Patients with episodic migraines had significantly fewer headache days when treated with a monoclonal antibody targeting calcitonin gene–related peptide (CGRP), results of a recent randomized clinical trial show.
The treatment was generally well tolerated, and also improved secondary efficacy outcomes; however, the investigators qualified the results, noting that the trial included patients who had failed two or fewer previous classes of migraine preventive medication.
“Further research is needed to assess effectiveness against other preventive medications, and in patients in whom multiple preventive drug classes have failed,” wrote , of Mayo Clinic, Phoenix, Ariz., and his coauthors. Long-term safety and efficacy also are needed, they added. Their report was published in .
Fremanezumab is a subcutaneously administered, fully humanized monoclonal antibody that binds to the CGRP ligand. A previous randomized phase 2b study showed that the treatment was effective in preventing migraine, with no serious treatment-related adverse events.
The current 12-week phase 3 trial (clinicaltrials.gov Identifier: ) was designed to evaluate the efficacy and safety of fremanezumab in two different dosing regimens. A total of 875 patients (742 women; 85%) with episodic migraine were randomly assigned to fremanezumab monthly dosing (225 mg at baseline, 4 weeks, and 8 weeks), a single higher dose of fremanezumab (675 mg at baseline) intended to support a quarterly dosing regimen, or placebo.
Both dosing approaches significantly reduced the mean number of migraine days per month vs. placebo, Dr. Dodick and his coinvestigators reported.
In the monthly dosing group, the mean number of migraine days per month decreased from 8.9 to 4.9, and compared with placebo (with a decrease from 9.1 to 6.5 days), the mean number of migraine days at 12 weeks was 1.5 days lower (P less than .001). Similarly, the mean number of migraine days decreased from 9.2 to 5.3 days in the single higher dose group, with a difference of 1.3 days vs. placebo (P less than .001).
Significantly more patients receiving fremanezumab had a 50% or greater reduction in mean number of migraine days per month, suggesting a clinical response to the CGRP monoclonal antibody, the investigators said.
The most common adverse events leading to discontinuation included erythema at the injection site in three patients, along with induration, diarrhea, anxiety, and depression occurring in two patients each, according to the report. There was one death in the study due to suicide 109 days after the patient received a single higher dose of the study drug. However, the investigators determined that the death was unrelated to treatment.
One limitation of the study, investigators said, is that it excluded patients with treatment refractory migraine who had failed at least two previous preventive drug classes, and those who had continuous headache.
“Further studies are needed to define the full spectrum of efficacy and tolerability of fremanezumab, including in patients who are treatment refractory and who have a range of coexistent diseases,” they wrote.
Teva Pharmaceuticals supported the study. Dr. Dodick and his coauthors reported disclosures related to Teva, Amgen, Novartis, Pfizer, and Merck, among other entities.
SOURCE: Dodick DW et al. .
While this report on fremanezumab by Dr. Dodick and colleagues adds important evidence on the efficacy and safety of CGRP monoclonal antibodies, authors of a related editorial said several questions remain regarding this particular clinical trial and the drug class in general.
Of note, the study of fremanezumab excluded patients who failed two or more previous classes of medications. “This means the results of this trial may not necessarily apply to patients with severe, treatment-resistant migraine, who are the patients most likely to be prescribed and have access to these treatments in clinical practice,” Elizabeth W. Loder, MD, MPH, and Matthew S. Robbins, MD, wrote in their
Patients who received monthly fremanezumab had fewer migraine days per month versus placebo, as did patients who received a single higher dose of the medication. However, in both instances, the differences were smaller than the 1.6-day difference that was specified in the sample size calculation, added Dr. Loder and Dr. Robbins.
Though long-term safety data are needed, fremanezumab seemed generally well tolerated over 12 weeks in this study. “An important apparent benefit of fremanezumab and the other 3 CGRP monoclonal antibodies in development is their low burden of common nuisance adverse events,” they wrote.
However, it is “sobering to consider” the three deaths documented in clinical trials of CGRP monoclonal antibodies, they said. That total includes one patient in this study who committed suicide 109 days after receiving a 675-mg dose of fremanezumab.
The death may not have been related to treatment, the editorial authors said, noting that depression and other affective disorders are often comorbid with migraine.
“The [Food and Drug Administration] undoubtedly will scrutinize the deaths and adverse events reported in the trials of fremanezumab and other CGRP monoclonal antibodies,” they wrote. “If the result is restrictive labeling, it could greatly limit the patient population for these drugs, which are in any case likely to prove costly and challenging for patients to access.”
Dr. Loder is in the division of headache, department of neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Robbins is with Montefiore Headache Center, Albert Einstein College of Medicine, New York. These comments are derived from their editorial in JAMA. Dr Loder reported receiving grants and other funds from companies developing CGRP antibodies. Dr. Robbins reported that he is principal investigator for a clinical trial sponsored by eNeura.