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CGRP-targeted therapies: A great leap forward in migraine treatment?

Jairia Dela Cruz
13 Feb 2018

Fully monoclonal antibodies (mAb) that target the calcitonin gene–related peptide (CGRP), particularly fremanezumab and erenumab, show potential in migraine prevention, significantly reducing the frequency of attacks in patients with chronic or episodic migraine, according to data from two phase III trials.

In the first trial, 1,130 adult patients with chronic migraine were randomized to receive subcutaneous injections of fremanezumab 675 mg either quarterly (n=376) or monthly (n=379) or monthly injections of placebo (n=375) over 12 weeks. The mean number of headache days per month at baseline in the respective treatment groups was 13.2, 12.8 and 13.3. [N Engl J Med 2017;377:2113-2122]

Over the 12-week treatment period, the primary endpoint of mean change in the number of headache days per month was greater with both the quarterly and monthly dosing of the anti-CGRP mAb vs placebo (4.3 and 4.6 vs 2.5, respectively; p<0.001 for both comparisons). A reduction of at least 50 percent in the mean number of headache days per month was observed in 38 percent in the quarterly group and 41 percent in the monthly group as compared with 18 percent in the placebo group (p<0.001 for both comparisons).

In terms of safety, hepatic function abnormalities were documented in patients in each fremanezumab group (1 percent) and three patients in the placebo group (<1 percent). Injection-site reactions were common, occurring in 47 percent of those receiving fremanezumab quarterly and monthly and in 40 percent of those receiving placebo.

Meanwhile, in the second trial, 955 episodic migraine patients (mean age 40.9 years) were randomized to receive monthly subcutaneous injections of erenumab at either 70 mg (n=317) or 140 mg (n=319) or placebo (n=319) for 6 months. [N Engl J Med 2017;377:2123-2132]

The primary endpoint of change in mean number of migraine days per month from baseline to months 4 through 6 was significantly higher with both erenumab dosing vs placebo. From the mean baseline number of 8.3 days overall, there was a reduction of 3.2 days with the 70-mg dosing and of 3.7 days with the 140 mg dosing vs 1.8 days with placebo (p<0.001 for both erenumab dosing vs placebo).

A reduction of 50 percent in the mean number of migraine days per month was reported for 43.3 percent of patients in the 70-mg group and 50.0 percent in the 140-mg group as compared with 26.6 percent in the placebo group (p<0.001 for both). Furthermore, the number of days of use of acute migraine–specific medication decreased significantly in both erenumab groups vs placebo (–1.1 and –1.6 days, respectively, vs –0.2 days; p<0.001 for both).

Treatment with erenumab also yielded notable improvements in physical-impairment scores (4.2 points with 70-mg and 4.8 points with 140-mg erenumab vs 2.4 points with placebo; p<0.001 for both) and in everyday-activities scores (5.5 points with 70 mg and 5.9 with 140 mg vs 3.3 points with placebo; p<0.001 for both).

No significant between-group differences were seen in the frequency and severity of adverse events, serious adverse events, and adverse events leading to discontinuation of the trial regimen.

Next frontier for migraine

A 37-amino acid neuropeptide widely distributed throughout the central and peripheral nervous systems, CGRP is said to play a significant role in migraine pathophysiology. As reported previously, CGRP concentrations are elevated interictally in chronic migraine and to a lesser extent in episodic migraine. The levels rise during spontaneous attacks and drop after administration of triptans in parallel with symptomatic relief. [Curr Treat Options Neurol 2017;19:27]

In a linked editorial piece, Dr Andrew D. Hershey from the University of Cincinnati College of Medicine in US highlighted that a migraine-specific preventive treatment directed against a suspected underlying pathophysiological mechanism is an important advance for patients with migraine. [N Engl J Med 2017;377:2190-2191]

“As mechanisms of migraine are revealed by advances in neuroimaging, biomarker identification and genomic analysis, one may expect new compounds to bring a brighter future to our patients who have migraine,” he added.

However, Hershey noted that it will be a challenge to identify unique patient populations who will respond to a specific drug or determine whether one agent is superior to others given the ongoing development of four different antibodies targeting the CGRP pathway.

“Furthermore, many patients will probably still have a response to standard multidisciplinary treatment that is less costly in patient and provider time and dollars,” he wrote.

Still, Hershey did not discount that the anti-CGRP mAbs might find a specific role in the treatment of patients with migraines refractory to treatment or those who are severely disabled by headaches in light of evidence indicating the rapid effect of the agents and a number of patients becoming completely headache-free.

“For the long term, it will be important to determine whether the beneficial effect can be sustained after discontinuation or whether continued treatment will be necessary,” he said.

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