Migraine induction with calcitonin gene-related peptide in patients from erenumab trials

Abstract

Background: Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP.

Methods: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark.

Results: Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p = 0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0-90 min (p = 0.009), and 2-12 h (p = 0.014). The median peak headache intensity score was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p = 0.004).

Conclusions: Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy.

Trial registration: Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400 .

Keywords: Biomarker; CGRP; Headache; Monoclonal antibody.

Conflict of interest statement

MA is a consultant or scientific advisor for Allergan, Amgen, Alder, Eli Lilly, Novartis and Teva, principal investigator for: Amgen 20120178 (Phase 2), 20120295 (Phase 2), 20130255 (Open label extension), 20120297 (Phase 3), 20150308 (Phase 2), ElectroCore GM-11 gamma-Core-R, TEVA TV48125-CNS-30068 (Phase 3), Novartis CAMG334A2301 (Phase 3) and Alder PROMISE-2. MA has no ownership interest and does not hold stock in any pharmaceutical company. MA serves as associated editor of Cephalalgia and co-editor of the Journal of Headache and Pain. SK has acted as invited speaker for Novartis. The remaining authors report no competing interests.

Figures

Fig. 1

Intracellular signaling pathways of calcitonin gene-related peptide receptor activation. One effect of CGRP receptor activation is adenylate cyclase-mediated cyclic adenosine monophosphate (cAMP) elevation, which leads to protein kinase A (PKA) activation, and activation of multiple targets depending on cell type. Nitric oxide synthesis may be the result of nitric oxide synthase (NOS) phosphorylation, gene transcription changes may be a result of cAMP response element binding protein (CREB) activation, and relaxation of vascular smooth muscle cells is partly a result of ATP-sensitive potassium channels (K+ channels) activation

Fig. 2

Questionnaire used for monoclonal antibody response stratification. Patients who reported excellent effect of treatment (efficacy score ≥ 50%) in at least two of the four outcome variables (i-iv) were defined as high responders. The remaining patients were defined as poor responders

Fig. 3

Inclusion flowchart. Twenty-three patients were enrolled in the study. Ten of these were excluded subsequently. One patient was excluded due to a cardiac conduction disease and one due to diabetes mellitus (well-regulated), according to the conventional CGRP provocation protocol. Three patients were excluded from analysis as they did not participate in the erenumab trials. One patient withdrew consent before the experiments. Four patients were lost to follow-up and one of these had participated in the first study day. Data from these days were excluded from analyses. Of the ten patients, who were excluded, seven had received erenumab and six of these were high responders. Response status was not obtained from the last of the seven subjects

Fig. 4

Proportion of patients who developed migraine-like attacks and headache after CGRP and placebo. More patients developed migraine-like attacks after CGRP (n = 10), compared to placebo (n = 0) (p = 0.002)

Fig. 5

Headache intensity after CGRP and placebo. Individual headache intensity scores on the CGRP day (a) and placebo day (b). Black lines: Median intensity at each time point. The median headache intensity was 0 for all time points after placebo. The median time (range) to onset of migraine was 50 min (20–152.5) after CGRP