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Novel DHE Nasal Spray Safe, Effective For Acute Treatment of Migraine in Long-Term Safety Trial
Use of the unique STS101 drug device combination proved safe, well tolerated, and effective with as needed use over 12 months, reported Satsuma Pharmaceuticals.
STS101, a novel investigational dihydroergotamine (DHE) nasal powder therapy for the acute treatment of migraine in adults, was associated with a favorable safety profile and was well tolerated with repeated, as needed use over a study period of 18 months. The findings, from the phase 3 open label ASCEND clinical trial were published online in the journal CNS Drugs on October 7.
In addition to safety and tolerability, ASCEND investigators assessed patient-reported exploratory efficacy of the drug-device combination and reported two-thirds of participants achieved pain relief at 2 hours post-dose with relief from pain and from most bothersome migraine symptom (MBS) sustained through 48 hours.
"Even with the introduction of new treatment options in the past few years, there is a critical need for novel non-oral treatment options for patients who are often unable to achieve rapid relief with oral routes of administration," lead investigator Stewart Tepper, MD, of the New England Institute for Neurology and Headache, in Stamford, CT, said in a statement from STS101 producer Satsuma Pharmaceuticals.
STS101 is a single-use nasal delivery device prefilled with 5.2 mg DHE powder (6.2 mg DHE mesylate). Other secondary endpoints, based on a patient global impression questionnaire, showed that most ASCEND participants had an overall positive impression of STS101, agreed that it was easy to use, and that they would use it if it were available, Tepper and colleagues wrote.
ASCEND Phase 3 Trial
Enrollment in ASCEND required that participants be aged 18 – 65 years and have a 1-year or longer history of migraine with or without aura and onset of migraine before age 50 years. Eligible participants experienced 4 – 12 migraine attacks per month and had fewer than 15 headache days per month during each of the 3 months before ASCEND study screening. Factors for exclusion included diagnosis of non-migraine headache, a history of cerebrovascular disease, and 2 or more cardiovascular risk factors.
During the study, after training on how to use the STS101 device, participants could self-administer STS101 5.2 mg as needed for up to 2 doses within 24 hours to treat a single migraine and were permitted up to 12 doses per month, according to the study. Participants were permitted to use rescue medications 2 hours after an STS101 dose and recorded use for 48 hours after STS101 administration. Use of some rescue medications, among them other DHE products, gepants, and cannabis, was restricted 24 hours before and after taking the study medication.
The specified safety endpoints were the incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and the assessment of any relationship between these events and STS101 administration.
Tepper and colleagues evaluated safety and tolerability through adverse event (AE) monitoring, subjective nasal symptom assessments, objective nasal examinations, and physical examinations. Participants tracked efficacy parameters in an electronic diary, noting features including headache pain intensity pre-STS101 administration, and at 1, 2, 4, 24, and 48 hours after taking the dose; most bothersome symptom (MBS; photophobia, phonophobia, or nausea) immediately before and at the same time points as reporting pain; and time and use of rescue medication. They responded to impression questionnaires at study months 3, 6, and 12, focused on ease of use, consistency of effect, likelihood of use, and global impression of treatment.
FINDINGS
The final cohort numbered 344 participants, with a mean age of 40 years. Nearly one-half (47.4%) reported migraine with aura, and just fewer than one-third (31.7%) reported allodynia. Over the study period, 8234 doses of STS101 were used to treat 6610 migraine attacks. Approximately 1 in 5 (19.9%) headaches were treated with a second dose of STS101.
The most common participant-reported TEAEs were nasal discomfort (11.3%), dysgeusia (7.6%), nasal congestion (5.2%), nasopharyngitis (5.2%), and nausea (4.9%). The majority of these were either mild or moderate, according to the published study. Just over 10% (14.3%) of the 6610 migraine attacks were associated with a TAEA. Only 2.6% of participants experienced one or more severe TEAEs.
A total of 25.9% of participants experienced a TEAE considered related to study treatment, with nasal discomfort (11.0%), dysgeusia (7.6%) and rhinalgia (4.7%), nasal congestion (4.4%) and rhinorrhea (2.6%). Severe TEAEs were reported for only 0.2% of treated attacks.
The authors reported the safety profile of STS101 as comparable to that of dihydroergotamine nasal spray 1.45 mg. In clinical trials the most commonly reported AEs with the latter were rhinitis (26%), nausea (10%), vomiting (4%), dysgeusia (8%), application site reaction (6%), and dizziness (4%).
Patient-Reported Efficacy
In terms of patient-reported efficacy, Tepper and team reported that STS101 was associated with rapid onset of pain freedom (36.6%, 67.1%, and 85.5% of treated attacks at 2-, 4-, and 24-hours post-dose, respectively), freedom form MBS (54.3%, 79.6%, 91.3%), and headache relief (66.5%, 89.1%, and 94.3%). The majority of participants rated the treatment results as “good or very good,” and “easy or very easy” to use at months 3, 6, and 12.
In acknowledging the study’s limitation, the team noted the open label design that does not include an active comparator, blinding, or formal statistical analyses. Aura rates may have been high as a result of self-report. An interim and final version of STS101 were both used during the study, which could have led to variations in experience. Finally, Tepper et al recognize the potential for intrinsic study bias as those who remained in the long-term study are likely those for whom the treatment
"The development of STS101 is intended to augment the migraine treatment armamentarium," by providing a means to deliver DHE that is more reliable than with the current liquid nasal formulations, the researchers wrote
“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.”
