A Phase 1, Randomized, Open‐Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects

Abstract

Objective To investigate and compare the safety and the pharmacokinetics of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal®), and intramuscular (IM) DHE injection in healthy subjects. Methods This was a 2‐part, active‐controlled, 3‐period crossover study over 3 weeks, separated by 1‐week washout periods. In part 1, 3 ascending dosage strengths of STS101 (1.3, 2.6, and 5.2 mg) were administered to 15 healthy subjects with no history of migraine. In part 2, 27 healthy subjects were administered 1 dose each of STS101 5.2 mg, Migranal DHE Mesylate Liquid Nasal Spray 2.0 mg, and IM DHE Mesylate 1.0 mg in a randomized order. Liquid chromatography, tandem mass spectrometry was used to determine plasma levels of DHE and its major metabolite, 8′OH‐DHE. Pharmacokinetic parameters (Cmax, Tmax, AUC0‐2 h, AUC0‐48 h, AUC0‐inf, and t1/2) for DHE and metabolite were calculated. Geometric means and 90% confidence intervals of log‐transformed data were calculated and the ratio of means compared. Safety was evaluated by monitoring adverse events, vital signs, electrocardiograms, subjective and objective assessments of nasal signs and symptoms, and changes in laboratory parameters. The study is registered as NCT03874832. Results Forty‐three subjects were enrolled and received study medication. Forty completed all study activities, 14 in part 1 and 26 in part 2. In part 1, DHE plasma levels showed a dose‐dependent increase, with STS101 5.2 mg reaching a mean Cmax of 1870 pg/mL with a Tmax of 23 minutes. In part 2, STS101 5.2 mg showed rapid absorption, achieving mean DHE plasma concentrations of 1230 and 1850 pg/mL at 10 and 15 minutes after administration, respectively. In comparison to Migranal, STS101 5.2 mg showed approximately 2‐fold higher Cmax (2175 vs 961 pg/mL), AUC0‐2 h (2979 vs 1316 h × pg/mL), and AUC0‐inf (12,030 vs 6498 h × pg/mL), respectively. The mean AUC0‐inf of STS101 5.2 mg was comparable to IM DHE (12,030 vs 13,650 h × pg/mL). STS101 5.2 mg showed substantially lower variability compared to Migranal for Cmax (41% vs 76%), AUC0‐2 h (39% vs 75%), and AUC0‐inf (39% vs 55%). The incidence of treatment emergent AEs (TEAEs), all mild and transient, reported in parts 1 and 2 combined was 9/15 (60%), 5/15 (33%), and 16/41 (39%) of the subjects after 1.3, 2.6, and 5.2 mg STS101, respectively, and 4/26 (15%) and 5/27 (19%) of the subjects after IM DHE and Migranal, respectively. Conclusion STS101 showed rapid absorption, achieving effective DHE plasma concentrations within 10 minutes. It achieved substantially higher Cmax, AUC0‐2 h and AUC0‐inf, compared to Migranal suggesting potentially better efficacy than Migranal. Its variability was better than Migranal, thus offering improved consistency of response. AUC0‐inf was comparable to IM DHE, suggesting prolonged action and low recurrence. Additionally, the Cmax was sufficiently low to avoid any significant nausea reported with IV DHE. Thus, STS101 is an easy to administer, non‐injected, acute treatment for mig...

Nasal Delivery of Acute Medications for Migraine: The Upper Versus Lower Nasal Space

“…A Phase 1, randomized, open-label, safety, tolerability, and comparative bioavailability study of STS101 demonstrated quick systemic absorption, attaining effective DHE plasma concentrations (>1000 pg/mL) within 10 min. Although the pharmacokinetics of STS101 demonstrated values that were 2.3-fold higher than those of MIGRANAL, it utilized a 6 mg dose that was 300% of the approved MIGRANAL 2 mg dose [89]. The results of topline data from the EMERGE trial, a Phase 3, multicenter, single-dose, randomized, double-blind, placebo-controlled, parallel-group efficacy study, showed that although numerical differences were in favor of STS101, the study did not demonstrate statistically significant differences between dosage strengths (4 and 6 mg) compared to placebo on coprimary endpoints of pain and most bothersome symptom freedom (among photophobia, phonophobia, or nausea) at 2 h post-administration [90].…”

New Approaches to Shifting the Migraine Treatment Paradigm

“…Another formulation of DHE utilizes a dry powder for administration, STS 101. It demonstrated excellent pharmacokinetics ( 88 , 89 ). STS101 achieved rapid and sustained high drug exposure with low variability.…”

Delivery of Dihydroergotamine Mesylate to the Upper Nasal Space for the Acute Treatment of Migraine: Technology in Action

“…( 101 ) Although not marketed, data from the clinical development program of MAP0004 is frequently used as reference for all DHE mesylate development products. ( 9 , 103 ) Migraine pain relief was reported as early as 10 minutes in some patients with severe pain (with significance at 30 minutes overall compared with placebo) in a Phase 3, placebo-controlled study of MAP0004. ( 95 ) In STOP 101, INP104 delivery resulted in high plasma exposure to DHE in the first 2 hours, with values similar to MAP0004 (1603 and 1447 h*pg/mL reported for INP104 and MAP0004, respectively), and in STOP 301 pain relief as an exploratory efficacy outcome was reported with INP104 as early as 15 minutes, the first timepoint investigated.…”