Introduction
Etrasimod is an investigational, once-daily (QD), oral, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator in development to treat immune-mediated inflammatory disorders. CULTIVATE (NCT04173273) is a seamless phase 2/3 trial comprising 5 substudies designed to evaluate the efficacy, safety and tolerability of etrasimod in patients with moderately to severely active Crohn’s disease (CD).
Aims & Methods
Here, we report the induction data from the first substudy (Substudy A). Substudy A was a phase 2, randomised, double-blind study using a 14‑week induction period followed by a 52-week extension period. Adults (18–80 years) with moderately to severely active CD and an inadequate response, loss of response or intolerance to ≥1 conventional or advanced treatments for CD were randomised 1:1 to etrasimod 2 or 3 mg QD. Patients were stratified by baseline biologic failure status and oral corticosteroid use. The primary efficacy endpoint was achievement of endoscopic response (defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD score) at Week 14. Secondary/exploratory endpoints included achievement of endoscopic remission, clinical remission (CDAI <150) and IBDQ remission (IBDQ ≥170), at Week 14. Outcomes were analysed in the full analysis set (all randomised patients treated with ≥1 dose of etrasimod) using non-responder imputation or observed data.
Results
Of 83 patients randomised to either etrasimod 2 or 3 mg QD, 32/42 (76.2%) and 36/41 (87.8%) completed Week 14, respectively. Overall, 21.4% and 9.8% of patients receiving etrasimod 2 and 3 mg QD, respectively, achieved the primary endpoint of endoscopic response, 14.3% and 7.3% achieved endoscopic remission, 31.0% and 43.9% achieved clinical remission, and 33.3% and 40.0% achieved IBDQ remission at Week 14. Most TEAEs were mild or moderate. The incidence of serious TEAEs (4.8% and 2.4%) and TEAEs leading to discontinuation (4.8% and 7.3%) was low with etrasimod 2 and 3 mg QD, respectively (Table). Two patients randomized to etrasimod 3 mg QD experienced second-degree atrioventricular block type I TEAEs (one patient during 2-mg titration).
Table. Baseline demographics and clinical characteristics, proportions of patients achieving endoscopic remission, endoscopic response, and clinical remission at Week 14 (full analysis set), and overall summary of safety data (safety set)
|
|---|
Baseline demographics and clinical characteristics
| Etrasimod 2 mg QD (N=42)
| Etrasimod 3 mg QD (N=41)
|
Age, mean (SD), years
Female, n (%)
Extent of CD, n (%)
Ileal disease
Colon
Both
CDAI, mean (SD)
SES-CD, mean (SD)
Prior oral or intravenous corticosteroids, n (%)
No. of prior biologic therapies, n (%)
0
1
2
>3
| 38.3 (12.6)
22 (52.4)
7 (16.7)
13 (31.0)
22 (52.4)
330.6 (80.7)
13.4 (7.7)
36 (85.7)
18 (42.9)
12 (28.6)
4 (9.5)
8 (19.0)
| 40.8 (14.0)
19 (46.3)
12 (29.3)
10 (24.4)
19 (46.3)
303.5 (60.2)
11.2 (7.4)
32 (78.0)
16 (39.0)
8 (19.5)
6 (14.6)
11 (26.8)
|
% achieving response
| Etrasimod 2 mg QD (N=42)
| Etrasimod 3 mg QD (N=41)
|
Endoscopic responsea
Endoscopic remissionb
Clinical remissionc
IBDQ remissiond
| 21.4
14.3
31.0
33.3
| 9.8
7.3
43.9
40.0
|
Safety events, n (%)e
| Etrasimod 2 mg QD (N=42)
| Etrasimod 3 mg QD (N=41)
|
Any TEAE
Any serious TEAE
TEAEs leading to study discontinuation
TEAEs leading to study interruption
Deaths
Infections and infestations
Most frequently reported TEAEs
Headache
Arthralgia
Fatigue
TEAEs of special interest
Severe infections (≥ CTCAE Grade 3)
Opportunistic infectionsf
Herpes zoster
Macular oedema
Cardiovascular events
Bradycardia
First-degree AV block
Second-degree AV block, Mobitz type I
Hypertension
| 29 (69.0)
2 (4.8)
2 (4.8)
5 (11.9)
0
7 (16.7)
5 (11.9)
4 (9.5)
4 (9.5)
0
0
0
0
0
1 (2.4)g
0
1 (2.4)
| 35 (85.4)
1 (2.4)
3 (7.3)
2 (4.9)
0
13 (31.7)
8 (19.5)
8 (19.5)
4 (9.8)
0
0
0
0
0
1 (2.4)h
2 (4.9)h,i
0
|
aEndoscopic response is defined as endoscopic remission or ≥50% decrease in SES-CD score (non-responder imputation)
bEndoscopic remission is defined as SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1 (non-responder imputation)
cClinical remission is defined as CDAI <150 (non-responder imputation)
dIBDQ remission is defined as IBDQ ≥170 (as observed)
eSubjects assigned to the 3 mg QD group received etrasimod 2 mg QD during the first week
fMedDRA version 24.1 System Organ Class and Preferred Terms. Opportunistic infections were identified using SMQ Opportunistic infection (narrow scope)
