Phase 3 Data Supports the Long-Term Safety of STS101 for Acute Treatment of Migraine

Stewart J. Tepper, MD, FAHS

Credit: The New England Institute for Neurology and Headache

This week, a research team published new phase 3 data demonstrating the 18-month safety of STS101 for the acute treatment of migraine.¹

Back in January, the US Food and Drug Administration (FDA) issued a complete response letter to Satsuma Pharmaceuticals’ STS101, a dihydroergotamine nasal powder therapy for adults with acute migraine.² The FDA did not provide any notes on clinical trial concerns but did have comments related to the drug’s formulation.

As of now, the investigational STS101 consists of 5.2 mg dihydroergotamine (DHE) power, or 6.0 mg DHE mesylate, in a single-use nasal delivery device.¹ Investigators, led by Stewart J. Tepper, MD, FAHS, from The New England Institute for Neurology and Headache in Stamford, Connecticut, aimed to evaluate the long-term safety and tolerability of STS101 in the acute treatment of migraine across 12 – 18 months. The secondary objective was to assess the long-term efficacy of STS101 and investigators hoped it would provide more success than the current liquid nasal dihydroergotamine sprays.

“STS101 provides [dihydroergotamine] plasma concentrations similar to the IM [dihydroergotamine] injection, leading to rapid freedom from pain and most bothersome symptoms and sustained treatment benefits,” investigators wrote.

ASCEND, an open-label study, included adults aged 18 – 65 years with a ≥ 1-year history of migraine with (47.4%) or without aura. Participants had to have migraine onset before the age of 50 years and experienced 4 – 12 migraine attacks per month and < 15 headache days or months in the 3 months before screening. Participants were excluded if they were diagnosed with non-migraine headaches, had a history of cerebrovascular disease, and had ≥ 2 cardiovascular risk factors.

During the study, participants could self-administer STS101 5.2 mg as needed for up to 2 doses within 24 hours. They were allowed up to 12 doses a month.

The team evaluated safety and tolerability through physical and nasal examinations, vital signs, laboratory tests, and treatment-emergent adverse event assessment. Participants also used an electronic diary to track efficacy parameters, such as headache pain intensity and associated migraine symptoms including photophobia, phonophobia, and nausea. Participants were asked questions about their impression of STS101 at months 3, 6, and 12.

Among the participants (n = 344), there were 6610 migraine attacks and 8234 STS101 doses. Only 14.3% (n = 9) were linked to a treatment-emergent adverse event (TEAE), which was predominantly mild or moderate and rarely led to study discontinuation (4.4%). The most common adverse events included nasal discomfort (11.3%), dysgeusia (7.6%), nasal congestion (5.2%), nasopharyngitis (5.2%), and nausea (4.9%). Only 2 adverse events led to discontinuation: rhinalgia (n = 3) and nasal discomfort (n = 2).

“Notably, the incidence of local TEAEs was highest in the first 3-month period and decreased over time,” investigators wrote.

Two participants experienced severe TEAEs, with reports of abdominal pain, acute myocardial infarction, ligament rupture, nasal discomfort, nasopharyngitis, rhinalgia, sinus pain, throat irritation, upper abdominal pain, and vomiting.

Only 1 TEAE was considered serious—a non-ST-elevation myocardial infarction. This was due to the fact the participant, a 45-year-old Caucasian male with prior myocardial infarction and a diagnosis of bipolar disease, did not report contraindication for the use of dihydroergotamine at baseline. This event was not considered life-threatening and was resolved.

The safety profile of STS101 was comparable to the dihydroergotamine nasal spray 1.45 mg, which had common adverse events of rhinitis (26%), nausea (10%), vomiting (4%), dysgeusia (8%), application site reaction (6%), and dizziness (4%). However, STS101 demonstrated a lower incidence of adverse events than the other nasal sprays.

STS101 brought migraine relief to many and was associated with rapid pain relief (36.6%, 67.1%, and 85.5% of treated attacks at 2-, 4-, and 24-hours post-dose, respectively), relief of the most bothersome symptoms (54.3%, 79.6%, 91.3%), and headache relief (66.5%, 89.1%, and 94.3%).

Many participants were pleased with the results of STS101, rating it “good or very good,” and “easy or very easy” at months 3, 6, and 12. Participants said they were very likely to use STS101 again.

The team said the results were limited by the lack of an active comparator, blinding, no formal statistical analyses performed, and not checking the validity of the self-reported aura rates. Investigators also recognized intrinsic bias since those who stayed in the long-term study were the ones who had success with the medication thus far. Additionally, some participants used an earlier version of STS101 while some used updated versions, leading to potential variations in their experiences with the drug.

Although STS101 did not surpass the effectiveness of current liquid nasal dihydroergotamine sprays, the study still produced positive results.

“The repeated long-term, as-needed use of STS101 for the acute treatment of a migraine attack demonstrated a favorable safety profile and was well tolerated in appropriately indicated adults,” investigators concluded. “Relative to the known safety profile of DHE, no new safety signals were identified. Notably, there were no new safety signals related to the route of administration or the novel powder formulation of STS101.”

References

1. ^{Tepper SJ, Albrecht D, Ailani J, Kirby L, Strom S, Rapoport AM. Long-Term (12-Month) Safety and Tolerability of STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment of Migraine: Data from the Phase 3 Open-Label ASCEND Study. CNS Drugs. Published online October 7, 2024. doi:10.1007/s40263-024-01118-8}
2. ^{Hoffman, M and Ciccone, I. FDA Issues Complete Response Letter for Satsuma’s DHE Nasal Powder STS101 to Treat Acute Migraine. NeurologyLive. January 18, 2024. https://www.neurologylive.com/view/fda-issues-crl-satsuma-dhe-nasal-powder-sts101-acute-migraine. Accessed October 11, 2024.}