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 (C max, T max, AUC0‐2 h, AUC0‐48 h, AUC0‐inf, and t 1/2) 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 C max of 1870 pg/mL with a T max 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 C max (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 C max (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 C max, 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 C max was sufficiently low to avoid any significant nausea reported with IV DHE. Thus, STS101 is an easy to administer, non‐injected, acute treatment for migraine, with a favorable tolerability profile and is expected to provide rapid and consistent freedom from pain and associated migraine symptoms without recurrence.
Keywords: dihydroergotamine mesylate, dihydroergotamine, migraine, pharmacokinetics, intranasal
Abbreviations
- CYP
cytochrome
- DHE
dihydroergotamine
- ECG
electrocardiogram
- IM
intramuscular
- IV
intravenous
- LC‐MS/MS
liquid chromatography, tandem mass spectrometry
- PK
pharmacokinetic
- VAS
visual analog scale
Introduction
Dihydroergotamine (DHE), especially after intravenous (IV), or intramuscular (IM) administration, is an effective acute treatment for migraine, and could potentially have a broader role in the management of migraine given its unique advantages over triptans.1, 2, 3 However, there is currently no patient‐friendly, rapidly absorbed, reliably and consistently effective, easy‐to‐administer DHE dosage form. The only approved non‐injectable DHE product, Migranal® liquid nasal spray, suffers from cumbersome preparation, requires more than 15 minutes to administer a full dose, and has highly variable and unpredictable pharmacokinetic (PK) properties that lead to inconsistent and unreliable clinical response.1, 2, 4, 5 STS101 (Satsuma Pharmaceuticals, Inc, South San Francisco, CA; Figs. 1 and 2) is a discreet, single‐use, drug‐device combination product designed to facilitate quick, simple, and intuitive intranasal administration of a novel DHE powder formulation that provides favorable PK properties; in particular, it results in rapid and sustained absorption via the nasal mucosa to achieve DHE plasma concentrations that have been demonstrated to be effective.6, 7, 8, 9, 10, 11, 12, 13 By improving upon ease and speed of administration and providing favorable PK properties, STS101 may facilitate broader utilization of DHE and realization of the unique benefits of DHE by people with migraine. The objective of this Phase 1 study was to evaluate and compare the safety and the pharmacokinetics of DHE after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal), and IM DHE injection in healthy subjects.
Figure 1.
STS101.
Figure 2.
STS101 administration.
Methods
Study Design
This was a 2‐part, active‐controlled, 3‐period crossover study over 3 weeks, separated by 1‐week washout periods (Fig. 3). In part 1, 3 ascending dosage strengths of STS101 were administered in 15 healthy subjects. 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.
Figure 3.
Study design.
The study was conducted at the Seaview (Quotient) Phase 1 Clinic in Miami, FL in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and in compliance with United States Food and Drug Administration regulations for informed consent and protection of subject rights. The study was approved and monitored by Advarra IRB, Columbia, MD and written informed consent was obtained from each subject before study enrollment. The study is registered as NCT03874832.
Study Subjects
Participants were 18‐50 year old healthy subjects of any race and either gender, with no clinically significant abnormality identified in the medical or laboratory evaluations, including a 12‐lead electrocardiogram (ECG). Exclusion criteria included any clinically significant central nervous system, cardiac, pulmonary, metabolic, renal, hepatic, or gastrointestinal conditions, and smoking within 12 months before the study. Use of drugs or foods known to interfere with metabolization of DHE via the cytochrome (CYP) 3A4 P450 pathway or peripheral vasoconstrictors, for example triptans, was not permitted. Use of nonprescription medications, including vitamins and natural, herbal, and dietary supplements, had to be discontinued 7 days prior to the screening visit.
Treatments
In part 1, eligible subjects received 1.3, 2.6, and 5.2 mg (equivalent to 1.5, 3.0, and 6.0 mg DHE mesylate, respectively) of STS101 (Satsuma Pharmaceuticals, Inc, South San Francisco, CA) in an ascending dose order. In part 2, eligible subjects received STS101 5.2 mg, Migranal 2.0 mg (Valeant Pharmaceuticals, Bridgewater, NJ) and IM DHE 1.0 mg (Perrigo, Minneapolis, MN) in a randomized order based on a randomization list with 9 blocks containing all 3 sequences. The randomization list was generated by the study statistician using “Proc Plan” in SAS. The randomization at the study site was done by a study nurse after subjects had completed screening and were determined to be eligible to participate. All subjects remained in the Phase 1 unit for 48 hours after drug administration. Prior to dosing, they refrained from consuming alcohol for 48 hours and caffeinated beverages for 12 hours.
