Selective Activation of the Adrenomedullin Receptors in Migraine

Adrenomedullin is an endogenous neuropeptide structurally related to CGRP that can activate both the adrenomedullin receptor and, to a lesser extent, the CGRP receptor. Prior human provocation studies have shown that administration of adrenomedullin can elicit migraine attacks in people with migraine. Because adrenomedullin lacks receptor selectivity, physiological responses observed after its administration might represent a composite of adrenomedullin-receptor activation and potential off-target activation of the CGRP receptor. The extent to which selective activation of the adrenomedullin receptor alone can provoke migraine-relevant responses remains unknown.

To isolate adrenomedullin receptor-mediated effects, participants will receive the monoclonal antibody erenumab prior to adrenomedullin administration in order to block CGRP receptor activation.

This study therefore aims to determine whether selective activation of adrenomedullin receptors - isolated from confounding CGRP receptor activation - can induce migraine-relevant physiological responses.

Inclusion criteria

• Written informed consent has been obtained prior to the initiation of any study-specific procedures.
• Age ≥18 years at the time of screening.
• History of migraine without aura for at least 12 months prior to screening, with a frequency of 1-5 migraine attacks per month, based on medical records and/or patient self-report, and diagnosed in accordance with the ICHD-3 criteria.

Exclusion criteria

• History of any other primary headache disorder, except for tension-type headache with <5 headache days per month, based on ICHD-3 classification.
• History of any secondary headache disorder, per ICHD-3 criteria, prior to screening.
• Use of prophylactic migraine medication within 30 days or within 5 plasma half-lives (whichever is longer) prior to screening.
• Previous use of any therapies targeting the CGRP signaling pathway, including anti-CGRP ligand monoclonal antibodies, anti-CGRP receptor monoclonal antibodies, or small molecule CGRP receptor antagonists.
• Known risk of self-harm or harm to others, including a history of suicidal behavior.
• Any clinically significant disorder, condition, or disease (other than those permitted in the protocol) that, in the opinion of the investigator, could compromise participant safety or interfere with study procedures or data integrity.
• Positive urine pregnancy test at screening or on Day 1 in female participants of childbearing potential.
• Pregnancy or breastfeeding, or plans to become pregnant or breastfeed during the study period.
• Evidence of current pregnancy or breastfeeding based on self-report or medical records.
• Inability or unwillingness to complete all protocol-required visits and procedures, or concerns regarding protocol adherence, as judged by the investigator.