FormalPara Key Points

The results of this study show that STS101 has a favorable safety profile and is well tolerated when used long-term and as needed for the acute treatment of migraine attacks, with most considering STS101 easy to use.

Up to two thirds of all treated migraine attacks in this study demonstrated headache pain relief at 2 h post-dose.

Exploratory effectiveness analyses in this long-term safety study showed high rates of freedom from headache pain and most bothersome symptom from 2 through 48 h post-dose of STS101.

1 Introduction

Migraine is a common and often debilitating disease that affects more than 1 billion individuals worldwide [1]. In 2019, it was reported as the second largest cause of disability globally, with 46.6 million years lived with disability being attributed to migraine [1]. Migraine symptoms commonly interfere with an individual’s ability to function in daily life, at work, at school, or at home, as well as affect relationships and social situations [2,3,4]. Many patients continue to experience migraine symptoms and impaired work productivity and activity despite current acute and/or preventive migraine therapy [5,6,7,8]. The goals of acute therapy for a migraine attack, as defined by the American Headache Society, are to provide rapid and sustained relief from headache pain and associated symptoms, as well as to restore function, all with good tolerability and safety, minimal need for repeat dosing/rescue medications, and/or further healthcare resource utilization [9].

Dihydroergotamine (DHE) has a long history of use (since 1946) for the acute treatment of migraine with or without aura [10, 11]. It interacts with a broad range of receptors thought to contribute to migraine pathophysiology, including receptors for serotonin, dopamine, and noradrenaline [12]. As it is a migraine-specific agent with established efficacy, the American Headache Society advocates the use of DHE in patients with moderate or severe migraine attacks and in patients with mild-to-moderate migraine attacks that respond poorly to nonsteroidal anti-inflammatory drugs (NSAIDs) or to combination medications containing caffeine [9, 13]. Currently available formulations of DHE (solution for subcutaneous, intramuscular, or intravenous administration, and liquid nasal sprays) contain the mesylate salt of DHE (1.0 mg, 1.45 mg, and 2.0 mg DHE mesylate/mL, respectively) and are indicated for the acute treatment of migraine attacks with or without aura and cluster headache episodes (injectable only) [14,15,16].

STS101 is an investigational drug–device combination of a DHE mesylate powder formulation prefilled in a single-use delivery device for nasal administration [17]. It is designed to be an easy-to-use, easy-to-carry, prefilled, single-use, nasal delivery device that does not require assembly or priming and can be stored at room temperature. STS101 provides rapid DHE absorption, with plasma concentrations of DHE over the 2 h following STS101 administration (AUC0–2 h) more than twofold greater than those following the administration of DHE liquid nasal spray (both 1.45 mg and 2.0 mg spays) [16, 17]. The primary objective of the ASCEND study was to assess the long-term safety and tolerability of STS101 in the acute treatment of migraine attacks over 12 months, and up to 18 months in a subset of participants who entered an extension phase. The secondary objective of the study was to describe the efficacy of STS101 in the acute treatment of migraine attacks over 12 months.

2 Methods

2.1 Trial Population

Adults 18–65 years of age were eligible for participation if they had ≥ 1-year history of migraine, with or without aura, as diagnosed using the International Classification of Headache Disorders, 3rd edition (ICHD-3) [18] with onset before 50 years of age, history of 4–12 attacks per month in each of the 3 months prior to screening, < 15 headache days per month in each of the 3 months prior to screening, and an intact nasal mucosa. Women of child-bearing potential were permitted to participate but had to use adequate contraceptive drugs or devices during the study.

Individuals were excluded from participation if they had a diagnosis of a headache condition other than migraine with or without aura; history of significant cardiovascular disease, presence of ≥ 2 cardiovascular risk factors [diagnosis and/or treatment of hypertension, diagnosis of hypercholesteremia defined as low-density lipoprotein (LDL) cholesterol > 159 mg/dL, or receiving cholesterol-lowering medication, obesity (body mass index > 31), diabetes mellitus, family history of premature coronary artery disease, surgically or physiologically postmenopausal female, or male > 45 years of age)]; severely impaired hepatic function [alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal] or renal function (serum creatinine > 1.5 times the upper limit of normal); any clinically significant electrocardiogram (ECG) abnormality; systolic blood pressure < 90 or > 140 mmHg; diastolic blood pressure < 50 or > 90 mmHg at screening or baseline; diagnosis of major depression with current symptoms, psychosis, alcohol abuse or dependence, drug abuse or dependence, major psychiatric conditions, dementia, or other significant neurological or psychiatric disorders; use of concomitant potent CYP3A4-inhibitors; current use of > 2 preventive migraine medications; or a score of > 0 on any of the questions 1 through 14 of the Sheehan Suicidality Tracking Scale (S-STS) [19].