Study Assessments
Vital signs (respiration rate, heart rate, blood pressure) were recorded before dosing and post dose at 30 and 60 minutes and 2, 4, and 24 hours. Physical examinations were performed pre‐dose and post dose at 24 hours. Adverse events were elicited pre‐dose and post‐dose at 5, 10, 15, 30, 45, 60, and 90 minutes and at 2, 4, 6, 8, 12, 24, 36, and 48 hours. An ECG was performed at screening, pre‐dose and post dose at 15, 30, 60, and 90 minutes, and at 2, 4, 8, and 24 hours. Blood samples were taken for eligibility at screening and for routine clinical laboratory evaluations pre‐dose and post‐dose at 24 hours. An 8‐item instrument was used to assess the severity of nasal signs and symptoms (discomfort, burning, itching, sneezing, pain, runny nose, obstruction, and abnormal taste) on a 0‐100 mm visual analog scale (VAS), where 0 represents absence of symptom and 100 represents the worst severity of symptom. Subjects completed the VAS pre‐dose and post dose at 5, 15, and 60 minutes, and at 4 and 24 hours. Nasal examinations were completed by the same trained and qualified nurse practitioner using a 5‐item instrument evaluating the presence and severity of erythema, edema, rhinorrhea, bleeding, and ulceration pre‐dose and post dose at 5, 15, and 60 minutes, and at 4 and 24 hours. Blood samples to determine concentrations of DHE and the metabolite were obtained pre‐dose and at 5, 10, 15, 30, 45, 60, and 90 minutes and at 2, 4, 6, 8, 12, 24, 36, and 48 hours post‐dose.
Bioanalytical and PK Methods
Quantitative liquid chromatography, tandem mass spectrometry (LC‐MS/MS) was used to determine plasma levels of parent DHE and its primary metabolite, 8′OH‐DHE. Following extraction, samples were subjected to LC‐MS/MS analysis in electrospray positive ion mode using a Sciex API 5000 machine. The method was linear over the standard concentration ranges studied (8‐8000 pg/mL for DHE and 19‐1900 pg/mL for 8′OH‐DHE); imprecision (coefficient of variation) did not exceed 5.6% (CV on CS: DHE: 3.7%/β: 5.6%/α: 5.1%). Replicate analyses of intra‐ and inter batch DHE quality control samples showed accuracy of 98.2%‐108.5% and assay imprecision <5.2%. Replicate 8′OH‐DHE analyses of intra‐ and inter batch quality control samples showed accuracy of 100.7%‐107.9% and 94.5%‐107.8% and assay imprecision <3.6% and <18.4% for β‐8′OH‐DHE and α‐8′OH‐DHE, respectively. Mean (standard deviation) Recovery from human plasma at low, medium, and high levels were of 98.2, 96.5, and 92.3% for DHE, 97.6, 96.9, and 92.5% for β‐8′OH‐DHE and 90.7, 88.7, and 84.2% for α‐8′OH‐DHE. All bioanalytical analyses were performed by Syneos/Inventive Health, Quebec City, Canada.
Statistical Methods
No formal calculation of sample size was performed. Based on similar previous studies, the number of subjects enrolled in this study was considered sufficient to generate meaningful safety and pharmacokinetic data.5, 6, 7
DHE and 8′OH‐DHE concentrations through 48 hours after dosing were used to calculate summary statistics (n, arithmetic mean, SD, %CV, minimum, median, maximum, geometric mean [converting back to the original units], and %CV for the geometric mean) of these pharmacokinetic parameters: C max, T max, AUC0‐30 min, AUC0‐2 h, AUC0‐24 h, AUC0‐48 h, AUC0‐inf, and t 1/2.
