Preclinical and clinical evaluation of LY3451838, a PACAP-neutralizing monoclonal antibody, in randomized, double-blind, placebo-controlled phase 1 and phase 2 studies involving healthy adults and adults with treatment-resistant migraine

Aim LY3451838 is a monoclonal antibody against pituitary adenylate cyclase-activating peptide (PACAP), a target in migraine research. The present study aimed to evaluate LY3451838 as a preventive treatment for participants with treatment-resistant migraine. Methods Following preclinical assessment of LY3451838, including pharmacokinetic and pharmacodynamic studies, safety was evaluated in a phase 1 study of LY3451838 (n = 33) versus placebo (n = 13) in healthy participants. A phase 2 trial was carried out in treatment-resistant participants with chronic migraine (CM) (n = 16) or episodic migraine (EM) (n = 22). In phase 2, participants received a single intravenous (IV) dose of 1500 mg LY3451838 (n = 19) or placebo (n = 19) and completed ePRO daily diaries. Participants were followed for safety for 140 days. Results In phase 2, at one-month post-dose, patients who had received a single IV dose of LY3451838 exhibited greater changes from baseline than placebo in mean monthly migraine headache days in both the CM and EM subgroups (CM: −4.7 days vs. −3.0 days; EM: −1.7 days vs. −1.2 days), but the treatment contrast was not statistically significant in either subgroup. Similar non-significant results were seen at the three-month time point. The percentage of participants reporting treatment-emergent adverse events was similar for LY3451838 and placebo, with one serious adverse event of B-cell lymphoma in an LY3451838-treated participant that led to study discontinuation. Conclusions LY3451838 did not demonstrate superior efficacy over placebo in patients with treatment-resistant CM or EM. However, the difference observed between LY3451838 and placebo among CM patients is similar to the statistically significant difference reported in the recent HOPE trial, which primarily consisted of CM patients. Further clinical research with larger sample sizes is needed to inform on the utility of blocking PACAP in various migraine populations. Trial Registration ClinicalTrials.gov: NCT03692949 (phase 1); NCT04498910 (phase 2).