Deborah Brauser

June 14, 2017

BOSTON — The investigational calcitonin gene-related peptide (CGRP) antibody fremanezumab (TEV-48125, Teva Pharmaceuticals) is safe and highly effective for adult patients with migraine, results of two phase 3 studies show.

After the release earlier this month of positive topline results from the HALO-CM trial, which assessed more than 1000 patients with chronic migraine (CM), more detailed results were presented here at the American Headache Society Annual Scientific Meeting (AHS) 2017.

Those who received 675 mg of fremanezumab for 1 month followed by either a 225-mg dose at each of the following 2 months ("monthly dosing") or placebo for the next 2 months ("quarterly dosing") had a significantly reduced number of monthly headache days compared with those who received three monthly placebo injections only.

"Study results demonstrated robust statistical superiority of fremanezumab in primary and all secondary endpoints in both dose regimens," Ernesto Aycardi, MD, vice president and head of research and development for the therapeutic area of migraine and headache at Teva, told meeting attendees.

Last week, the manufacturer also released findings from its phase 3 HALO-EM trial, which included 873 patients with episodic migraine (EM). It showed that both the monthly and quarterly dosing groups in that study had greater reduction in monthly migraine days (MMDs) at 12 weeks than the placebo group (the primary endpoint).

On the basis of all the results, Dr Aycardi told Medscape Medical News that Teva plans to file a Biologics License Application with the US Food and Drug Administration in the second half of this year.

"When you see the whole package that fremanezumab is providing in these trials, it seems to be fulfilling the great majority of need that patients have, especially because we used a patient-centric design," he said.

Excitement in the Field

Currently, intense focus is on four investigational anti-CGRPs for the prevention of migraine.

Earlier this year, findings from the STRIVE and ARISE trials, which were presented at the American Academy of Neurology annual meeting, showed reduced frequency of episodic migraine in patients who received erenumab (AMG 334, Amgen and Novartis).

At the same AHS meeting session where HALO-CM was presented, positive results were reported for the phase 3 EVOLVE-1, EVOLVE-2, and REGAIN trials for galcanezumab (LY295174, Eli Lilly) and phase 2 results were presented for eptinezumab (ALD403, Alder BioPharmaceuticals).

Topline results from eptinezumab's phase 3 PROMISE trial are expected to be released by the end of this month.

Dr Aycardi pointed out, however, that fremanezumab's efficacy at both monthly and quarterly dosing in two types of migraine makes it, in his view, stand out from the other investigational drugs in this class.

"We are the only one with subcutaneous monthly and subcutaneous quarterly dosing," he said. "If approved, this will give flexible delivery for patients. They can choose the best way they want to manage their disease."

Chronic Migraine Results

In HALO-CM, 1130 patients (88% women; mean age, 41 years) were enrolled and randomly assigned to monthly (n = 379) or quarterly (n = 376) dosing of the study drug or to matching placebo (n = 375).

The primary endpoint of mean change from baseline in monthly days of at least moderate-severity headache was met for the fremanezumab groups, with reductions of 4.6 and 4.3 days vs 2.5 days, respectively (P < .0001 for both comparisons).

The following table also shows significant efficacy compared with placebo in key secondary endpoints. (All comparisons shown are P < .0001 except for quarterly dosing group on disability, measured by the Headache Impact Test [HIT-6], which was P = .0004.)

Table 1. Secondary Endpoints for Treatment Groups

Outcome Monthly Dosing Quarterly Dosing Placebo
≥50% reduction in headache days (responder rate, %) 40.8 37.6 18.1
Days of use of acute headache meds (change from baseline) –4.2 –3.7 –1.9
HIT-6 measured disability (change from baseline) –6.8 –6.4 –4.5


In addition, there were significantly greater reductions in headache days during the first 4 weeks for the combined fremanezumab group than for the placebo group (P < .0001).

Although 71% of the active drug group had at least one adverse event (AE), so did 64% of the placebo group. Injection site pain was the most commonly reported AE; no treatment-related serious AEs occurred.

Table 2. Adverse Events and Discontinuations by Treatment Group

Adverse Event Monthly Dosing (%) Quarterly Dosing (%) Placebo (%)
Injection site pain 26 30 28
Injection site induration 24 20 18
Injection site erythema 20 21 16
Injection site hemorrhage 2 2 3
AE-caused discontinuations 2 1 2


Session moderator Elizabeth Loder, MD, chief of the Division of Headache at Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News that all CGRP antibody trials have had "very consistent findings."

"They definitely seem to be statistically significantly superior to placebo, although the magnitude of the benefit is modest," said Dr Loder. She added that clinicians will want a lot of information about AEs, "and they are anticipating that these drugs will be very expensive."

"So with the modest reduction in number of headache days, they're going to want to weigh tolerability and other things that might sway you to choose this."

And in the future, "we're certainly going to be interested in subgroup analyses that will tell us who is more likely to benefit," she said.

Episodic Migraine

In the HALO-EM trial, 256 patients with EM were randomly assigned to receive 3 monthly doses of fremanezumab at 225 mg, 256 received 675 mg at initiation and then placebo for 2 months, and 361 received placebo only.

According to the topline press release, the full study population had a mean of 9.1 MMDs at baseline, which was reduced by 3.7 days for the monthly dosing groups and by 3.4 days for the quarterly group vs 2.2 days for the placebo group (P < .0001).

In addition, the number of days with disability was reduced by 64.7% for the treatment group and medication consumption was decreased by 39.0% (both outcomes, P < .0001).

MMDs were also significantly reduced for the monthly dosing group members who were taking stable doses of other prophylactics compared with the placebo group (–4 vs –2.0, respectively; P = .001), as well as for the quarterly dosing group members (–3.7;  P = .006).

"All other prespecified analyses were met and were highly statistically significant," the manufacturer reported. As in HALO-CM, injection site pain was the most commonly reported AE.

Dr Aycardi noted that more detailed results will be presented at the upcoming Congress of the International Headache Society in Vancouver, British Columbia, Canada. And the investigators plan to delve into multiple subgroup analyses, especially in women vs men and in various age groups.

Further, patients in both HALO studies will continue to receive active medication up to 1 year in order to evaluate long-term safety and efficacy, he added.

The study was funded by Teva. Dr Aycardi is an employee of Teva. Dr Loder has disclosed no relevant financial relationships.

American Headache Society Annual Scientific Meeting (AHS) 2017. Abstract IOR-5. Presented June 10, 2017.

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