2.2 Trial Oversight

This trial was conducted in compliance with International Conference on Harmonization Good Clinical Practice guidelines, the principles of the Declaration of Helsinki, and all applicable regulatory requirements and laws. The protocol was approved by the central institutional review board (Advarra) and/or the ethics committee or institutional review board of each study center. All participants provided written informed consent. The study is registered as NCT04406649 at ClinicalTrials.gov.

2.3 Trial Design

This multicenter, open-label study comprising a 30-day screening period and a 12-month treatment period was conducted at 54 sites in the USA. Originally, the plan was to enroll 300 participants. The sample size was increased to 480 participants due to a device modification and a higher-than-expected discontinuation rate related to the sponsor’s proactive discontinuation of participants who did not use the study medication at the US Food and Drug Administration (FDA)-required frequency of twice per month within the first 3 months of participation. A small subset of participants (n = 15) entered an extension phase and continued to use the study medication for an additional 6 months, for a total of 18 months.

After establishing eligibility, participants self-administered STS101 5.2 mg as needed for up to 2 doses within 24 h to treat a single migraine attack and up to 12 doses per month. Both the first version of the STS101 administration device and the final version of the STS101 device were used in this study; both containing 5.2 mg DHE, which was delivered as 6.0 mg DHE mesylate. The final version (Fig. 1) incorporated a stainless-steel ball as a check valve, which was not present in the first version of STS101. Study site personnel trained the participants in study drug administration.

Fig. 1
figure 1

Final version of STS101 and administration

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Rescue medications (NSAIDs, neuroleptics, corticosteroids, antiemetics, muscle relaxants, and sleep medications and/or gabapentin) were permitted 2 h post-dose and were recorded for 48 h after study drug administration. The use of triptans or other DHE products, gepants, lasmiditan, opioids, cannabis, or cannabinoid-containing medications was not allowed for 24 h prior to and following study medication administration.

2.4 Assessments

Safety and tolerability were evaluated via adverse event (AE) monitoring, subjective nasal symptom assessments, objective nasal evaluations, and physical examinations (including clinical laboratory testing, vital signs assessments, and ECGs). AEs were recorded as volunteered by the participant or solicited through indirect questioning.

Participants used an electronic diary to record the following exploratory efficacy parameters: intensity of headache pain at the onset of each migraine attack immediately before STS101 administration, at 1 h post-dose and at 2, 4, 24, and 48 h post-dose; their most bothersome symptom (MBS: either photophobia, phonophobia, or nausea) immediately before STS101 administration and presence or absence of this symptom at 1 h post-dose and at 2, 4, 24, and 48 h after STS101 administration; and use and time of rescue medication or a second STS101 dose. Participant impression questions were asked at months 3, 6, and 12. These included the participant global impression of treatment, ease of use, participant likelihood of use if STS101 were available, and consistency of STS101 effect (collected at month 12 only).

2.5 Endpoints

The 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.

Exploratory efficacy endpoints were the proportion of attacks with pain freedom at 1, 2, 4, 24, and 48 h post-dose; the proportion of attacks with MBS freedom at 1, 2, 4, 24, and 48 h post-dose; the proportion of attacks with pain relief [reduction in headache pain intensity from severe or moderate (3 or 2 on a 4-point scale) to mild or none (1 or 0 on the scale)] at 1, 2, 4, 24, and 48 h post-dose; the proportion of attacks with rescue medication use within 24 and 48 h post-dose; the proportion of attacks with use of a second STS101 dose within 24 and 48 h post-dose; sustained pain freedom and MBS freedom at 2–24 and 2–48 h post-dose; and participant impression of study treatment (rated on a 5-point verbal Likert scale; response options: very good, good, no opinion, poor, or very poor); ease of use (rated on a 5-point verbal Likert scale; response options: very easy, easy, no opinion, not easy, or not easy at all); and likelihood of using the study medication if available (rated on a 5-point verbal Likert scale; response options: very likely, likely, no opinion, unlikely, or very unlikely) at months 3, 6, and 12.

