Exploratory Efficacy of INP104 by Migraine Attack Severity and Time of Dosing: Results From the Phase 3 STOP 301 Study

Presented at PAINWeek Conference, September 7-11, 2021, Las Vegas, NV, USA

Authors: Brian D. Loftus, MD, Michelle Murphy, PhD, Christopher J. Fitzpatrick, PhD, Sutapa Ray, Stephen B. Shrewsbury, MB ChB, Sheena K. Aurora, MD

Purpose: It is increasingly recognized that oral drug delivery for the acute treatment of migraine may not be ideal for all patients due to underlying autonomic dysfunction. This is particularly evident in patients whose migraine attacks (MAs) are accompanied by gastrointestinal (GI) symptoms and comorbidities, which may affect the absorption of oral medications and/or lead to patient reluctance or inability to use oral therapies. Dihydroergotamine mesylate (DHE) is an efficacious acute treatment option for migraine that is familiar to headache specialists because of its long history of demonstrating sustained benefits even when used for difficult-to-treat migraine. DHE has also shown efficacy in treating MAs irrespective of time of dosing, whereas some other acute therapies are reported to be effective only when administered early in a MA or when the MA is still of mild severity. Intravenous (IV) administration of DHE is associated with a high response rate but is considered invasive and is not suitable for at-home use. Furthermore, adverse events such as nausea and vomiting frequently accompany its high maximum serum concentration (C_max) and limit its use. INP104 is an investigational drug-device combination product that delivers DHE to the upper nasal space using Precision Olfactory Delivery (POD®) technology, which avoids the issues associated with the gut and may be a suitable option for patients looking for an alternative to oral acute therapies. Results from a Phase 1 study (STOP 101) showed that INP104 achieved IV DHE-like blood levels from 30 minutes to 48 hours, but with a lower (C_max; ~1/10^th of IV DHE)and adverse event rate than IV DHE. The primary focus of the Phase 3 (STOP 301) study of INP104 for the acute treatment of migraine was to evaluate safety and tolerability of repeat use over 24/52 weeks, data which have been previously presented, but the study also included several self-reported exploratory efficacy outcomes. Here we report exploratory efficacy for MAs treated with delayed administration of INP104 and for INP104-treated MAs of moderate to severe intensity.

Methods: STOP 301 was a pivotal Phase 3, interventional, open-label, single-group assignment study that assessed the safety, tolerability, and exploratory efficacy of INP104 over long-term use (up to 52 weeks) at 38 centers across the United States. The study included a 28-day screening period during which patients took their best usual care (i.e. baseline), a 24-week treatment period in which patients self-administered INP104, a 28-week treatment continuation (52-week period) for a subset of patients, and a 2-week post-treatment follow-up for all patients. Following the screening period, all eligible patients were provided with up to 3 doses/week of INP104 to nasally self-administer (1.45 mg in a dose of 2 sprays) with self-recognized MAs. Daily eDiaries were completed to capture headache and migraine details, headache medication usage, and most bothersome symptom (MBS) severity from screening through 24 weeks and, if applicable, 52 weeks. Eligible patients were adult males or females aged 18-65 years with a documented diagnosis of migraine with or without aura not qualifying as chronic migraine and who were in general good health, which included no history of cardiovascular events. Patients were required to have experienced ≥2 MAs per month for the previous 6 months and also during screening, and to have completed eDiary entries on ≥23 of the 28 days during screening for eligibility. Primary endpoints included the number of patients reporting treatment-emergent adverse events, change in nasal mucosa as detected by nasal endoscopy, and change in olfactory function over 24 and 52 weeks. Exploratory measures included self-reported efficacy outcomes, such as pain and most bothersome symptom (MBS) freedom at 2 hours; pain and MBS freedom at 2 hours when INP104 was administered between 2-4 hours and >4 hours from migraine onset; and pain relief over 2 hours for MAs of any severity and for moderate to severe MAs only for the first INP104-treated MA. Because patients were permitted to administer acute therapies of their choice, sometimes more than one, to treat their MAs during baseline, statistical comparisons to best usual care during baseline were not possible.

Results: In total, 360 patients were screened and enrolled into the 24-week treatment period. Of those, 354 patients self-administered at least 1 dose of INP104 over the 24-week treatment period and comprised the 24-week full safety set (24-week FSS), with 73 patients continuing into the 28-week extension period (52-week FSS). A total of 262 and 66 patients completed the 24- and 52-week treatment periods, respectively. Most patients in the 24-week FSS were female (85.9%), with a mean age of 41.3 years, a long history of migraine (mean of 19.5 years) and experienced an average of 4.6 MAs during the screening. The majority of patients reported severe (65.3%; n=231) or moderate (32.2%; n=114) headache severity, while 2% (n=7) of patients reported mild headache severity during the 4-week screening period. Of patients who reported mild, moderate, or severe headache intensity prior to INP104 treatment, pain freedom at 2 hours was self-reported by 49%, 40%, and 30% of patients during Weeks 1-12, respectively, and by 60% , 31%, and 23% during Weeks 13-24, respectively. For those patients who treated their first MA with INP104 more than 2 hours after onset, pain freedom at 2 hours was self-reported by 39.4% (13/33) and 30.9% (17/55) of patients who treated their first MA with INP104 >2-4 and >4 hours from migraine onset. MBS freedom at 2 hours was self-reported by 65%, 56%, and 43% of patients who reported mild, moderate, or severe headache intensity prior to INP104 treatment, respectively, during Weeks 1-12. During Weeks 13-24, MBS freedom at 2 hours was self-reported by 78%, 50%, and 30% of patients who reported mild, moderate, or severe headache intensity prior to INP104 treatment, respectively. For those patients who treated their first MA with INP104 >2-4 and >4 hours from migraine onset, MBS freedom was self-reported by 57.6% (19/33) and 40.0% (22/55) of patients, respectively. Initial onset of pain relief (i.e. a decrease from severe or moderate pain to mild or no pain, or a decrease from mild pain to no pain) was self-reported for the first INP104-treated MA as early as 15 minutes by 16.3% (n=42) of patients and by 66.3% (n=167) of patients at 2 hours. Pain relief for only moderate or severe MAs was similarly self-reported by 17.3% (n=39) for patients at 15 minutes and by 68.9% (n=151) of patients at 2 hours.

Conclusion: Pain relief as early as 15 minutes and up to 2 hours irrespective of pain intensity was reported with INP104 use. While most patients treated their first MA within 2 hours of onset (as instructed), INP104 provided similar benefit at later administration time points. Results suggest that INP104 may be a promising acute treatment for migraine patients with all levels of symptom severity, including moderate to severe MAs, and that it can be efficaciously administered with no treatment window limitations.

Citation: Loftus BD, Murphy M, Fitzpatrick CJ, Ray S, Shrewsbury SB, Aurora SK, Exploratory Efficacy of INP104 by Migraine Attack Severity and Time of Dosing: Results From the Phase 3 STOP 301 Study, PAINWeek Conference, September 7-11, 2021