Migraine Polygenic Risk Score Is Associated with Severity of Migraine - Analysis of Genotypic Data from Four Placebo-controlled Trials of Erenumab

Objective: To explore how disease and response to preventive treatment manifests across a range of migraine polygenic risk scores (mPRS), using clinical/genotypic data from placebo-controlled erenumab trials. Background: Migraine is a common disease with heterogeneous manifestations, the genetic basis of which is largely unknown. Examining patient-level mPRS and clinical characteristics/outcomes from clinical trials offers an opportunity to better understand how genetics influences disease and response to treatment. Design/Methods: 1,585 blood samples from consenting patients, ages 18–65, participating in 4 erenumab trials (3 episodic migraine, 1 chronic migraine) were genotyped and raw mPRS scores were pooled/standardized. Baseline characteristics and disease history were obtained; baseline and post-treatment clinical outcomes were assessed using a daily electronic diary. Results: mPRS distribution curves were similar across studies. There was no difference in baseline monthly migraine days (MMD), moderate to severe headache days, HIT-6 scores, or common comorbidities as a function of mPRS. With increasing mPRS, however, there was greater use of acute migraine-specific medication (AMSM), more common failure of prior migraine preventive medications (due to lack of efficacy or poor tolerability), and earlier onset of migraine. Lower placebo responses for change in MMD and change in monthly AMSM days were observed with increasing mPRS (statistically significant for latter). With increasing mPRS, statistically significantly greater efficacy of erenumab vs. placebo was noted for the endpoint assessing change in monthly AMSM days (but not for change in MMD): the additional erenumab treatment benefit vs. placebo at month 3 was 0.4 days reduction from baseline in monthly AMSM use per 1-unit increase in mPRS (p=0.02). Conclusions: Based on mPRS, migraine/nonmigraine headache frequency does not appear to have a strong genetic underpinning. mPRS-dependent phenotypic differences include earlier age of onset and greater likelihood of treatment with acute/preventive medications, suggesting that migraine patients with greater genetic predisposition may have greater disease severity. Disclosure: Dr. Mikol has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Amgen Inc.. Dr. Mikol has received compensation for serving on the Board of Directors of Amgen Inc.. Dr. Mikol holds stock and/or stock options in Amgen Inc.. Dr. Picard has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Amgen. Dr. Picard holds stock and/or stock options in Amgen which sponsored research in which Dr. Picard was involved as an investigator. Dr. Klatt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis. Dr. Klatt has received compensation for serving on the Board of Directors of Novartis. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Amgen. Dr. Peng has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Amgen. Dr. Stefansson has nothing to disclose.