2.6 Statistical Analysis

No formal sample size calculations were performed. It was assumed that a sample size of 480 participants would be sufficient to detect clinically important AEs with an event rate of ≥ 1%.

Safety data were analyzed using all participants and attacks treated only with the final version of STS101 (final device safety population; primary safety population) as well as all enrolled participants who used either the first or the final version of STS101 at least once (all subjects safety population; secondary safety population). Effectiveness data were analyzed only in participants who exclusively used the final version of STS101 (expansion population).

All study data were summarized using descriptive statistics. All summaries, statistical analyses, and individual participant data listings were completed using SAS software, version 9.3 or later (SAS Institute, Inc., Cary, NC). No formal hypothesis testing was performed.

3 Results

3.1 Participants

A total of 482 participants enrolled in the study, and 205 (42.5%) completed it; 344 participants used the final version of STS101 at least once during the study and were included in the final device safety population (Fig. 2). The all subjects safety population included a total of 446 participants who used either the first or the final version of STS101 at least once during the study to treat a total of 9091 migraine attacks. Most early study discontinuations were due to an inadequate number of treated migraine attacks (defined as < 2 attacks per month per the FDA requirement [20]; 97/482 [20.1%] enrolled participants) and withdrawal of consent [83/482 (17.2%) enrolled participants]. A total of 34/446 (7.6%) participants experienced ≥ 1 TEAE that led to study drug discontinuation. No significant differences in demographic or clinical characteristics were noted between the all subjects safety population and final device safety population (Supplementary Table 1).

Fig. 2
figure 2

Study populations and disposition

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The 344 participants included in the final device safety population used 8234 doses of study medication to treat a total of 6610 migraine attacks during the study. Of the 6610 migraine attacks treated, 1315 (19.9%) were treated with a second dose of study medication. A majority of participants had a monthly average of 2–4 treated attacks [170/344 (49.4%)].

The expansion population comprised 172 participants who used the final version of STS101 exclusively, treating 3394 migraine attacks during the study.

Baseline demographic and clinical characteristics of study participants are summarized in Table 1. The average duration of migraine prior to study participation was 18.5 years, with participants reporting an average of 7.5 headache days and 5.5 migraine attacks per month during the 3 months prior to screening (Table 2). Typical migraine symptoms included photophobia, phonophobia, and nausea for the majority of participants (97.4%, 95.1%, and 84.6%, respectively). Nearly half (47.4%) reported aura, and nearly one-third (31.7%) reported allodynia.

Table 1 Baseline demographics and clinical characteristics
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Table 2 Migraine history
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3.2 Safety

TEAEs in the final device safety population are summarized by participant in Table 3. The most commonly reported TEAEs by participant [n/N (%)] were nasal discomfort [39/344 (11.3%)], dysgeusia [26/344 (7.6%)], nasal congestion [18/344 (5.2%)], nasopharyngitis [18/344 (5.2%)], and nausea [17/344 (4.9%)]. The majority of TEAEs reported were of mild or moderate severity. Only 9 (2.6%) participants in this population experienced ≥ 1 severe TEAE. A severe TEAE of migraine was reported in 2 (0.6%) participants. Severe TEAEs of abdominal pain, acute myocardial infarction, ligament rupture, nasal discomfort, nasopharyngitis, rhinalgia, sinus pain, throat irritation, upper abdominal pain, and vomiting were reported by 1/344 (0.3%) participant each.

Table 3 TEAEs reported by ≥ 2% of participants who used the final device at least once (final device safety population)
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A total of 89/344 (25.9%) participants experienced an event considered related to study treatment. The most commonly reported treatment-related TEAEs were nasal discomfort [38/344 (11.0%)], dysgeusia [26/344 (7.6%)], rhinalgia [16/344 (4.7%)], nasal congestion [15/344 (4.4%)], and rhinorrhea [9/344 (2.6%)]).

