Improvements in Disability and the Interictal Period with INP104: Results from the Phase 3 STOP 301 Study
posted in Presentations by Brooke Eger
Presented at PAINWeek Conference, September 7-11, 2021, Las Vegas, NV, USA
Authors: Dawn C. Buse, PhD, Cynthia E. Armand, MD, Robert Vann, PhD, Sutapa Ray, Stephen B. Shrewsbury, MB ChB, Sheena K. Aurora, MD
Purpose: Migraine is a highly prevalent and debilitating condition. In 2016, it was estimated that 1.04 billion individuals have experienced a migraine attack and 45.1 million years were lost to disability. The consequences of migraine can include significant functional, physical, emotional, economic, and social impairments and places substantial burden on individuals during (i.e. the ictal period) and in between attacks (i.e. the interictal period). Unlike the ictal burden, which is well-recognized and understood, the interictal burden is complex and can extend past the days of the migraine attack into other aspects of daily life. Several epidemiological studies reported that it is common to feel anticipatory anxiety or depression about future migraine attacks, which can result in difficulty making plans and avoidant behavior, thereby negatively affect one’s quality of life. As disease burden, anxiety, and headache-related disability increases with headache frequency, and given the unpredictability of migraine attacks, some patients overuse acute medications during headache-free periods out of anticipation or fear of a migraine developing. A recent study reported that patients with acute medication overuse were more likely to have moderate to severe interictal burden. Therefore, there is a need for new and effective acute treatment options to rapidly resolve migraine symptoms and provide a sustained benefit to potentially reduce interictal symptoms. INP104 is an investigational drug-device combination product for the acute treatment of migraine that targets delivery of dihydroergotamine mesylate (DHE) to the upper nasal space using Precision Olfactory Delivery (POD®) technology. Previously presented exploratory efficacy data reported that INP104 was associated with improvements in pain freedom, most bothersome symptom freedom, and pain relief at 2 hours; sustained pain freedom at 24 and 48 hours; low use of rescue medication; low recurrence rates; and consistency of response for either the first treated migraine attack or across multiple attacks over 24 and 52 weeks. Here we report data on headache-related disability using the Migraine Disability Assessment (MIDAS) questionnaire, evaluating time between migraine attacks and frequency of migraine attacks, which were exploratory outcome measures relevant to interictal burden, from the Phase 3, STOP 301 study of INP104 for the acute treatment of migraine.
Methods: STOP 301 was a pivotal, Phase 3, open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 at 38 centers across the United States. Following a 28-day screening period during which patients were on their best usual care (i.e. baseline), eligible patients continued into a 24-week treatment period with INP104, with a subset allowed into a 28-week treatment extension (52-week period). All patients were included in a 2-week, post-treatment, follow-up 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 migraine attacks at the end of screening. Eligible patients were adult males or females aged 18-65 years with a documented diagnosis of migraine with or without aura and not qualifying as chronic migraine. Daily eDiaries were completed to capture headache and migraine details. Patients were required to be in general good health, with no history of cardiovascular events, must have experienced ≥2 migraine attacks 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. Exploratory efficacy measures included the MIDAS questionnaire, which is a validated, highly reliable instrument that measures headache-related disability. The MIDAS questionnaire grading system categorizes disability as follows: Grade I = minimal or infrequent disability (scores of 0-5); Grade II = mild or infrequent disability (scores of 6-10); Grade III = moderate disability (scores of 11-20); Grade IVa = severe disability (scores of 21-40); and Grade IVb = severe disability (41-270). The MIDAS questionnaire was completed by patients during screening, baseline, at Weeks 12 and 24, and if applicable, at Weeks 36 and 52. The time between migraine attacks was also determined during screening and Weeks 1-24 of INP104 treatment using Kaplan-Meier methods to estimate the median interval length.
Results: A total of 360 patients were screened and enrolled into the 24-week treatment period and 354 patients self-administered at least 1 dose of INP104 over 24 weeks (24-week full safety set [FSS]). Of the 262 patients who completed 24 weeks of treatment, 73 patients were allowed to continue into the 28-week extension period (52-week FSS) and 66 patients completed the 52-week treatment period. For the 24-week FSS, the mean MIDAS total score for patients was 25.1 at baseline. The most frequent scores were Grade III (28.8%; 102/354) and Grade IVa (27.7%; 98/354), indicating moderate to severe disability at study initiation. For the 24-week FSS population, the mean MIDAS total score at Week 12 was 18.4, with a mean change from baseline of -5.5, and at Week 24, the mean 24-week FSS MIDAS total score was 17.4, with a mean change from baseline of -7.4. Most patients had improved MIDAS scores of Grade III or better at Weeks 12 and 24. For the 52-week FSS, the mean MIDAS total score for patients was 24.6 at baseline. The most frequent scores were Grade III (31.5%; 23/73) and Grade IVa (31.5%; 23/73), indicating moderate to severe disability at study initiation. At Weeks 12, 24, 36, and 52, the mean 52-week FSS MIDAS total score was 18.8, 20.3, 15.3, and 14.9, with a mean change from baseline of -5.8, -5.1, -7.8, and -8.9, respectively. Most patients had MIDAS scores of Grade III or better at Weeks 12, 24, 36, and 52. During Weeks 1-24, the median time between migraine attacks was 6 days compared to 4 days at baseline. The mean number of migraine attacks by 4-week intervals was 1303, 980, 785, 726, 676, and 638 at Weeks 4, 8, 12, 16, 20, and 24, respectively.
Conclusion: Use of INP104 was associated with improvements in migraine-related disability as assessed by the MIDAS questionnaire. At each post-baseline visit, the mean MIDAS total score in both 24-week and 52-week FSS populations decreased, with mean total scores suggestive of moderate residual disability. The time between migraine attacks was longer with INP104 use over 24 weeks compared to baseline when patients were on their best usual care. Furthermore, the frequency of migraine attacks decreased over 24 weeks. Results suggest that long-term use of INP104 may have positive effects on interictal burden by reducing disability attributed to migraine, prolonging the headache-free period, and decreasing the frequency of migraine attacks.
Citation: Buse DC, Armand CE, Vann R, Ray S, Shrewsbury SB, Aurora SK, Improvements in Disability and the Interictal Period with INP104: Results from the Phase 3 STOP 301 Study, PAINWeek Conference, September 7-11, 2021