Safety of INP104 in Migraine Patients With Cardiovascular Risk Factors: Post Hoc Subgroup Analysis of the Phase 3 STOP 301 Study

Presented at the AHS 65^th Annual Scientific Meeting, June 15-18, 2023, Austin, Texas

Authors: Dafer R, Tietjen G, Rothrock J, Hirman J, Vann R, Gutierrez J, Ray S, Shrewsbury S, Aurora S

One sentence summary: This post hoc subgroup analysis of the Phase 3 STOP 301 study evaluated the safety of INP104 (dihydroergotamine mesylate and the Precision Olfactory Delivery device) in migraine patients with non-significant cardiovascular risk factors, and the results were shown to be similar to those of the broader group.

Background: INP104 is a combination of dihydroergotamine mesylate (DHE) and the Precision Olfactory Delivery device approved for the acute treatment of migraine with or without aura in adults. The safety of INP104 has been previously reported in the Phase 3 STOP 301 trial. Although INP104 was well tolerated, DHE is contraindicated in patients with cardiovascular (CV) disease or significant risk factors for CV disease because of a theoretical risk for arterial vasoconstriction. Since migraine can be associated with a risk of CV events, evaluating the safety of INP104 or any migraine treatment specifically in patients with CV risk factors is warranted.

Methods: STOP 301 was a Phase 3 open-label study assessing the safety and tolerability of nasally self-administered INP104 (1.45 mg) in migraine patients over 24 weeks, with a subset continuing to 52 weeks. Exclusion criteria included ischemic heart disease; clinical symptoms or findings consistent with coronary artery vasospasm (including Prinzmetal’s variant angina); significant risk factors for coronary artery disease (CAD); current use of tobacco products; smoking history (≥10 cigarettes per day within the 12 months prior to screening); history of diabetes; known peripheral arterial disease; Raynaud’s phenomenon; vascular surgery (within 3 months prior to study start); or potentially unrecognized CAD as demonstrated by history, physical examination, or screening electrocardiogram. Patients with non-significant CV risk factors were included, such as a history of hypertension (if the hypertension was stable and well controlled on current therapies for >6 months provided that no other risk factors for CAD were present) or obesity, for example. The rates of treatment-emergent adverse events (TEAEs) were monitored in this subgroup.

Results: A total of 139 patients within the STOP 301 full safety population (N=354; defined as enrolled patients who received ≥1 dose of INP104) were identified as having non-significant CV risk factors. TEAEs were reported in 74.8% (n=104/139) of patients within this subgroup, the most common (≥5%) of which were nasal congestion (19.4%), upper respiratory tract infection (12.2%), abnormal product taste (7.9%), nasopharyngitis (6.5%), nasal discomfort (6.5%), nausea (6.5%), and urinary tract infection (5.0%). Few CV-related TEAEs occurred, including hypertension (2.9%), cardiac murmur (1.4%), bradycardia (0.7%), and sinus bradycardia (0.7%).

Conclusion: This is a post hoc subgroup analysis of all patients from STOP 301 with known non-significant CV risk factors. Overall, the most frequently occurring TEAEs with INP104 use were not cardiac related in migraine patients with non-significant CV risk factors. Further studies in patients with known stable CV risk factors in the absence of CV contraindications for DHE may be warranted.