Introduction
Increased blood pressure (BP) and hypertension are known adverse effects of sphingosine 1-phosphate (S1P)1,4,5 receptor modulators. Etrasimod is an investigational, oral, once-daily, selective S1P1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC).
Aims & Methods
We assessed the impact of etrasimod on BP and hypertension development among patients (pts) in the etrasimod UC clinical programme. Pivotal (placebo [PBO]-controlled phase [p]3 [NCT03945188; NCT03996369] studies) and All UC (PBO-controlled plus open-label extension [OLE]; p2 [NCT02447302], p3 and OLE [NCT03950232 and NCT04176588, data snapshot Jan 31, 2022; NCT02536404] studies) cohort data were analysed. BP was assessed at each visit and at 2 and 4 weeks (wks) post‑treatment cessation. Proportions and exposure-adjusted incidence rates (EAIRs; pts with AEs divided by the total pt‑years [PY] at risk for AEs, per 1 PY) of treatment‑emergent Hypertension (Medical Dictionary for Regulatory Activities preferred term [PT]) AEs among pts receiving etrasimod (2 mg once daily; both cohorts) or PBO (Pivotal UC cohort) were assessed. Characteristics of pts with Hypertension AEs that met sponsor-designated events of interest (SDEI) criteria (related to hypertension associated with sustained increases in BP [systolic/diastolic: ≥ 160/100 mmHg], or requiring new or increased antihypertensive therapy) were analysed descriptively.
Results
In the Pivotal and All UC cohorts, 11/527 (2.1%; EAIR, 0.04; PBO: 2/260 [0.8%; EAIR, 0.02]) and 20/942 (2.1%; EAIR, 0.03) etrasimod-treated pts had PT Hypertension, respectively; none led to study treatment discontinuation. In the All UC cohort, 19/942 (2.0%; EAIR, 0.02) etrasimod-treated pts had hypertension-related SDEIs. Of these events, 6 were in pts with hypertension history; none were serious or led to treatment discontinuation; 6 resolved (5 with intervention), 8 were resolving/unknown outcome and 5 were unresolved. Etrasimod‑treated pts had minimal changes in BP over time (All UC cohort, mean change in systolic/diastolic BP at Wk52: 2.9/1.2 mmHg, respectively; Table). In the All UC cohort, at Wk104, no etrasimod-treated pts had a systolic/diastolic BP > 160/100 mmHg, respectively.
| Table. Change from baseline in BP over time among pts in the etrasimod UC clinical programme (Pivotal and All UC cohorts) |
|---|
| Time point | Pivotal UC cohort | All UC cohort |
| Systolic BP, mmHg | Diastolic BP, mmHg | Time point | Systolic BP, mmHg | Diastolic BP, mmHg |
Etrasimod
2 mg QD
(N=527) | PBO
(N=260) | Etrasimod
2 mg QD
(N=527) | PBO
(N=260) | Etrasimod 2 mg QD
(N=942) |
Baselinea, mean (SD)
[etrasimod, n=527; PBO, n=260] | 120.7 (12.50) | 121.3 (13.08) | 75.8 (8.53) | 77.2 (9.56) | Baselinea, mean (SD)
[n=942] | 119.6 (12.89) | 75.6 (8.57) |
Change at Wk12, mean (SD)
[etrasimod, n=474; PBO, n=231] | 2.0 (11.17) | -1.4 (10.68) | 1.6 (8.08) | -0.4 (8.07) | Change at Wk12, mean (SD)
[n=821] | 2.1 (10.78) | 1.7 (8.01) |
Change at Wk52, mean (SD)
[etrasimod, n=162; PBO, n=44] | 2.2 (11.08) | 1.3 (9.16) | 0.4 (8.47) | -0.8 (8.52) | Change at Wk52, mean (SD)
[n=246] | 2.9 (10.39) | 1.2 (8.36) |
Change at Wk78/ Wk104b,
mean (SD)
[N/A] | - | - | - | - | Change at Wk78/ Wk104, mean (SD)
[Wk78, n=147; Wk104, n=29] | 1.9 (10.65)/
-0.7 (13.54) | 1.1 (8.05)/
0.8 (7.40) |
Change at 2-/4-wk follow-up visitc, mean (SD)
[2‑wk: etrasimod, n=39; PBO, n=6; 4‑wk: etrasimod, n=36; PBO, n=10] | 0.2 (10.66)/
-0.4 (11.47) | 6.7 (10.61)/
8.1 (8.18) | 1.6 (7.99)/
0.2 (10.40) | 3.2 (3.71)/
3.0 (7.12) | Change at 2-/4-wk follow-up visitc, mean (SD)
[2‑wk; n=203; 4‑wk, n=105] | 2.6 (13.73)/
1.9 (12.43) | 1.3 (8.74)/
1.4 (9.18) |
