The Upper Nasal Space as a Promising New Route for Drug Administration : Implications for Nasal Safety Assessments From the Pivotal STOP 301 Study of INP104 - Abstract
Objective: To report the nasal safety of INP104, a drug-device that delivers dihydroergotamine mesylate to the upper nasal space using Precision Olfactory Delivery, for the acute treatment of migraine. Methods: STOP 301 was a Phase 3 open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 (1.45 mg) in adult migraine patients over 24 and 52 weeks. Primary endpoints were the number of patients reporting Treatment-emergent Adverse Event (TEAEs), change in nasal mucosa as detected by nasal endoscopy (Quantitative Scoring Scale for Evaluation of the Nasal Mucosa [QSS-NM]), and change in olfactory function (University of Pennsylvania Smell Identification Test [UPSIT]) over 24 and 52 weeks of treatment. Further, whether nasal endoscopy was necessary to monitor INP104 safety or whether monitoring patient-reported TEAEs was adequate was investigated. This involved an independent Nasal Safety Review Committee (NSRC) comprised of 3 otolaryngology experts who reviewed blinded data. Results: Overall, 354 patients received ?1 dose of INP104 over 24 weeks and 73 patients continued into extension period. Over 24 and 52 weeks, 45.8% and 58.9% of patients reported a nasal TEAE, respectively, of which none was serious. Minimal mean decreases (<0.5), over 24 weeks, and mean increases/decreases (?1.0), over 52 weeks, from baseline were observed in the UPSIT score and at all time points. The UPSIT detected 17 cases of subclinical olfactory reduction in patients with nasal TEAEs of “olfactory test abnormal,” most of which resolved (14 cases). Mean increases from baseline in QSS-NM total score were minimal (?0.2) at each visit up to 52 weeks. Conclusion: The NSRC concluded that patient-reported TEAEs were sufficient to monitor INP104 nasal safety, and that nasal endoscopies and the UPSIT added no clinical value. There were no significant safety concerns, including no reports of persistent olfaction decrease, and all TEAEs were minor.