Of the total 6610 migraine attacks treated with the final version of STS101, 945 (14.3%) were associated with a TEAE. Events occurring in ≥ 2% of attacks were nasal discomfort [425 (6.4%)], nasal congestion [253 (3.8%)], and dysgeusia [196 (3.0%)] (Table 3). A total of 777/6610 (11.8%) treated attacks were associated with TEAEs considered related to study treatment, the most common (occurring in ≥ 1% of attacks) being nasal discomfort [421/6610 (6.4%)], nasal congestion [250/6610 (3.8%)], dysgeusia [196/6610 (3.0%)], and rhinorrhea [68/6610 (1.0%)]. Most TEAEs were mild [844/6610 (12.8%)] or moderate [142/6610 (2.1%)] in severity. Severe TEAEs were reported for only 13/6610 (0.2%) treated attacks. Local TEAEs occurred at similar rates between the 1315 migraine attacks treated by participants who administered a second STS101 dose to treat ≥ 1 attack relative to the 5295 migraine attacks treated by participants who only used a single dose for treatment (Table 4). The incidence of local TEAEs was highest in the first 3-month period and decreased over time. There were no deaths reported.

Table 4 Local TEAEs reported by ≥ 2% of participants in the final device safety population
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One participant of 344 (0.3%) experienced an SAE. A 45-year-old Caucasian male with a prior myocardial infarction and a diagnosis of bipolar disease, which were not disclosed to the investigator at study enrollment, experienced a serious TEAE of non-ST elevation myocardial infarction. Both his previous myocardial infarction and his active bipolar disease were trial exclusions and, as noted, not disclosed. The participant developed intermittent chest pain approximately 2 h after use of STS101 and was admitted to the emergency department in the evening after experiencing sharp chest pain. The event was not considered life-threatening but was assessed as related to study medication. Unknown to the investigator, the participant used several more doses of study medication after the SAE without experiencing any additional TEAEs.

Five pregnancies were reported during the study; 4 of the pregnant participants were removed from the study, and 1 was lost to follow-up. Two participants delivered healthy babies; the outcomes of the other pregnancies remain unknown.

A similar safety profile was seen in the all subjects safety population and can be found in Supplementary Tables 2 and 3.

3.3 Exploratory Efficacy

Exploratory efficacy data from the 172 participants who participated in the expansion part of the study, and exclusively used the final device, are presented here. These participants treated a total of 3394 migraine attacks during the study.

Treatment was associated with rapid increases in pain freedom, from 12.7% (338/2665) and 36.6% (1014/2768) of treated attacks at 1 and 2 h post-dose, respectively, to 67.1% (1507/2247), 85.5% (1701/1990), and 88.8% (1521/1713) of treated attacks at 4, 24, and 48 h post-dose (Fig. 3).

Fig. 3
figure 3

Proportion of migraine attacks with pain freedom over time following the administration of STS101 (expansion population*). *Expansion population included data from 172 participants who treated a total of 3394 migraine attacks; data were available for 2665, 2768, 2247, 1990, and 1713 attacks at 1, 2, 4, 24, and 48 h post-dose, respectively

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Treatment also led to rapid increases in MBS freedom, from 26.6% (710/2665) and 54.3% (1504/2768) of treated attacks at 1 and 2 h post-dose, respectively, to 79.6% (1789/2247), 91.3% (1816/1990), and 91.5% (1567/1713) of treated attacks at 4, 24, and 48 h post-dose (Fig. 4).

Fig. 4
figure 4

Proportion of migraine attacks with MBS freedom over time (photophobia, phonophobia, or nausea) following the administration of STS101 (expansion population*). *Expansion population included data from 172 participants who treated a total of 3394 migraine attacks; data were available for 2665, 2768, 2247, 1990, and 1713 attacks at 1, 2, 4, 24, and 48 h post-dose, respectively. MBS most bothersome symptom

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Headache relief was reported for 37.9% (1011/2665) and 66.5% (1840/2768) of treated attacks at 1 and 2 h post-dose, respectively, increasing to 89.1% (2002/2247), 94.3% (1877/1990), and 93.5% (1602/1713) of treated attacks at 4, 24, and 48 h post-dose (Fig. 5).

Fig. 5
figure 5

Proportion of migraine attacks with headache relief over time following the administration of STS101 (expansion population*). *Expansion population included data from 172 participants who treated a total of 3394 migraine attacks; data were available for 2665, 2768, 2247, 1990, and 1713 attacks at 1, 2, 4, 24, and 48 h post-dose, respectively

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For many attacks [718/2768 (25.9%)], treatment was associated with sustained pain freedom from 2 to 24 h post-dose (Supplementary Fig. 1). The proportion of attacks with sustained pain freedom increased from 68/356 (19.1%) at month 1 to 13/55 (23.6%) at month 12, with some month-to-month variability.