Pivotal UC cohort comprised patients from the placebo-controlled p3 ELEVATE UC 52 (NCT03945188) and p3 ELEVATE UC 12 (NCT03996369) studies. All UC cohort comprised patients from the p2 OASIS (NCT02447302), p2 OASIS OLE (NCT02536404 [completed Nov 01, 2018]), p3 ELEVATE UC 52 (NCT03945188), p3 ELEVATE UC 12 (NCT03996369) and p3 ELEVATE UC OLE (NCT03950232 [data snapshot Jan 31, 2022]) studies, and the open-label phase of the p3 study NCT04176588 (data snapshot Jan 31, 2022)
aBaseline is defined, by study treatment group received, as the last non-missing measurement taken on or prior to the study treatment group start date
bWk78 and 104 data are not provided for the Pivotal UC cohort as only data up to Wk52 of ELEVATE UC 52 are included for pts in this cohort
cPts who did not participate in the OLE study had 2-wk and 4-wk follow-up visits after their last treatment administration
BP, blood pressure; N, total number of patients; n, number of patients with evaluable data at a visit; N/A, not applicable; OLE, open-label extension;
p, phase; pts, patients; PBO, placebo; QD, once daily; SD, standard deviation; UC, ulcerative colitis; wk, week |
Conclusion
Hypertension events were infrequent among etrasimod-treated pts. No clinically meaningful changes in BP with etrasimod 2 mg over time or following treatment discontinuation were observed up to 2 years. Data interpretations are limited by small pt numbers.
Disclosure
SV: lecture/speaker fees: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Hospira, MSD, Takeda, Tillotts; consultancy/advisory fees: AbbVie, AbolerIS, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts, Zealand Pharma; grant/research support: AbbVie, MSD, Pfizer Inc, Galapagos, Takeda.
DTR: grant support: Takeda, Helmsley Charitable Trust and GastroIntestinal Research Foundation; consultancy fees/advisory boards: AbbVie, AltruBio, ASLAN Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chronicles, Syneos, ClostraBio, Connect Biopharma, EcoR1, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Eli Lilly, Pfizer, Prometheus, Reistone, Seres Therapeutics, Takeda, Target RWE, Trellus Health; Board of Trustees: Crohn’s & Colitis Foundation and Cornerstones Health, Inc; stock options: Alike Health, AltruBio, Datos Health, Iterative Health.
LP-B: grant/research support: Takeda, Fresenius Kabi, Celltrion; lecture/speaker fees: Galapagos, AbbVie, Janssen, Genentech, Ferring Pharmaceuticals, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena Pharmaceuticals, Lilly, Gilead Sciences, Viatris, Medac, Sanofi; consultancy fees: AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; stockholder: CTMA.
MCD: consultancy fees: AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer Inc, Prometheus Laboratories, Takeda, Trellus Health, UCB; grant/research support: Janssen; shares/royalties: Trellus Health; directorship/ownership interests: Trellus Health.
MR: Unrestricted Educational Grants: Abbvie, BMS, Janssen, UCB, Pfizer, Takeda, Celgene, Genentech, Gilead; advisory boards/Consultant: Abbvie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., Bristol-Myers Squibb (BMS), CME Companies: CME Outfitters, Imedex, GI Health Foundation (GiHF), Cornerstones, Remedy, MJH life sciences; royalties: Wolters Kluwer Health: Author/Editor of UpToDate.
PMI: grant support: Celltrion, Janssen, MSD, Takeda; lecture fees: AbbVie, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, Warner Chilcott; advisory fees: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Genentech, Gilead Sciences, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor, Warner Chilcott.
MG and KL: employees & shareholders of Pfizer AG.
JW, IM, JCW, CR: employees & shareholders of Pfizer Inc.
AM: employee of Pfizer Ltd and shareholder of Pfizer Inc.
AY: consultancy fees: Pfizer, Arena Pharmaceuticals, Takeda, Bristol-Myers Squibb; lecture/speaker fees: Bristol-Myers Squibb.
