Subcutaneous injections of the investigational calcitonin gene–related peptide (CGRP) antibody galcanezumab (Eli Lilly and Co) is especially effective at 120 mg for the prevention of episodic migraine, suggests a phase 2b dosing trial.
The study of more than 400 patients showed that those who self-administered a once-monthly injection of galcanezumab 120 mg or 300 mg had significantly greater overall change from baseline to 3 months in migraine headache days (MHDs) than those receiving matching placebo.
However, only the 120-mg dose met the primary objective of “posterior probability of greater improvement (Bayesian analysis) in MHDs” than the specified threshold of 95% for mean change vs placebo, write the investigators. The posterior probability was 99.6% for this treatment group, which had mean reductions of 4.8 MHDs by week 12 vs reductions of 3.7 MHDs in the placebo group.
“It’s always important to find the lowest effective dose and to confirm previous studies that reported on the efficacy and tolerability of galcanezumab,” David W. Dodick, MD, professor of neurology and director of the headache program at the Mayo Clinic, Scottsdale, Arizona, and chair of the American Migraine Foundation, told Medscape Medical News.
Common treatment-related adverse events (AEs) for the galcanezumab group vs the placebo group included injection-site pain, upper respiratory tract infection, and nasopharyngitis — with most being mild to moderate in intensity.
The study findings were published online December 18 in JAMA Neurology.
FDA Review
According to a press release from the manufacturer last week, the US Food and Drug Administration (FDA) has accepted a Biologics License Application (BLA) to review galcanezumab, in auto-injector pen or prefilled syringe, for preventive treatment of migraine in adults.
The BLA application included data from the phase 3 EVOLVE-1 and EVOLVE-2 trials of more than 1700 total patients with episodic migraine, as well as more than 1100 patients with chronic headache who participated in the phase 3 REGAIN trial.
As reported by Medscape Medical News from this year’s American Headache Society (AHS) Annual Scientific Meeting, patients in both EVOLVE studies who received 120 or 240 mg of galcanezumab had significantly greater reductions in MHDs at 6 months than did those receiving matching placebo, the primary endpoint.
In REGAIN, MHDs were reduced by 4.8 and 4.6 vs 2.7 days, respectively, at 3 months (all, P < .001).
Significantly greater AEs in the treatment group than the placebo group included injection-site reaction in all three trials, injection-site pruritus in the two EVOLVE trials, injection-site erythema in EVOLVE-2 and REGAIN, and sinusitis in REGAIN only.
Also presented earlier this year were positive results for the anti-CGRP agents fremanezumab (Teva Pharmaceuticals) from the phase 3 HALO-CM and HALO-EM trials, eptinezumab (Alder BioPHarmaceuticals) from the phase 3 PROMISE trial, and erenumab (Amgen and Novartis) from the phase 3 STRIVE and ARISE trials.
“This is the first class of medicine designed specifically to treat migraine. All of the other treatments were originally approved for some other use,” Eric Pearlman, MD, PhD, medical lead for headache in the US Medical Affairs Group at Eli Lilly, said at this year’s AHS meeting.
“There are some very exciting days ahead for patients and for clinicians, in my opinion. This is a brand new era in migraine therapy,” said Dr Dodick. “It’s having multiple biologics in a class that are becoming available, perhaps, in the same year and that are disease-specific. The pipeline looks very promising.”
Superior Efficacy
The current multisite trial was conducted in the United States between July 2014 and August 2015. A total of 936 patients were originally assessed, but only 410 met entry criteria, which included having 4 to 14 MHDs per month and being aged 18 to 65 years (mean age, 40.2 years; 83% women).
After initial screening and washout for other treatments, the patients were monitored for 28 to 38 days to establish a baseline for MHD frequency.
The participants were then randomly assigned to receive once-monthly self-administered subcutaneous injections of placebo (n = 137) or galcanezumab 5 mg (n = 68), 50 mg (n = 68), 120 mg (n = 70), or 300 mg (n = 67) for a total of 3 months.
All treatment group members combined had a mean of 6.7 MHDs per month vs 6.6 per month for the placebo group members.
As stated earlier, the galcanezumab 120-mg group showed superiority to the placebo group, with a 99.6% posterior probability of greater improvement at 3 months — and reductions by 4.8 MHDs vs 3.7 MHDs, respectively. The 90% Bayesian credible intervals for each were –5.4 to –4.2 MHDs vs –4.1 to –3.2 MHDs, respectively.
At 1 month, the placebo group had 3 fewer MHDs than at baseline. Compared with placebo, mixed-model repeated measures showed that galcanezumab at 5, 50, and 300 mg had significantly greater MHD reductions (by 3.8, 4.0, and 4.2 MHDs, respectively) at this time period (P = .045, .02, and .004; respectively).
At month 2, only the 300-mg group had significantly greater reductions in MHDs than the placebo group (–4.5 vs –3.6 MHDs, respectively; P = .03).
However, the overall change from baseline through month 3 was significantly greater for the 120-mg and 300-mg groups (both, –4.3 MHDs vs –3.4 MHDs for placebo; P = .02).