Similarly, treatment was associated with sustained freedom from MBS from 2 to 24 h post-dose in 1063/2768 (38.4%) of migraine attacks, with a rate of 141/356 (39.6%) at month 1, which was generally sustained with some month-to-month variability, to 19/55 (34.5%) at month 12 (Supplementary Fig. 1).

Rescue medication was used in 3.5% and 4.6% of migraine headache attacks within 24 and 48 h after the initial STS101 dose, respectively. A second dose of study medication was used in 19.3% and 19.4% of migraine headache attacks within 24 and 48 h after the initial STS101 dose.

3.4 Participant Impression

Most participants rated treatment as good or very good at month 3 [104/124 (83.9%)], month 6 [87/96 (90.6%)], and month 12 [113/142 (79.6%)].

Similarly, most rated treatment as easy or very easy to use at month 3 [113/124 (91.1%)], month 6 [90/96 (93.8%)], and month 12 [132/142 (93.0%)] (Fig. 6).

Fig. 6
figure 6

Participant ease of use impression (expansion population*). *n = 165

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Finally, most participants indicated that they would be likely or very likely to use the treatment again at month 3 [95/124 (76.6%)], month 6 [75/96 (78.1%)], and month 12 [83/142 (58.5%)]. At month 12, most participants agreed or strongly agreed [89/140 (63.6%)] that STS101 treated their migraine attacks more consistently than their prior medications.

4 Discussion

The results of this multicenter, open-label study demonstrate that STS101 is well tolerated, with a favorable safety profile for up to 18 months in the acute treatment of migraine attacks in appropriately indicated adults. Whereas approximately half [167/344 (48.5%)] of participants who used STS101 experienced a TEAE, event incidence was lower in relation to the number of attacks treated [945 events among 6610 attacks treated (14.3%)]. Furthermore, only one-fourth of treated participants 89/344 (25.9%) experienced events that were deemed related to study treatment, most commonly nasal discomfort, dysgeusia, and nasal congestion. Again, the treatment-related event incidence was lower in comparison with the number of attacks treated [777 treatment-related events among 6610 treated attacks (11.8%)]. Notably, the incidence of local TEAEs was highest in the first 3-month period and decreased over time.

There was only 1 treatment-related SAE, a non–ST elevation myocardial infarction in a participant who had failed to report contraindications for the use of DHE at the time of enrollment. The event was not considered life-threatening, resolved, and did not result in significant disability or recurrence after subsequent (unauthorized) doses of STS101.

Whereas 15/344 (4.4%) participants experienced ≥ 1 TEAE that led to study drug discontinuation (final device), only 2 events led to discontinuation in more than 1 participant [rhinalgia (n = 3) and nasal discomfort (n = 2)]. This rate is comparable to those reported in clinical studies of DHE mesylate liquid nasal sprays (1.4–6.8%) [15, 21].

The safety profile of STS101 is similar to that of DHE nasal spray 1.45 mg, for which the most commonly reported AEs in clinical trials were rhinitis (26%), nausea (10%), vomiting (4%), dysgeusia (8%), application site reaction (6%), and dizziness (4%) [16]. The incidence of local events in the current study is also comparable to that of DHE mesylate liquid nasal spray 2.0 mg (28.8% versus 30%, respectively), but significantly lower than that of DHE nasal spray 1.45 mg (28.8% versus 52%) [15, 16]. The incidence of nausea and vomiting may be lower with intranasal administration versus administration by intravenous (≤ 62%) or intramuscular (≤ 15%) routes [14]. Furthermore, STS101 demonstrated a lower incidence of these AEs than other nasal sprays [15, 16, 22].

4.1 Study Limitations

This was an open-label study, primarily to assess safety and tolerability over time, with no active comparator or blinding and with no formal statistical analyses performed. Among the participant self-reported baseline migraine symptoms, the aura rates are high, most likely because it was based on a single question in which the participant reported aura without further validation by the investigators. Intrinsic bias may be present, as participants who stay in a long-term study are the ones for whom the medication is working with few AEs. In participants who initially used the first version of STS101, the reported data for the final version may have been affected by the experience with the use of the first version of STS101, e.g., the type and frequency of AEs or the efficacy.

5 Conclusions

STS101 is intended to augment the migraine treatment armamentarium with a more reliable delivery of DHE than the current liquid nasal DHE formulations. STS101 provides DHE plasma concentrations similar to the IM DHE injection [17], leading to rapid freedom from pain and most bothersome symptoms and sustained treatment benefits. 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. 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.