The comparative bioavailability of STS101 to IM DHE and Migranal was assessed using a linear mixed model on the natural log‐transformed, unadjusted values for AUClast, AUC0‐inf, and C max. The model included sequence, period, and treatment as fixed factors, and subject within sequence as a random effect. For each comparison, estimates of the mean difference and corresponding 90% confidence interval (CI) were obtained from the model and exponentiated to provide an estimate of the ratio of geometric means and the 90% CI for the ratio. WinNonlin (Pharsight Corporation, Mountain View, CA, USA) and SAS (SAS Institute, Cary, NC, USA) were used for analyses.
Results
Baseline demographics showed a mean age of 41.1 years (range: 29‐50) in part 1 participants and a mean age of 36.8 years (range: 18‐49) in part 2 participants (Table 1). In part 1, 14 subjects completed all 3 administrations. One subject was discontinued due to a positive drug screen before receiving the STS101 5.2 mg dose strength. In part 2, 1 subject withdrew for personal reasons after receiving STS101 and did not receive IM DHE and Migranal. Twenty‐seven subjects were dosed with STS101 and are included in the PK and safety analyses. Twenty‐seven subjects were dosed with Migranal and are included in the safety analysis because 1 subject, in whom no post dosing blood samples were drawn due to poor venous access, was replaced with an additional subject. Twenty‐six subjects who received Migranal are included in the PK analysis. Twenty‐six subjects were dosed with IM DHE and are included in the PK and safety analyses.
Table 1.
Baseline Characteristics of Study Population
| Parameter | Part 1 | Part 2 |
|---|---|---|
| Number of subjects | 15 | center |
| Gender (F/M) | 8/7 | 12/16 |
| Age, years† | 41.1 (7.0) | 36.8 (7.9) |
| Range | 29‐50 | 18‐49 |
| Race | ||
| White | 13 | 25 |
| Black or African American | 2 | 3 |
| Weight, kg† | 77.6 (13.6) | 77.5 (14.5) |
| Range | 58.8‐113.5 | 52.5‐108.6 |
| Body mass index, kg/m2 † | 27.2 (2.3) | 26.7 (2.5) |
| Range | 23.6‐31.3 | 21.3‐30.9 |
Mean ± standard deviation.
PK Evaluation
DHE
Part 1
Following administration of ascending doses of STS101 dose‐dependent DHE plasma concentrations and pharmacokinetics were shown (Table 2; Fig. 4). The mean C max was 645, 1244, and 1870 pg/mL for the 1.3, 2.6, and 5.2 mg dose strengths, respectively. Mean AUC0‐2 h was 956, 1683, and 2549 h × pg/mL, and mean AUC0‐inf was 4172, 7022, and 10,150 h × pg/mL, for the 1.3, 2.6, and 5.2 mg dose strengths, respectively.
Table 2.
Summary of Pharmacokinetic Parameters for DHE; Part 1
| Mean ± Standard Deviation | |||
|---|---|---|---|
| PK Parameter | STS101 1.3 mg (n = 15) | STS101 2.6 mg (n = 15) | STS101 5.2 mg (n = 14) |
| C max, (pg/mL) | 645 (418) | 1243 (576) | 1870 (823) |
| C max, CV (%) | 65 | 46 | 44 |
| AUC0‐2 h, h × pg/mL | 956 (592) | 1683 (719) | 2549 (1132) |
| AUC0‐last, h × pg/mL | 3931 (1800) | 6653 (2411) | 9696 (3717) |
| AUC0‐inf, h × pg/mL | 4172 (1860) | 7022 (2557) | 10,150 (3814) |
| AUC0‐inf, CV (%) | 45 | 36 | 38 |
| T max, h (median [min, max]) | 0.75 | 0.50 | 0.50 |
| 0.50, 1.50 | 0.25, 2.00 | 0.25, 0.50 | |
| t 1/2 (h) | 12.9 (2.12) | 12.6 (1.28) | 12.0 (1.61) |
| CL/F, L/h | 423 (176) | 476 (158) | 673 (265) |
| Vz/F, L | 8074 (4493) | 8529 (2413) | 11,650 (4680) |
Figure 4.
Mean DHE plasma concentrations in healthy subjects after administration of a single dose of STS101 (1.3, 2.6 and 5.2 mg DHE; 0‐24 hours; Part 1).