gOne patient randomised to the 2 mg group had an asymptomatic first-degree AV block on Day 1
hOne patient in the 3 mg group had both an asymptomatic second-degree AV block type I (on day 7 following 3-mg dose escalation) and an asymptomatic first‑degree AV block (second week)
iOne patient in the 3 mg group had a symptomatic second-degree AV block type I (during 2-mg titration)
AV, atrioventricular; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CTCAE, Common Terminology Criteria for Adverse Events version 5; IBDQ, Inflammatory Bowel Disease Questionnaire; MedDRA, Medical Dictionary for Regulatory Activities; N, total number of patients; n, number of patients with evaluable data within each category; QD, once daily; SD, standard deviation; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SMQ, Standardised MedDRA Queries; TEAE, treatment-emergent adverse event
|
Conclusion
Data from this substudy of patients with moderately to severely active CD suggest endoscopic and clinical improvement with both etrasimod 2 and 3 mg QD. However, the small sample size and lack of a placebo arm limit the ability to draw conclusions about efficacy, including comparison between the etrasimod 2 and 3 mg groups. Both doses were well tolerated, and safety was consistent with other etrasimod clinical programmes. Data from the extension phase of Substudy A and the placebo-controlled, dose-ranging phase 2b Substudy 1 are forthcoming.
Disclosure
GD’H: advisor: AbbVie, AstraZeneca, Alimentiv, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson & Johnson, Takeda, Pfizer, Polpharma, Prometheus, Tillotts, Ventyx; speaker: AbbVie, Boehringer Ingelheim, Celltrion, Johnson & Johnson, Takeda, Pfizer, Tillotts.
MCD: grant/research: Janssen; consultancy: AbbVie, Arena, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; shares/royalties: Trellus; directorship/ownership interests: Trellus.
LPB: grant/research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
SD: consultancy/advisory: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; speaker: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda; directorship/ownership interests: Gastroenterology and Endoscopy.
BES: grant/research: Arena, Janssen. Lecture fees/Speakers Bureau: BMS, Janssen, Lilly, Pfizer, Takeda; consultancy/advisory: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus Biosciences, Sun Pharma Global, Takeda Pharmaceuticals International, Teva Branded Pharmaceutical Products R&D; stock: Ventyx Biosciences; non-financial support: Janssen, Lilly, Pfizer, Takeda.
DCW: grant/research: AbbVie, Arena, Bristol Myers Squibb, Janssen, Pfizer, Takeda, Ventyx; speaker: AbbVie, Bristol Myers, Squibb, Janssen, Pfizer, Takeda; consultancy: AbbVie, Arena, Bristol Myers Squibb, Janssen, Pfizer, Takeda.
AJY: consultancy: Pfizer, Arena, Takeda, Bristol-Myers Squibb; speaker: Bristol-Myers Squibb.
MVC: grant support: Pfizer, Janssen, Novartis, Bristol-Myers Squibb; consultancy fees: AbbVie, Arena, Bristol-Myers Squibb, Medtronic, Pfizer, Prometheus, Eli Lilly, Janssen, Takeda; speaker fees: AbbVie, Janssen, Medtronic, Pfizer, Bristol-Myers Squibb, Takeda.
DD: employee of Pfizer Inc at the time of the abstract.
IM, HT, GG, CS: employees & shareholders of Pfizer Inc.
CL, FC: employees of Pfizer Inc at the time of this analysis.
JZ: employee & shareholder of Arena Pharmaceuticals.
AMcD: employee & shareholder of Pfizer Ltd.
SS: speaker: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention, Takeda, Theravance.
BGF: consultant/advisory board: AbbVie, AbolerIS, AgomAB, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital, Atomwise, BIOJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, Celgene/Bristol-Myers Squibb, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, FirstWord, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge, HotSpot, InDex, Imhotex, Immunic, JAK, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K., Lenczner Slaght, LifeSci, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Diagnostics, Play to Know AG, Progenity, Protagonist, PTM, Q32, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, YSOPIA, Zealand; speaker: AbbVie, Janssen, Takeda; Alimentiv Senior Scientific Director, provides central reading services; not a company employee, no equity stake; shareholder: Gossamer.
SV: grant/research: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy/advisory: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.
