Investigational DHE Nasal Powder STS101 Shows Tolerability in Phase 3 Study

Author(s):

The most common adverse events reported by individuals using the dihydroergotamine nasal powder were nasal discomfort, dysgeusia, and nasal congestion, all of which were mild and transient in nature.

Stewart J. Tepper, MD

Results from the ongoing, open-label ASCEND safety study (NCT04406649) showed that STS101 (Satsuma Pharmaceuticals), a novel investigational dihydroergotamine (DHE) nasal powder, was well-tolerated by individuals with migraine over a 12-month period and when needed on a PRN basis.¹

Led by Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine, Dartmouth, most of the adverse events (AEs) recorded with STS101 were mild and transient, with no serious AEs related to the study drug. In the follow-up examinations, investigators found no clinically significant differences on nasal examinations, electrocardiograms, and vital signs. The multicenter, open-label, 12-month study presented at the 2022 American Headache Society (AHS) Annual Meeting, June 9-12, in Denver, Colorado, included 273 individuals who were treated with up to 2 doses of STS101 5.2 mg within 24 hours of their attack for up to 12 doses per month. The population mean age was 39 (±11) years, 89% of the cohort was female, and 84% were Caucasian.

During his presentation, Tepper was asked about the decision to use a dose of 5.2 mg, with the questioner noting generally higher than what is seen with other nasal interventions, and whether the dose was what led to the rates of AEs observed. “There have been multiple presentations of the pharmacokinetics of the different formulations, and there was a lot of discussion as to whether the 5.2-mg dose was the proper dose,” he said. “It appeared to put the Cmax, as well as the steady state, into the correct range for DHE that we thought would be useful clinically. It had a lower Cmax than intravenous or parenteral DHE, and a higher Cmax than the original nasal DHE formulation, and the Cmax and steady state appeared to be more comparable to the inhaled DHE preparation, [for] which were kind of aiming. So, I don’t think it has anything to do with the powder. We thought that this was the optimal delivery amount of DHE by pharmacokinetic prediction."

Throughout the study period, 7.3% (n = 20) of the cohort discontinued treatment due to AEs, including 2.9% (n = 8) who experienced nasal AEs. Nasal discomfort (13.9%), dysgeusia (7.7%), and nasal congestion (6.2%), were among the most commonly reported AEs by individuals in the study. Postural orthostatic tachycardia syndrome and cholecystitis, considered serious AEs, were observed in 1 individual each, and were not related to the study treatment. No differences in AE rates or severity were observed when an optimized STS101 device was introduced midway through the study.

Recently, investigators from ASCEND conducted an analysis looking at STS101’s impact on cardiovascular (CV) measures, mainly because the DHE package inserts carry warnings regarding use for patients with CV disease or CV risk factors. Similarly, the investigational agent continued to show a well-tolerated profile with no clinically relevant CV AEs. Five of the 6 CV AEs reported were related to STS101, but all were transient and resolved without treatment or sequelae. They included 1 event of moderate tachycardia, 1 event of mild increased blood pressure, and 3 events of flushing/hot flashes in 2 subjects (2 mild, 1 moderate).2

STS101’s powder formulation offers several advantages of traditional liquids, according to Satsuma, including less susceptibility to drip out of the nose or down the back of the throat, adherence to the nasal mucosa, providing better absorption, and better stability. In June 2021, Satsuma published positive results from a phase 1 study that showed that all 3 dose strengths (5.2 mg, and 2 higher dose strengths) of the second-generation nasal delivery device were well-tolerated and achieved the target pharmacokinetic profile. STS101 5.2 mg resulted in rapid mean DHE plasma concentrations of 2.0 ng/mL within approximately 15 to 20 minutes and remained above 1.0 ng/mL for 2 hours after administration.3

STS101 is currently being evaluated in the phase 3 SUMMIT trial (NCT04940390), the main study to ASCEND. The double-blind, placebo-controlled, parallel group study is designed in accordance with FDA recommendations outlined in the FDA Guidance Migraine: Developing Drugs for Acute Treatment, published in February 2018. Those included in the study are randomized 1:1 to either STS101 5.2 mg or matching placebo, with freedom from pain and freedom from most bothersome symptom as the co-primary end points of the study.

Click here for more coverage of AHS 2022.

REFERENCES
1. Tepper SJ, Strom S, Albrecht D. Long-term safety and tolerability of STS101, a dry powder intranasal dihydroergotamine product: initial data from the ASCEND study. Presented at: AHS Annual Meeting; June 9-12, 2022; Denver, CO. Abstract IOR-08.
2. Rapoport A, Strom S, Albrecht D. Cardiovascular safety of STS101, a novel investigational DHE nasal powder product: initial data from the ASCEND study. Neurology. 2022;98(18 suppl).
3. Satsuma Pharmaceuticals announces positive pharmacokinectic, tolerability and safety results from phase 1 trial of STS101 at multiple dose strengths. Satsuma Pharmaceuticals. June 16, 2021. Accessed June 13, 2022. https://www.globenewswire.com/news-release/2021/06/16/2248536/0/en/Satsuma-Pharmaceuticals-Announces-Positive-Pharmacokinetic-Tolerability-and-Safety-Results-From-Phase-1-Trial-of-STS101-at-Multiple-Dose-Strengths.html