Part 2
DHE plasma concentrations rose rapidly after STS101 5.2 mg and IM DHE injection, with mean concentrations exceeding 1000 pg/mL at 10 minutes and 5 minutes after dosing, respectively (Table 3). STS101 5.2 mg showed DHE plasma concentrations and pharmacokinetics comparable to IM DHE and 2‐3‐fold higher values compared to Migranal (Table 4 and Fig. 5). The mean C max was 2175, 3368 and 961 pg/mL for the STS101 5.2 mg, IM DHE and Migranal, respectively. The median T max was 30, 15 and 60 minutes for STS101 5.2 mg, IM DHE and Migranal, respectively. The mean AUC0‐2 h was 2979, 4791 and 1316 h × pg/mL, and the mean AUC0‐inf was 12,030, 12,650 and 6498 h × pg/mL for STS101 5.2 mg, IM DHE and Migranal, respectively. The elimination half‐life was 11.8, 11.2 and 12.7 hours for STS101 5.2 mg, IM DHE and Migranal, respectively. The variability (coefficient of variation) for C max, AUC0‐2 h, and AUC0‐inf with STS101 was 41%, 39% and 39%, respectively (Table 4). This was substantially lower than for Migranal, which had %CV of 76%, 75% and 55%, for C max, AUC0‐2 h, and AUC0‐inf, respectively.
Table 3.
Mean DHE Plasma Concentrations 0‐120 Minutes (pg/mL; ±SD); Part 2
| Time Point (Minutes) | STS101 5.2 mg | IM DHE | Migranal |
|---|---|---|---|
| 5 | 251 (221) | 2672 (978) | 13 (12) |
| 10 | 1229 (814) | 3008 (1009) | 116 (122) |
| 15 | 1849 (917) | 3020 (905) | 264 (225) |
| 30 | 2074 (872) | 3039 (828) | 757 (633) |
| 60 | 1654 (648) | 2576 (459) | 876 (689) |
| 120 | 1171 (442) | 1659 (255) | 634 (432) |
Table 4.
Summary of Pharmacokinetic Parameters for DHE; Part 2
| Mean ± Standard Deviation | |||
|---|---|---|---|
| PK Parameter | STS101 5.2 mg (n = 27) | IM DHE (n = 26) | Migranal (n = 26) |
| C max, (pg/mL) | 2175 (884) | 3368 (840) | 961 (727) |
| C max, CV (%) | 41 | 25 | 76 |
| AUC0‐30 min | 686 (326) | 1357 (389) | 152 (131) |
| AUC0‐2 h | 2979 (1147) | 4791 (908) | 1316 (990) |
| AUC0‐2 h, CV (%) | 39 | 19 | 75 |
| AUC0‐last, h × pg/mL | 11,440 (4357) | 13,240 (2022) | 5973 (3409) |
| AUC0‐inf, h × pg/mL | 12,030 (4716) | 13,650 (2143) | 6498 (3551) |
| AUC0‐inf, CV (%) | 39 | 16 | 55 |
| T max, h (median [min, max]) | 0.50 | 0.25 | 1.00 |
| 0.25, 2.00 | 0.08, 1.00 | 0.50, 2.00 | |
| t 1/2 (h) | 12 (2) | 11 (2) | 13 (2) |
| CL/F, L/h | 594 (284) | 75 (13) | 478 (442) |
| Vz/F, L | 10,030 (5030) | 1204 (239) | 8393 (6628) |
Figure 5.
Mean DHE plasma concentration in healthy subjects after administration of a single dose of STS101 5.2 mg, IM DHE, and migranal (Top, 0‐24 hours; Bottom, 0‐4 hours Part 2).
The comparative bioavailability showed ratios of geometric means (and associated 90% confidence intervals; CI) for STS101 5.2 mg and IM DHE of 83% (68, 100), 81% (66, 99) and 61% (48, 77) for AUCinf, AUClast, and C max, respectively (Table 5). The ratios of the geometric means for the comparison of STS101 5.2 mg to Migranal were 205% (169, 250), 217% (178, 266), and 283% (222, 359) for AUCinf, AUClast, and C max, respectively (Table 5).
Table 5.
