No Benefit of Fremanezumab in Posttraumatic Headache

Jim Kling

June 09, 2021

A phase 2 study of the anti-calcitonin gene–related peptide (CGRP) antibody fremanezumab found no benefit of treatment in persistent posttraumatic headache. Anti-CGRP therapy had been predicted to be effective, given its history of improving other forms of headache, and preclinical studies had suggested that CGRP plays a role in late pain sensitization that can occur after mild brain injuries.

"There was a decrease in migraine headache days of moderate or severe intensity in both groups. But the difference between fremanezumab and placebo treatment was not statistically significant, either looking at that on a monthly basis or over the total 12 weeks of treatment," Egilius L.H. Spierings, MD, PhD, said during his presentation of the results at the American Headache Society’s 2021 annual meeting. Spierings is medical director of the Boston Headache Institute.

Disappointing Findings

"That’s sad. It’s just dreadful news," Stewart J. Tepper, MD, professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., said in an interview. Tepper was not involved in the study. The results suggest that CGRP mechanisms may not be relevant to persistent posttraumatic headache, but it could still play a role at onset. "We have to rethink this. Either it’s that chronic, persistent posttraumatic headache does not have a CGRP biology, or it’s that you have to get to them earlier [in the disease process]," he said.

The negative results were surprising, according to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and former president of the International Headache Society. He noted that the study was small, and the researchers were unable to conduct subgroup analyses. "Posttraumatic headaches are usually broken down into those that phenotypically look like migraine, or phenotypically look like tension-type headache. It would have been nice to know if most of them had what clinically appears to be tension-type headache, and maybe that’s why they didn’t respond. Or did most of them have a migraine phenotype, and then it would be a little more surprising that they didn’t respond," Rapoport said in an interview.

As a result, he believes that further studies might show that fremanezumab is an effective treatment for posttraumatic headache. "I would not give up on it. I expect that a larger study with better power, and a better idea of exactly what was wrong with the patients, might end up being a positive study," he said.

Although most posttraumatic headaches resolve within weeks or months, some can linger or become chronic for years. Pain medication is often prescribed but should not be, according to Rapoport, because it can lead to medication overuse headache that worsens the problem. "So we badly need a good temporary preventive treatment. The thought of giving our newest, most effective preventive medications, with few adverse events, is a good one. It just didn’t seem to work in this fairly small and underpowered study," he said.

The Phase 2 Trial

The trial included 87 patients with new-onset or significant worsening of headache following a minor traumatic brain injury or concussion, who were randomized to treatment with 675 mg subcutaneous fremanezumab once monthly, or placebo. The average elapsed time since the trauma was 8.1 years in the placebo group and 9.3 years in the fremanezumab arm. The average number of moderate to severe headache days was 18.5 days in the placebo group and 18.4 days in the fremanezumab group. The initial 12-week randomized period was followed by an open-label period in which patients on placebo received the study drug.

After 12 weeks of treatment, there was a greater decrease in moderate to severe headache days in the placebo arm, though the difference was not statistically significant (–5.1 versus –3.6 days; P = .1876). At 1 month, the two groups were similar (–4 days placebo versus –3.6 days fremanezumab), but there was a greater reduction in the placebo arm at 2 months (–6.7 versus –3.7 days) and 3 months (–7.21 versus –5.2 days).

A secondary endpoint was the proportion of patients who experienced a 50% or greater reduction in moderate to severe headache days, and there was no significant difference between placebo and fremanezumab after 12 weeks (26% versus 21%) or at month 1 (26% versus 19%), month 2 (33% versus 19%), or month 3 (28% versus 33%).

Adverse events occurred more often in the placebo group (81% versus 72%), and all were mild or moderate, with the exception of one that occurred in the placebo group. There were no deaths, and no meaningful changes in laboratory or clinical examinations.

Spierings is on the advisory board for Satsuma, is a speaker for Teva, Amgen, Novartis, Eli Lilly, Lundbeck, Biohaven, and AbbVie, and has been a clinical trial principal investigator for Teva, Novartis, Eli Lilly, Biohaven, and Satsuma. Tepper has been a consultant for Teva. Rapoport has consulted for Teva and has been a speaker for Teva.

This article originally appeared on, part of the Medscape Professional Network.


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