Secondary outcomes that were greater for the 120-mg group than for the placebo group included reductions in migraine plus probable MHDs (P < .001), in probable MHD (P < .05), and in migraine attacks (P = .003) and having a 50% or 100% response rate (P = .03 and .04, respectively).
Blocking the CGRP Pathway
Treatment-emergent AEs (TEAs) were found in 51.1% of patients receiving placebo vs 53.1% of all participants receiving some dose of galcanezumab. This finding was not significantly different.
TEAs that were significantly greater in an active treatment group than in the placebo were the following:
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Injection-site pain in the 120-mg group (P = .006) and 300-mg group (P = .01);
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Nasopharyngitis in the 5-mg group (P = .007); and
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Dysmenorrhea in the 50-mg group (P = .02).
Upper respiratory tract infection was reported by 10.3%, 11.8%, 11.4%, and 6.0% of the 5-, 50-, 120-, and 300-mg groups, respectively — none of which were significantly different from the 8.8% reported by the placebo group.
No patients died in this study. Only two galcanezumab group members withdrew from the trial because of an AE.
Serious AEs included Crohn’s disease in one participant in the 5-mg group, suicidal ideation in one patient in the 300-mg group with a history of prior suicide attempts, and one occurrence of hospitalization for appendicitis in the 120-mg group. Also, there was one report of congenital ankyloglossia in an infant whose father was in the 300-mg group. None of these serious AEs were considered to be treatment related.
Overall, “galcanezumab administered in monthly…injections for 3 months was efficacious and well tolerated for the prevention of episodic migraine,” write the investigators.
They add that the findings “justify further development” of galcanezumab, especially at 120 mg, in larger trials.
“This study also reinforces the whole concept of blocking the CGRP pathway in patients with migraine,” said Dr Dodick. “This is one of a number of studies that have been done in four different antibodies in the episodic and chronic migraine populations that have consistently shown favorable efficacy and tolerability profiles,” he said.
“This just reinforces what is becoming obvious to the entire academic community. This is a pathway that is important in the biology of migraine and clearly when one blocks that pathway, one gets favorable patient outcomes.”
Justifiable Excitement, With Caveats
Asked to comment, Elizabeth Loder, MD, chief of the Division of Headache, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts, told Medscape Medical News that the results were in line and consistent with other antibody studies in migraine.
“There weren’t any surprises here. And, as with the other studies, I’d characterize the results as ‘modest.’ It was a modest reduction and not the home run everybody would like to see,” said Dr Loder.
“But clearly these treatments are effective, I don’t think there’s any doubt about that, and they are fairly well tolerated.”
She noted, though, that upper respiratory tract infections and nasopharyngitis are AEs that “seem consistent across some of the trials — and it’s not clear what’s going on there. That doesn’t seem like a particularly serious adverse event, but it does call into question what the mechanism might be,” she said.
In addition, the serious AEs “seem to include inflammatory conditions: the Crohn’s disease exacerbation, the appendicitis. I’ve seen a few adverse events like that in the other trials, and it makes me wonder if there might be something going on with these treatments,” said Dr Loder.
“Of course that’s the sort of thing we’ll have a better understanding on” once these treatments are in use in clinical practice. “These preapproval trials are just too small to pick up rare adverse events that will then become more obvious once the antibody is in widespread use.”
Dr Loder added that postmarketing data for this class of drugs will be especially important because it’s completely new and not similar to anything that is currently available for the treatment of migraine. “And they’re being used for long periods of time in a population that is otherwise healthy and relatively young.”
Many of the patients are also women of child-bearing age. A patient could get an injection and then become pregnant, so exposure is inevitable, she noted. “So I certainly hope that the FDA will mandate pregnancy registries being maintained by the manufacturers.”
Overall, “there’s justifiable excitement because this is a new approach to treating migraine. And it’s gratifying to see years of laboratory research into CGRP and its effects pay off in the form of new treatments,” said Dr Loder.
But a big concern will be pricing, she added. “I will be very disappointed if these treatments are priced at a level that will prevent the most severely affected patients from accessing them.”
The study was funded by Eli Lilly and Company. Dr Dodick has served without compensation on advisory boards and/or has consulted within the past 5 years for Eli Lilly and Company, Allergan, Amgen, Alder, Arteaus, Pfizer, Colucid, Merck, NuPathe, Autonomic Technologies, Ethicon J&J, Zogenix, Supernus, Labrys, Boston Scientific, Medtronic, St Jude, Bristol-Myers Squibb, Lundbeck, Impax, MAP, Electrocore, Tonix, Novartis, Teva, Alcobra, Zosano, Insys, GBS/Nocira, and Acorda; has served as a paid consultant on an advisory board for eNeura; owns equity in Epien, GBS/Nocira, and Second Opinion; and has received funding for travel, speaking,or editorial activities or royalty payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, American Academy of Neurology, American Headache Society, West Virginia University Foundation, Canadian Headache Society, Healthlogix, Wiley, Universal Meeting Management, WebMD, UptoDate, Medscape, Oregon Health Science Center, Starr Clinical, Decision Resources, and Synergy. A full list of disclosures for the other study authors is in the original article. Dr Loder has disclosed no relevant financial relationships.
JAMA Neurol. Published online December 18, 2017. Abstract
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