Plasma DHE Comparative Bioavailability Assessment (STS101 5.2 mg vs Migranal and STS101 5.2 mg vs IM DHE)
| PK Parameter | STS101 5.2 mg (Geometric Mean) | IM DHE (Geometric Mean) | Ratio of Geometric Means (%) | One‐sided 90% CI for Ratio of Geometric Means (%) (Lower, Upper) |
|---|---|---|---|---|
| AUC0‐last (h × pg/mL) | 10,580 | 13,030 | 81 | 66, 99 |
| AUC0‐inf (h × pg/mL) | 11,090 | 13,410 | 83 | 68, 100 |
| C max (pg/mL) | 1974 | 3253 | 61 | 48, 77 |
| PK Parameter | STS101 5.2 mg (Geometric Mean) | Migranal (Geometric Mean) | Ratio of Geometric Means (%) | One‐sided 90% CI for Ratio of Geometric Means (%) (Lower, Upper) |
|---|---|---|---|---|
| AUC0‐last (h × pg/mL) | 10,580 | 4873 | 217 | 178, 265 |
| AUC0‐inf (h × pg/mL) | 11,090 | 5402 | 205 | 169, 250 |
| C max (pg/mL) | 1974 | 699 | 283 | 222, 359 |
8′OH‐DHE
Dose dependent 8′OH‐DHE plasma concentrations and pharmacokinetics were shown in part 1. In part 2, STS101 5.2 mg showed a higher AUClast as compared to IM DHE and Migranal (Table 6).
Table 6.
Summary of Pharmacokinetic Parameters for 8′OH‐DHE; Part 2 (All Subjects)
| Mean ± Standard Deviation | |||
|---|---|---|---|
| PK Parameter | STS101 5.2 mg (n = 27) | IM DHE (n = 26) | Migranal (n = 26) |
| C max (pg/mL) | 126 (56) | 69 (26) | 35 (22) |
| C max CV (%) | 45 | 37 | 64 |
| AUC0‐last, h × pg/mL | 1382 (566) | 726 (328) | 546 (463) |
| AUC0‐inf, h × pg/mL | 1923 (512) | NC | NC |
| T max, h (median [min, max]) | 2.00 | 1.00 | 2.00 |
| 0.5, 4.00 | 0.75, 2.00 | 1.47, 6.00 | |
| t 1/2 (h) | 19 (6) | 17 (5) | 21 (7) |
NC = not calculated.
Adverse Events
The incidence of treatment emergent AEs (TEAEs) 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 (Table 7). All adverse events were mild and transient. No subject was withdrawn from the study for an adverse event. No deaths or serious adverse events occurred. Subjects treated with STS101 reported a higher frequency of nasal adverse events than those treated with IM DHE or Migranal. The most frequent adverse event reported after STS101 was mild nasal discomfort/burning. Subjects reporting dysgeusia noted a mild bitter or sour taste. The subjective evaluation of nasal signs and symptoms showed minimal average scores (Fig. 6) indicating the mild nature of the nasal adverse events. The nasal examinations did not show any clinically relevant findings. None of the ECGs, physical examinations, and laboratory tests showed any relevant clinical findings. No device malfunctions were reported.
Table 7.
Incidence of AEs Occurring in at least 2 Participants in Any Treatment Group
| Treatment Emergent AE | STS101 | Migranal (n = 27) | IM DHE (n = 26) | ||
|---|---|---|---|---|---|
| 1.3 mg (n = 15) | 2.6 mg (n = 15) | 5.2 mg (n = 41) | |||
| Any treatment emergent AEs | 9 (60.0%) | 5 (33.3%) | 16 (39.0%) | 5 (18.5%) | 4 (15.4%) |
| Eye disorders | |||||
| Lacrimation increased | 3 (7.3%) | ||||
| Gastrointestinal disorders | |||||
| Abdominal pain | 2 (4.9%) | ||||
| General disorders and administration site conditions | |||||
| Vessel puncture/injection site reactions | 3 (20.0%) | 3 (20.0%) | 1 (3.8%) | ||
| Nervous system disorders | |||||
| Dysgeusia | 1 (6.7%) | 1 (6.7%) | 9 (22.0%) | 2 (7.4%) | |
| Headache | 2 (13.3%) | 1 (3.8%) | 1 (3.7%) | 1 (3.8%) | |
| Respiratory, thoracic and mediastinal disorders | |||||
| Nasal congestion | 2 (13.3%) | 5 (12.2%) | |||
| Nasal discomfort | 4 (26.7%) | 3 (20.0%) | 14 (34.1%) | 2 (7.4%) | |
| Nasal pruritus | 3 (7.3%) | ||||
| Rhinalgia | 5 (12.2%) | 1 (3.7%) | |||
| Rhinorrhea | 1 (6.7%) | 1 (6.7%) | 6 (14.6%) | ||
| Sneezing | 2 (4.9%) | ||||
Figure 6.
