.7 days and 4.6 days with doses of 120 mg and 240 mg, respectively, compared with an average reduction of 2.8 days with placebo (P < 0.001 for both comparisons).
  • EVOLVE2: galcanezumab reduced headache days by an average of 4.3 days and 4.2 days with doses of 120 mg and 240 mg, respectively, compared with an average reduction of 2.3 days with placebo (P < 0.001 for both comparisons).
  • REGAIN: galcanezumab reduced headache days by an average of 4.8 days and 4.6 days with doses of 120 mg and 240 mg, respectively, compared with an average reduction of 2.7 days with placebo (P < 0.001 for both comparisons).

In all 3 studies, response rates and measures of daily activities also were significantly improved in patients taking galcanezumab compared with placebo.

Practitioners’ Clinical Perspective

The EVOLVE1 and EVOLVE2 trials show a significant reduction in the frequency of episodic migraine days, and that the results were reproducible, Dr. Ready told Practical Pain Management. Dr. Ready raised concerns, however, regarding the similar level of improvement found in the REGAIN (chronic migraine) trial compared to the EVOLVE (episodic migraine) trials.

“I would be interested in knowing the factors that might explain this similarity,” said Dr. Ready. “It may be that migraine progresses along a different pathway and that blocking CGRP only takes you so far. CGRP may start the process of progression from episodic to chronic migraines, but another mechanism may continue the progression. It is also important to know if these results are stackable (ie, demonstrate continued improvement with longer duration of use).”

Lawrence Robbins, MD, neurologist at Robbins Headache Clinic in Riverwoods, Illinois said, “the studies demonstrate that  galcanezumab is useful for cutting down the number of migraine days." He noted that "while some people will not benefit from treatment, others will do well—with a 50% to 90% reduction in headache days—and will probably continue treatment long term.”

“CGRP is a key inflammatory compound, and we have drugs already that do involve blocking CGRP,” said Dr. Robbins, “onabotulinumtoxinA [Botox] may [block CGRP] and the triptans may, in a final common pathway, block CGRP.”

Long-Term Safety Data Is Needed

“At present, the cost, and therefore the availability of these drugs in unknown, which will influence how they can be used,” Dr. Colman said. “They all appear to be safe and have a low side-effect profile, which is very important, but long-term safety data is lacking since these [agents] are only currently used inside of clinical trials.”

“Currently, onabotulinumtoxinA and topiramate are our most effective preventives,” Dr. Robbins noted. “The CGRP inhibitors will help many patients with migraine, but they will not change everything. For one, doctors will (rightly) be cautious about prescribing these agents initially as we do not know about their long-term side effects.”

“CGRP is widely distributed throughout the body, is a vasodilator, and may be involved in cardiac disease and possibly cerebrovascular disease as a protecting agent,” Dr. Robbins said. “If we block CGRP long-term, we do not know if, and how much, that increases our risk of cardiovascular disease.”

“Utility of CGRP monoclonal antibodies will entirely depend on access,” Dr. Ready told Practical Pain Management. “I would imagine that cost will be the same whether the diagnosis is episodic migraine or chronic migraine,” said Dr. Ready, who added that insurance companies may be reticent to cover the costs for the treatment of episodic migraine or may limit treatment to a certain duration of time.

Lifestyle Modifications Remain Necessary

“The danger with CGRP monoclonal antibodies isn’t in the possibility of adverse events, but rather the potential complacency that these agents might cultivate in patients,” Dr. Ready said. “They may look at having migraine as indicating that they have too much CGRP, rather than as a product of a sensitive nervous system that requires management.”

“Just as taking a statin medication does not mean that we are able to have that chicken fried steak with gravy on a regular basis, using a CGRP monoclonal antibody will not relieve patients of the responsibility for managing their sensitive nervous system,” Dr. Ready told Practical Pain Management. “The great opportunity that these therapies afford is reducing headache frequency, which is a significant perpetuating factor for migraines. The more migraines patients have, the more they are going to have in the future. It is as if the brain learns how to make migraines.”

“The purpose of the migraine pain is to shut the individual down, and the principal pathway by which it does this is typically with CGRP,” Dr. Ready continued. “However, if that pathway is blocked, there is no way to know if the brain will not use a different pathway to accomplish the same results. Thus, it will be important for clinicians to work even more vigilantly with patients to completely manage their sensitive brain through adherence to lifestyle modifications."

Going forward, researchers are assessing the efficacy of the treatment in cluster headache, which earned fast track status from the FDA, with phase 3 trial results anticipated in 2018.

Dr. Colman has no relevant disclosures. Dr. Ready has served on the advisory boards for Alder and Amgen. Dr. Robbins is a speaker for Merck and has trained physicians on the use of onabotulinumtoxinA for chronic migraine through Allergan. 

Last updated on: June 1, 2017
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