乌鸦传媒

LAS VEGAS -- Fremanezumab (Ajovy) received FDA approval in 2018 for the prevention of episodic and chronic migraine prevention. But the trials supporting approval of the agent, which functions by targeting calcitonin gene-related peptide (CGRP), excluded patients who had failed two or more preventive medications, and those who had common comorbidities.

Two studies presented at the 2019 PAINWeek conference explored fremanezumab effects in these subgroups.

FOCUS Trial

Fremanezumab reduced headache among patients who had failed to respond to two to four other classes of migraine preventive treatments at 12 weeks versus placebo, according to results from the FOCUS study.

Among 837 participants, fremanezumab showed significantly reduced mean monthly migraine days versus placebo when administered quarterly (95% CI −3.8 to −2.4, P<0.0001) and monthly (95% CI −4.2 to −2.8, P<0.0001), reported Ladislav Pazdera, MD, of Vestra Clinics in Rychnov nad Kněžnou, Czech Republic.

And it worked fast, achieving at least a 50% reduction in the number of monthly migraines compared with placebo by as early as 4 weeks, though less than half of patients achieved this endpoint, she reported in a poster. The findings were published in 2019 in the .

"Placebo responses were low and decreased with increasing number of classes of prior preventive treatments failed, while significant improvements in efficacy were observed with fremanezumab compared with placebo, even in patients who had previously experienced an inadequate response to 4 different classes of migraine preventive treatments," Pazdera's group wrote.

Elizabeth Loder, MD, MPH, of Harvard Medical School in Boston said the follow-up in this study was "relatively short" and its not known whether the "quite modest" improvements in migraine days will be sustained over time.

Loder, who was not involved in the study, also noted that, as with many trials evaluating preventive treatments for migraine, this study struggled to reach the benchmark 50% reduction in migraine days in even half of patients, which perhaps reflects the heterogeneity of the condition.

"The question of whether medications work in patients who have not benefited from other preventive medications is an important one, since those patients are difficult to treat," Loder told 乌鸦传媒. "It makes sense that prior treatment failures may indicate the presence of more severe disease."

She also noted the overall number of headache days are not shown, meaning some participants might be classified as achieving the endpoint because they have a reduction in severity of headache.

The trial enrolled adult patients who had failed to respond to preventative migraine medications within the past 10 years across 104 international sites. Participants were then randomly assigned to either the quarterly fremanezumab arm -- in which they got 675 mg at month 1 and placebo at months 2 and 3 -- or the monthly arm, in which episodic and chronic migraine patients got 225 mg and 675 mg of fremanezumab in month 1, respectively, and then 225 mg at months 2 and 3. A third arm was administered monthly placebo for 12 weeks.

Adverse events (AEs) were similar across all arms; the most common were injection-site erythema, injection-site induration, and nasopharyngitis. Serious adverse events occurred in six patients but were not treatment-related.

HALO Trial

Fremanezumab was also effective among chronic migraine patients with acute medication overuse, according to a post-hoc analysis of the HALO trials, which were used to support the drug's approval.

Among 477 chronic migraine patients with acute medication overuse, fremanezumab reduced the number of migraine days by at least half in 37% and 48% of patients on the quarterly and monthly regimen, respectively, reported Stephen Silberstein, MD, of Thomas Jefferson University in Philadelphia.

Also, roughly 60% no longer met the criteria for acute medication overuse at 6 months in both the quarterly and monthly arms, which was maintained through the 1-year mark, he reported.

The "medication overuse" diagnosis is controversial and it remains unclear whether frequent use of medication is causing headaches to be worse, or rather that individuals with more severe headache tend to require more medication, Loder said.

"Some people -- not me -- feel that overuse of symptom relieving medication might render preventive treatment less effective," Loder said. "Thus, it is reasonable to do a post-hoc analysis of trial participants who had medication overuse to see how they fare."

For this study, adult patients with confirmed chronic migraine were rolled over from the phase III HALO trials and also enrolled from the community. New enrollees were allowed to continue stable use of two concomitant migraine preventive medications and rollover participants were permitted to continue using one. Rollover patients were not enrolled if using onabotulinumtoxinA, opioids, or barbiturates in the time preceding the study, though these exclusions were not applied to new patients.

In this study, acute medication overuse was defined as acute headache medication use on ≥15 days, migraine-specific acute medication use on ≥10 days, or use of combination medications for headache on ≥10 days.

Loder emphasized that the post-hoc nature of this analysis and the lack of a placebo comparator make this study "hypothesis-generating" at most.

"It is also the case that the method of enrolling participants in these studies may have favored positive findings," Loder said, adding that rollover patients were the ones who did not drop out of the study due to adverse events or lack of efficacy.

Participants on the quarterly schedule received 675 mg at baseline and placebo at weeks 4 and 8, while those in the monthly arm were administered 675 mg at baseline and 225 mg at weeks 4 and 8.

Those included were a mean age of about 46, who had been diagnosed with migraine 23 years prior. About a quarter were on current preventive medication at the time of the trial as well.

Fremanezumab also reduced the number of days patients required medication by about 8 days at 1 year in both the quarterly and monthly arm, Silberstein reported. It also reduced headache-related disability, measured through scores at 1 year in the quarterly (-6.9 points) and monthly groups (-8.1).

The most common AEs were injection-site reactions in both groups, with <10% of patients in both the quarterly and monthly arms experiencing a serious AE. However, 12% and 11% of patients developed an upper respiratory tract infection in the quarterly and monthly arms, respectively.