Subjective nasal symptoms visual analog scale data (STS101 5.2 mg; Part 2). VAS score of 0 represents absence of symptom and 100 represents the worst severity of symptom.
Discussion
Migraine continues to be an area of high unmet medical need with considerable burden and disability for patients that results in substantial direct and indirect costs.14, 15, 16 Consensus goals for acute migraine treatment include rapid and consistent freedom from pain and associated symptoms without recurrence, restored ability to function, minimal need for repeat dosing or rescue medications and minimal or no AEs.14
Although oral triptans are commonly prescribed for the acute treatment of migraine attacks, a large meta‐analysis of 24,089 patients treated with oral triptans in double‐blind, controlled studies found that only approximately 30% on average achieved freedom from pain and approximately 40% did not experience relief by 2 hours following treatment.17 In addition triptans suffer from inconsistency of response, high rate of recurrence, and high potential for medication overuse headaches.1, 10, 17 These results suggest that the current treatment approach for many people with migraine is suboptimal and may explain the low treatment adherence and persistence with oral triptans that has been reported.18
DHE has been a staple in migraine therapy for over 70 years and is recognized in migraine treatment guidelines as being a safe and effective initial treatment option for moderate and severe migraine attacks.1, 2 The broad receptor activity profile of DHE may contribute to the benefits of DHE treatment given that migraine pathophysiology involves multiple transmitter systems.1, 3, 17 DHE's unique anti‐migraine activity includes effectiveness even when administered long after the onset of an attack, effectiveness despite the presence of cutaneous allodynia/ central sensitization, low migraine recurrence rates producing a long refractory period after treatment, and a low risk of causing medication overuse headache, that is believed to be lower than that of triptans.1, 2, 3 However, the need for an injection (intravenous, intramuscular, or subcutaneous) to administer DHE solution and the highly variable pharmacokinetic and consequent inconsistent clinical performance of Migranal, as well as burdensome and time‐consuming administration procedure, have limited use of DHE in the acute management of migraine.1, 2 MAP0004, an orally inhaled, pulmonary‐route dosage form of DHE was developed and demonstrated favorable efficacy and safety in Phase 2 and 3 clinical studies.13 However, due to manufacturing issues, MAP0004 failed to receive approval from the US Food and Drug Administration, and its development was subsequently discontinued.5 Thus, there continues to be a significant unmet clinical need for a non‐injected DHE dosage form that can be quickly and easily self‐administered by migraine patients and results in rapid, consistent, and robust efficacy without significant adverse events.
This healthy subject study was designed to evaluate the tolerability, safety, and PK profile of STS101, a novel drug‐device combination product containing a powder formulation of DHE that is self‐administered into a single nostril by an air‐driven, single‐use, disposable nasal delivery device.
