PO-19 | Unraveling the spectrum of migraine resistant to treatments: searching for novel biological PHEnotypes and theRApeutic approaches (SPHERA project)

M. Giraudo,^1,2 R. De Icco,^1,2 G. Vaghi,^1,2 V. Grillo,^1,2 F. Bighiani,^1,2 M. Corrado,² A. Antoniazzi,^1,2 F. Cammarota,^1,2 B. Agostini,^1,2 A. Solfrizzi,^1,2 M. Allena,² E. Guaschino,² N. Ghiotto,² R. Greco,² C. Demartini,² A. Zanaboni,^1,2 M. Francavilla,^1,2 S. Facchetti,^1,2 G. Sances,² C. Tassorelli^1,2 | ¹Department of Brain and Behavioral Sciences, University of Pavia; ²Headache Science and Neurorehabilitation Unit, IRCCS Mondino Foundation, Pavia, Italy

Background: Around 30% of migraine individuals do not achieve a satisfactory disease control (Non-responders) with monoclonal antibodies targeting the CGRP pathway (mAbs). These subjects may bear a non CGRP-dependent migraine phenotype. We previously reported alterations in the endocannabinoid system (eCBome) in subjects with migraine, with alterations of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) peripheral expression. The primary objective of the SPHERA project is to assess whether migraine individuals Non-Responder to mAbs present specific dysfunctions of the eCBome system.

Methods: In this longitudinal prospective study, we enrolled 45 subjects (86.7% women, age 42.5±10.1) with either high frequency episodic or chronic migraine. 40% of participants were treated with fremanezumab, 34% with galcanezumab, 21% with erenumab and 5% with eptinezumab. Participants were evaluated at baseline (T0) and after three months of treatment with an anti-CGRP mAB (T1). Non-Responders were defined as those individuals who did not achieve a reduction of at least 50% in monthly migraine days (MMDs) at T1. At T0 and T1, all subjects underwent an extensive biochemical profiling, analyzing miRNA expression of MAGL and FAAH in peripheral blood mononuclear cells (PBMC), plasma levels of PEA and related lipids (AEA, 2-AG, OEA), neuropeptides (CGRP, PACAP, VIP), kinurenic and quinolinic acid, and pro- and anti-inflammatory cytokines (IL-1b, TNF-a, IL-4, IL-10).

Results: Of the 45 subjects who completed T1 evaluation, 26 were Responders (57.8%) and 19 were Non-Responders (42.2%). MAGL expression was higher in Non-responders (1.97±0.61 Relative quantification-RQ) compared to Responders (1.58±0.63 RQ, p=0.018), while FAAH expression did not differ between the two groups (Responders: 0.74±0.25 RQ vs. Non-responders 0.75±0.22 RQ, p=0.868). No differences were found in the other molecular markers assessed.

Conclusions: Non-responders to mAbs showed higher levels of MAGL, which suggests an increased turnover of the endocannabinoid 2-arachidonoylglycerol. This finding is in keeping with the demonstration that MAGL inhibitors block acute and chronic migraine-associated pain in experimental models and points to an additional pathway worth targeting in CGRP-resistant patients.