STOP 301: A Phase 3, open-label study of safety, tolerability, and exploratory efficacy of INP104, Precision Olfactory Delivery (POD® ) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients.

OBJECTIVE: To report the safety, tolerability, exploratory efficacy, and patient acceptability of INP104 for the acute treatment of migraine from the Phase 3 STOP 301 trial. BACKGROUND: Dihydroergotamine (DHE) has long been used to treat migraine, but intravenous administration is invasive, frequently associated with adverse events (AEs), and not suitable for at-home administration. INP104 is an investigational drug device that delivers DHE mesylate to the upper nasal space using a Precision Olfactory Delivery technology and was developed to overcome the shortcomings of available DHE products. METHODS: STOP 301 was an open-label, 24-week safety study, with a 28-week extension period. After a 28-day screening period where patients used their "best usual care" to treat migraine attacks, patients were given INP104 (1.45 mg) to self-administer nasally with self-recognized attacks. The primary objective of this study was to assess safety and tolerability, with a specific focus on nasal mucosa and olfactory function. Exploratory objectives included efficacy assessments of migraine measures and a patient acceptability questionnaire. RESULTS: A total of 360 patients entered the 24-week treatment period, with 354 patients dosing at least once. INP104-related treatment-emergent AEs were reported by 36.7% (130/354) of patients, and 6.8% (24/354) discontinued treatment due to AEs over 24 weeks. No new safety signals were observed following delivery to the upper nasal space. Pain freedom, the most bothersome symptom freedom, and pain relief at 2 h post-INP104 were self-reported by 38.0% (126/332), 52.1% (173/332), and 66.3% (167/252) of patients, respectively. A low recurrence rate at 24 and 48 h was observed (7.1% [9/126] and 14.3% [18/126], respectively). Most patients found INP104 easy to use and preferred it over their current therapy. CONCLUSIONS: INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient use. Results suggest INP104 may be a promising treatment for patients with migraine.

STOP 101: A Phase 1, Randomized, Open-Label, Comparative Bioavailability Study of INP104, Dihydroergotamine Mesylate (DHE) Administered Intranasally by a I123 Precision Olfactory Delivery (POD® ) Device, in Healthy Adult Subjects.

OBJECTIVE: Investigate the safety and pharmacokinetics (PK) of INP104, intranasal dihydroergotamine mesylate (DHE) administered via a Precision Olfactory Delivery (POD® ) device, (Impel NeuroPharma, Seattle, WA) vs intravenous (IV) DHE and DHE nasal spray (Migranal® ) in healthy adult subjects. METHODS: This was a Phase 1, open-label, randomized, single-dose, 3-period, 3-way crossover study. Subjects received a single dose of A) INP104 1.45 mg (a drug-device combination product composed of DHE and the I123 POD device); B) DHE 45® Injection (IV) 1.0 mg; and C) DHE by Migranal® Nasal Spray 2.0 mg. Plasma levels of DHE and the major bioactive metabolite, 8'OH-DHE, were measured, and PK parameters were determined for both. Comparative bioavailability (BA) was assessed by calculating the ratio of the geometric means between treatments for Cmax and AUC0-inf on the ln-transformed data. Safety was assessed from adverse events, vital signs, electrocardiograms, and clinical laboratory values. RESULTS: Thirty-eight subjects were enrolled, 36 were dosed with at least 1 IP and 27 were included in the evaluation of PK and comparative BA. DHE plasma levels following INP104 1.45 mg administration reached 93% of Cmax by 20 minutes and were comparable to IV DHE 1.0 mg by 30 minutes (1219 ng/mL for INP104 vs 1224 ng/mL for IV DHE), which was the Tmax for INP104. From 30 minutes onward, DHE levels for INP104 closely matched those of IV DHE to 48 hours, the last time point measured. In comparison, the Cmax for Migranal was 299.6 pg/mL (approximately 4-fold less than INP104) and occurred at 47 minutes, 17 minutes later than INP104. Plasma DHE AUC0-inf were 6275, 7490, and 2199 h*pg/mL for INP104, IV DHE, and Migranal, respectively. Variability (coefficient of variation [CV%]) for Cmax and AUC0-inf for INP104 compared to Migranal indicated more consistent delivery with INP104. In the BA comparison using the PK population (subjects who had received all 3 treatments), the ratios of geometric means (percent) for Cmax and AUC0-inf were 7.9% and 74.2%, respectively, for INP104: IV DHE, and 445% and 308% for INP104: Migranal. Mean plasma concentration profiles for 8'-OH-DHE were proportionately lower and followed a similar profile to the parent compound, regardless of route of administration (IN vs IV) or delivery system (Migranal vs INP104). Treatment emergent AEs (TEAEs), of mostly mild intensity, were reported by 15/31 (48.4%), 21/32 (65.6%), and 14/34 (41.2%) subjects after INP104, IV DHE, and Migranal, respectively. Treatment-related TEAEs occurred in 6/31 (19.4%), 16/32 (50.0%), and 4/34 (11.8%) subjects after INP104, IV DHE, and Migranal, respectively. CONCLUSION: INP104 met the predefined statistical criteria for comparative bioavailability with IV DHE and Migranal. The shorter time to reach Cmax and at 4 times the plasma concentration of DHE in comparison to Migranal combined with a favorable tolerability profile support further investigation of INP104 as an effective, well tolerated, and non-invasive treatment for acute episodic migraine.