In part 1 of the study, dose dependent DHE plasma concentrations were demonstrated over a range of 1.3‐5.2 mg STS101. In part 2, the DHE plasma concentrations for 5.2 mg STS101 exceeded concentrations previously reported for Migranal and were comparable to IM DHE.6, 7
Rapid absorption of any drug for acute treatment of migraine is assumed to be critical for the onset of pain relief.18, 19 The study data suggest that STS101 5.2 mg provides rapid DHE absorption achieving plasma concentrations and an AUC0‐30 min that have been previously shown to result in an onset of clinical efficacy within about 30 minutes.8, 13
The plasma concentration over 2 hours (AUC0‐2 h) is important for the 2‐hour efficacy endpoints of freedom from pain and most bothersome symptom (photophobia, phonophobia, nausea) in clinical efficacy studies.18 The reported AUC0‐2 h values showed more than 2‐fold higher DHE concentrations with STS101 compared to Migranal. The AUC0‐2 h values also exceed previously reported data for the oral inhaled DHE product (MAP0004) and INP104, a liquid DHE formulation administered by a novel, propellant‐driven nasal delivery device, by about 2‐fold.5, 8
DHE has been reported to have a long pharmacodynamic half‐life and a prolonged receptor residence time due to tight binding.19 Sustained high plasma concentrations beyond 2 hours (AUC0‐inf) may also contribute to the sustained efficacy and lower recurrence rates seen with DHE in general and especially with the IM and SC administration which provide the highest AUC0‐inf.6, 8, 9, 10, 15 In this study the AUC0‐inf for STS101 5.2 mg achieved 83% of the values of the IM DHE and 205% of the values for Migranal. Moreover, the AUC0‐inf of STS101 was about 2‐fold and 2.5‐fold larger in comparison to MAP0004 and INP104, respectively.5, 8
Migranal use has been hampered by high plasma concentration variability leading to inconsistent and unreliable clinical performance.17, 20 In this study the variability for C max and AUC were substantially lower with STS101 as compared to Migranal, suggesting STS101 may have more predictable, reliable, and robust clinical performance. Plasma concentrations observed following Migranal administration were similar to those reported in historical studies, despite the fact that the current study utilized different bioanalytical methods (LC‐MS/MS) than in historical studies (radioimmunoassay).6, 7
The major metabolite, 8′OH‐DHE showed higher C max and AUC after STS101 compared to IM DHE and Migranal. However, in a pharmacological receptor binding study no receptor activity of 8′OH‐DHE was demonstrated at values 3 times higher than the C max value reported here, establishing the metabolite as inactive at such low concentrations.21
All treatment emergent adverse events were mild in nature, transient and related to the nasal route of administration or known effects of DHE mesylate, for example, taste sensations. No clear dose response relationship for adverse events was seen for STS101. The reported frequency of nasal adverse events may have been impacted by the use of the 8‐item instrument visual analog scale for the assessment of subjective nasal irritation. The overall frequency of nasal adverse events was comparable to those of other nasal migraine products.4, 22, 23, 24 There was a notable absence of nausea and vomiting with STS101, which is a major limitation of IV DHE. A lower C max compared to the C max reported for IV administration of DHE may be a possible explanation.25
In conclusion, STS101 showed a favorable tolerability profile in healthy subjects and resulted in DHE plasma concentrations comparable to IM DHE and higher than Migranal. Based on this data, STS101 is expected to provide rapid pain relief, improvement in functionality and excellent 2‐hour and sustained pain freedom rates. To further evaluate the therapeutic utility of STS101 in the acute treatment of migraine, a large, double‐blind, placebo‐controlled Phase 3 efficacy study is planned (NCT03901482).
Statement of Authorship
Category 1
(a) Conception and Design
Detlef Albrecht, Mic Iwashima, Debbie Dillon, Stuart Harris, Jeff Levy
(b) Acquisition of Data
Stuart Harris, Jeff Levy
(c) Analysis and Interpretation of Data
Detlef Albrecht, Stuart Harris, Jeff Levy
Category 2
(a) Drafting the Manuscript
Detlef Albrecht, Mic Iwashima, Debbie Dillon, Stuart Harris, Jeff Levy
(b) Revising It for Intellectual Content
Detlef Albrecht
Category 3
(a) Final Approval of the Completed Manuscript
Detlef Albrecht, Mic Iwashima, Debbie Dillon, Stuart Harris, Jeff Levy
Acknowledgments
The authors would like to thank John Kollins, Rob Schultz and Shannon Strom for their support, Marie‐Eve Coulombe for managing the bioanalytical activities, Elisabeth Victor, Isis Fonseca, Maria Cuartas, Suhaills Perez‐Castillo, Beverlyn Campbell, Olga Acosta, and Michelle Suarez for performing all study activities with the subjects, Antonio Regueira and Nadege Noel for pharmacy support, Ann Weltervreden Penix for statistical analysis, Deb Koons for clinical monitoring and Cina Salas for writing assistance.
Conflict of Interest: DA, MI and DD are employees of Satsuma Pharmaceuticals, Inc. SH and JL are employees of Seaview/Quotient.
Funding: The study was funded by Satsuma Pharmaceuticals, Inc.
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