The CGRP monoclonal antibody outperformed placebo for prevention

Galcanezumab (Emgality), a calcitonin gene-related peptide (CGRP) monoclonal antibody, bested placebo in reducing monthly headache days for people with treatment-resistant migraine, the phase IIIb CONQUER trial found.

Patients with episodic or chronic treatment-resistant migraine who used galcanezumab for migraine prevention had a mean 4.1 fewer migraine headache days per month, while the placebo group had 1.0 day less on average, compared with baseline (P< 0.001, effect size 0.72).

Treatment-related adverse events were similar between the galcanezumab (51%) and placebo groups (53%), with two patients in each group reporting a serious adverse effect: Behcet’s syndrome and lower limb fracture in the placebo group, and hemorrhoids and tonsillitis in the active treatment group.

“Galcanezumab 120 mg per month (with a 240-mg loading dose) is well tolerated and efficacious in the prevention of migraine in patients who had treatment failures of two to four categories of standard-of-care migraine preventive medications,” wrote Wim M. Mulleners, MD, Neurology Department, Canisius Wilhelmina Ziekenhuis, Nijmegen, the Netherlands, and colleagues in Lancet Neurology.

“With a mechanism of action developed specifically for the preventive treatment of migraine by inhibiting the action of CGRP, galcanezumab might represent an important treatment option for patients who have not benefited from or tolerated previous standard-­of-­care treatments, none of which were developed specifically for migraine,” they noted.

Among patients with either episodic or chronic migraine taking oral preventive medication, side-effects and lack of efficacy are the most common reasons for discontinuation.

Galcanezumab is a humanized monoclonal antibody that binds CGRP but does not block its receptor. It was approved in 2018 for migraine prevention and has been studied previously in episodic and chronic migraine. “However, those phase III trials excluded patients who had not responded to more than three classes of migraine preventive treatment,” Mulleners and colleagues pointed out.

To evaluate the safety and efficacy of galcanezumab in patients with episodic or chronic migraine who had treatment failures from two to four preventive medication categories, researchers looked at data from 462 adults (86% female, mean age about 46) with episodic or chronic migraine, with or without aura, that began a year or more before screening and before age 50.

Patients were required to have at least 4 migraine headache days monthly and at least 1 headache-free day per month in the last 3 months. Preventive treatment failure was also required, defined as lack of efficacy after 2 months at maximum tolerated dose or discontinuation due to side effects over the last 10 years with standard-of-care migraine prevention treatments including propranolol or metoprolol, topiramate, valproate or divalproex, amitriptyline, flunarizine, candesartan, botulinum toxin A or B, and medications locally approved for prevention of migraine.

Researchers randomized participants to placebo (n=230) or monthly subcutaneous 120 mg galcanezumab with a 240-mg loading dose (n=232). There were no meaningful differences between treatment groups in the distribution of medication category failures or reasons for failure.

Both groups had about 13 monthly migraine days at baseline and were followed for 12 weeks.

The mean percentages of patients with at least 50%, at least 75%, and 100% reduction from baseline in monthly migraine headache days were significantly greater in the galcanezumab group compared with placebo in the total population (all P<0.0001) and in the episodic migraine subgroup.

In the chronic migraine subgroup, 54% of the galcanezumab group and 24% of the placebo had at least 30% reduction in monthly migraine headache days (OR 3.8, 95% CI 2.2–6.3; P<0.0001). A greater proportion of patients in the galcanezumab group had at least 50% reduction (P<0.0001) and at least a 75% reduction (P=0.019) from baseline in monthly migraine headache days.

Nasopharyngitis was the most frequently reported adverse event in both treatment groups (placebo 9%, galcanezumab 7%). Probable hypersensitivity events occurred in 3% of both groups, with no anaphylaxis; no hypersensitivity events were serious. One patient in the galcanezumab group discontinued due to likely hypersensitivity (a moderate generalized rash).

Subgroup analysis of 29 patients who were 65–75 years old at the time of screening (6% galcanezumab, 7% placebo) showed no meaningful differences between groups for adverse events or laboratory parameters.

In an accompanying editorial, Uwe Reuter, MD, PhD, of Charite University of Medicine in Berlin, noted that “several clinical questions around monoclonal antibodies targeting the CGRP pathway for migraine prophylaxis remain.”

Still unknown is whether CGRP-pathway drugs provide benefit over a standard of care prophylactic medication in head-to-head trials, whether combination monoclonal antibody with standard-of-care was superior to monoclonal antibody monotherapy, and long patients using a CGRP monoclonal antibody need treatment, he observed.

“It is also important to understand why some patients have a low or no response to CGRP-targeting drugs,” Reuter observed. “A substantial number of patients (up to 50%) have a less than 50% response rate. About one-third of patients remain with a monthly migraine day reduction below 30% and, in some cases, have no response at all.”

“Fluctuations of response are common even in excellent responders,” he added. “These results imply that other factors beyond CGRP have a role in migraine pathophysiology.”

Limitations include the exclusion of patients with failures of more than four standard-of-care migraine preventive medication categories in the past 10 years, as well as excluding patients with serious or unstable medical conditions. These factors limit the generalizability of the findings for those populations.

  1. Galcanezumab, a calcitonin gene-related peptide monoclonal antibody, was better than placebo in reducing monthly headache days for people with treatment-resistant migraine in a phase IIIb trial.

  2. Patients with episodic or chronic treatment-resistant migraine who used galcanezumab for migraine prevention had a mean 4.1 fewer migraine headache days per month, while the placebo group had 1.0 less day on average, compared with baseline.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was funded by Eli Lilly.

Detke is an employee of Eli Lilly.

Reuter reported personal fees, non-financial support, and other from Amgen, Eli Lilly, and TEVA; other from Alder, Journal of Headache and Pain, and Frontiers in Neurology

Cat ID: 35

Topic ID: 82,35,730,35,192,925