Acute Migraine Agent INP104 to Be Assessed in Phase 3 STOP 301 Trial

September 17, 2019

Impel NeuroPharma's nasal dihydroergotamine mesylate acute migraine therapy INP104 has shown excellent pharmacokinetic data, and is set to be assessed in a 24-week trial with a planned 28-week extension.

Stephen B. Shrewsbury, MD

New data of INP104, a nasal dihydroergotamine (DHE) mesylate administered by precision olfactory delivery (POD) device, support the progression of the Impel NeuroPharma agent to the phase 3 STOP 301 trial in acute migraine, suggesting that INP104 administration results in high plasma exposure to DHE in the first 2 hours.1

Additionally, a significant reduction was shown in the max plasma concentration (Cmax) of DHE following INP104 treatment relative to intravenous administration, which investigators noted may lead to more favorable tolerability of INP104. The data were presented at the 19th Congress of the International Headache Society (IHC) this month in Dublin, Ireland.

"Our growing body of evidence supports the potential of INP104 to be a transformative new therapy for acute migraine. INP104 utilizes our sophisticated and proprietary new device technology to deliver optimal doses of dihydroergotamine (DHE) to the vascular-rich upper nasal cavity, resulting in peak drug concentration levels that may be more effective for patients," said Stephen B. Shrewsbury, MD, chief medical officer, Impel NeuroPharma, in a statement.2

The pharmacokinetic data from STOP 101, a phase 1 safety study, showed that the area under the curve (AUC0—2hr) following the administration of1.45 mg INP104, 2 mg migranal, and intravenous DHE 45 was 1603 hr*pg/mL, 387.5 hr*pg/mL, and 3,022 hr*pg/mL, respectively. Following the 14,90 pg/mL Cmax value for intravenous DHE, INP104 was highest at 1301 pg/mL, with Migrainal’s Cmax registering as 299.6 pg/mL.

Additionally, utilizing a review of literature, Shrewsbury and colleagues found that the probability of nausea is <2% when plasma DHE Cmax is ≤5,000&thinsp;pg/mL, whereas at 13,400&thinsp;pg/mL, the probability of nausea is ≥50%.

The phase 3 STOP trial design was also presented at the IHC meeting, with the goal of enrolling 300 patients for a long-term 24-week study and 28-week extension evaluation seeking to enroll about 80 of the participants. It will assess the safety and efficacy of intermittent use of INP104 for the treatment of acute migraine. STOP 301 will explore the efficacy of INP104 compared to baseline, as well as its impact on the quality of life and healthcare utilization.3

All of the subjects enrolled will have extensive migraine history, healthcare utilization, and quality of life assessments conducted during screening, with treatment response recorded in an e-diary. Olfactory mucosal integrity and function will be collected by endoscopy of the upper and lower nasal spaces and using the University of Pennsylvania Smell Identification Test (UPSIT) at intervals.

"Importantly, because INP104 is designed to deliver a reduced dose of DHE compared to FDA-approved and investigational products in development, patients may be able to reap the established efficacy benefits of DHE, without the undesired side effects that are typically experienced with delivery to the lower nasal space," Shrewsbury said.

The findings of Impel’s I-BEAM patient survey further supported the use of INP104, with the agent meeting all 5 requirements described by the 50 surveyed patients, of which 34% and 30% reported rapid onset or early morning migraines, respectively. These patients noted they wanted an ideal medication to be fast-acting within 15-30 mins, long-lasting for 12 to 24 hours, to provide complete or near-complete relief, to be able to administer it during migraine, and to have few or no adverse effects. Although, many surveyed individuals noted they were willing to accept minor adverse effects as a tradeoff for increased speed and efficacy.4

That survey also unveiled that 96% of respondents were taking prescription medication for migraine, though only 30% felt it was satisfactory, with most patients reporting unreliable efficacy and short-lasting relief. More than half of the individuals stated that the speed of effect onset was dissatisfactory, and up to 68% noted that their relief lasted less than 12 hours, with pain often returning or worsening. Additionally, 30% of those surveyed reported seeking emergency migraine care in the past year despite access to the standard of care.

REFERENCES

1. Satterly KH, Shrewsbury SB, Hoekman J. Comparison of Early Plasma Exposure to DHE by Nasal, Oral Inhalation, or Intravenous Administration. Presented at: IHC 2019; September 5-8; Dublin, Ireland. Abstract IHC-DP-036.

2. Impel NeuroPharma to Present Data From INP104 Clinical Program at the 19th Congress of the International Headache Society [press release]. Seattle, Washington: Impel NeuroPharma; Published September 5, 2019. prnewswire.com/news-releases/impel-neuropharma-to-present-data-from-inp104-clinical-program-at-the-19th-congress-of-the-international-headache-society-300912746.html. Accessed September 16, 2019.

3. Shrewsbury SB, Jeleva M, Hocevar-Tnka J, Swardstrom M. STOP 301: Open-label Safety and Tolerability of Chronic Intermittent Usage for 24/52 Weeks of INP104 [Nasal Dihydroergotamine Mesylate (DHE) Administered by Precision Olfactory Delivery (POD) Device] in Migraine Headache. Presented at: IHC 2019; September 5-8; Dublin, Ireland. Abstract IHC-PO-377.

4. Shrewsbury SB, Ray S. Impact and Burden of Episodic, Acute Migraine (I-BEAM): A Patient Experience Study. Presented at: IHC 2019; September 5-8; Dublin, Ireland. Abstract IHC-PO-299.