Does "wearing off" of efficacy occur in galcanezumab-treated patients at the end of the monthly treatment cycle? Post hoc analyses of four phase III randomized trials

Abstract

Objective: The purpose of this study was to propose a definition of "wearing off" at the individual patient-level and determine the percentage of patients with migraine who experience "wearing off" of efficacy of galcanezumab at the end of a treatment cycle using this predefined threshold.

Background: Anecdotal reports suggest that some patients may experience "wearing off" of efficacy during the last week of their calcitonin gene-related peptide monoclonal antibody treatment cycle. A previous post hoc analysis of galcanezumab demonstrated consistent efficacy at each week throughout all monthly dosing intervals at the population-level, but "wearing off" has not been assessed at the individual patient-level.

Methods: Post hoc analyses of clinical trial data from four galcanezumab phase III, randomized, placebo-controlled studies in a total of 2680 patients with high-frequency episodic migraine (EVOLVE-1, EVOLVE-2, and CONQUER studies) or chronic migraine (CM; REGAIN and CONQUER studies) were conducted. "Wearing off" was defined as an increase of greater than or equal to 2 weekly migraine headache days in the last week of the treatment cycle compared to the second week for at least 2 months. The analyses were conducted (1) in all patients and (2) in patients with a clinically meaningful response to treatment.

Results: The percentage of patients meeting the threshold of "wearing off" was not statistically significantly different among the placebo, galcanezumab 120 mg, and galcanezumab 240 mg treatment groups, both in the total population and in patients with a clinically meaningful response (all ≤9.0%). Although the frequency of "wearing off" in patients with CM and prior preventive failures was numerically greater in the galcanezumab groups (8/89 or 9.0%) compared to placebo (3/95 or 3.2%), these differences were not statistically significant.

Conclusions: Consistent with previous analyses at the population-level that showed no evidence of decreased efficacy at the end of a treatment cycle, rates of individual patients meeting the threshold of "wearing off" in this analysis were low and similar among placebo, galcanezumab 120 mg, and galcanezumab 240 mg treatment groups.

Trial registration: ClinicalTrials.gov NCT02614183 NCT02614196 NCT02614261 NCT03559257.

Keywords: calcitonin gene-related peptide; galcanezumab; migraine; migraine prevention; monoclonal antibody; wear off.

Conflict of interest statement

J.A. has received honoraria for consulting from Amgen, Allergan/Abbvie, Aeon, Biohaven, Eli Lilly and Company, GlaxoSmithKline, Lundbeck, Teva, Impel, Satsuma, Nesos, Theranica, Axsome, and Medscape. She received honoraria for speaking from Allergan, Amgen, Biohaven, Eli Lilly and Company, Lundbeck, and Teva. She also received honoraria for editorial services from Current Pain and Headache Reports, Section editor, Unusual Headache Syndromes, NeurologyLive, and SELF. Clinical trial grants have been paid to J.A.’s institution from the American Migraine Foundation, Allergan, Biohaven, Eli Lilly and Company, Satsuma, and Zosano. DKK, MR, TO, KS, LW, and MP are employees and minor stockholders of Eli Lilly and Company. A.M.B. has received honoraria for serving on advisory boards of Allergan, Aeon, Alder, Amgen, Biohaven, Eli Lilly and Company, Novartis, Revance, Teva, Theranica, and Zosano. He has received fees for speaking from Allergan, Amgen, Eli Lilly and Company, and Teva and as a consultant for Allergan, Alder, Amgen, Biohaven, Eli Lilly and Company, Novartis, Teva, Theranica, and Zosano. He has been a contributing author in partnership with Novartis, Teva, Allergan, and Biohaven. He has received grant support from Allergan and Amgen.

© 2022 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.

Figures

FIGURE 1

Study design. The duration of the double‐blind treatment period was 6 months for EVOLVE‐1 and ‐2 and 3 months for REGAIN and CONQUER. Months 1 to 3 of EVOLVE‐1 and ‐2 and month 1 of REGAIN and CONQUER were used to determine whether the patient had a clinically meaningful response. “Wearing off” was calculated using data from months 4 to 6 in EVOLVE‐1 and ‐2 and months 2 and 3 in REGAIN and CONQUER. Month 1 was not included in the analysis because a loading dose of 240 mg was administered

FIGURE 2

Percentage of total patients who experienced “wearing off”. Percentage of patients with HFEM (A) and CM (B) who had “wearing off” for 2 months, and percentage of patients with HFEM who had “wearing off” for 3 months (C). “Wearing off” was defined as an increase of greater than or equal to 2 migraine headache days per week from week 2 (8 to 14 days post‐treatment) to week 4 (7 days prior to next dose) during 2 or 3 months of months 4 to 6 in EVOLVE‐1 and ‐2 or in both months 2 and 3 in REGAIN and CONQUER. Two‐sided Fisher’s exact test was used to compare rates of “wearing off” between treatment groups. The p values were greater than 0.05 for all comparisons between treatment groups. Refer to Table S2 for exact p values. CM, chronic migraine (≥15 monthly headache days of which ≥8 are migraine headache days); GMB, galcanezumab; HFEM, high‐frequency episodic migraine (8–14 monthly migraine headache days and <15 monthly headache days); N, number of patients in each subgroup; PBO, placebo

FIGURE 3

Percentage of patients with a clinically meaningful response who experienced “wearing off”. 1A clinically meaningful response was defined as patients with HFEM who had a ≥50% reduction from baseline in monthly migraine headache days across months 1 to 3 in EVOLVE‐1 and ‐2 and in month 1 in CONQUER, and patients with CM who had a greater than or equal to 30% reduction from baseline in monthly migraine headache days in month 1 in REGAIN and CONQUER. 2“Wearing off” was defined as an increase of greater than or equal to 2 migraine headache days per week from week 2 (8 to 14 days post‐treatment) to week 4 (7 days prior to next dose) during 2 or 3 months of months 4 to 6 in EVOLVE‐1 and ‐2 or in both months 2 and 3 in REGAIN and CONQUER. Two‐sided Fisher’s exact test was used to compare rates of “wearing off” between treatment groups. The p values were greater than 0.05 for all comparisons between treatment groups. Refer to Table S3 for exact p values. CM, chronic migraine (≥15 monthly headache days of which ≥8 are migraine headache days); GMB, galcanezumab; HFEM, high‐frequency episodic migraine (8–14 monthly migraine headache days and <15 monthly headache days); N, number of patients in each subgroup; PBO, placebo