Introduction
Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator. Within the phase 2/3 CULTIVATE trial (NCT04173273), we report extension data on the efficacy, safety and tolerability of etrasimod in patients with moderately to severely active Crohn’s disease (CD) from substudy A, a phase 2, randomised, double-blind study.
Aims & Methods
Adults (18–80 years) who completed the 14-week induction phase (data reported previously1) were eligible for the 52-week extension period. Patients receiving etrasimod 3 mg during induction continued this treatment within the extension period, regardless of response. Etrasimod 2 mg responders at Week 14 continued treatment during the extension period, while nonresponders were re‑randomised (1:1) to etrasimod 2 or 3 mg. Two analyses were performed based on two approaches for patients entering extension: treat-through (TT; outcomes reported for all randomised patients regardless of Week 14 response) and responders only (RO; outcomes reported for Week 14 responders only). Both used non‑responder imputation. The primary endpoint was the achievement of endoscopic response (defined by endoscopic remission or ≥50% decrease in Simple Endoscopic Score in Crohn’s Disease) at Week 52; other endpoints included the achievement of clinical remission based on Crohn’s Disease Activity Index (CDAI; <150) and based on PRO2 (<8) at Week 52 (Table). Treatment-emergent adverse events (TEAEs) were reported for the safety set (all randomised patients who received ≥1 dose).
Results
In total, 65 patients (safety set) were enrolled in the extension period with 38 completing the study; patient demographics and baseline characteristics are shown in the Table. For the TT analysis, 14.3% and 19.5% of patients receiving 2 mg or 3 mg etrasimod, respectively, achieved endoscopic response, 28.6% and 34.1% achieved CDAI remission, and 19.0% and 36.6% achieved PRO2 remission at Week 52 (Table). Among Week 14 responders (RO), 23.1% and 33.3% of patients receiving 2 mg or 3 mg etrasimod, respectively, achieved endoscopic response, 46.2% and 54.2% achieved CDAI remission, and 30.8% and 58.3% achieved PRO2 remission at Week 52 (Table). Most TEAEs were mild or moderate. Nine TEAEs led to discontinuation; one was deemed treatment-related (Table). No deaths or TEAEs of macular oedema or malignancies were reported.
| Table. Baseline demographics and clinical characteristics of patients entering the extension period, proportions of patients achieving efficacy endpoints at Week 52 and summary of safety data |
| Etrasimod 2 mg QD
(N=28)
| Etrasimod 3 mg QD
(N=37)
|
| Demographics and baseline clinical characteristics (extension period) |
Age, mean (SD), years
Sex, female (%)
Extent of disease (%)
Ileal disease
Colonic disease
Ileocolonic disease
Baseline CDAI, mean (SD)
Baseline SES-CD, mean (SD)
Baseline systemic corticosteroids (%)
Prior use of thiopurines/methotrexatea (%)
Number of prior biologicsa (%)
0
1
2
≥3
| 41.8 (12.8)
53.6
17.9
39.3
42.9
338.6 (81.2)
12.3 (7.3)
39.3
46.4
50.0
21.4
10.7
17.9
| 41.6 (14.2)
43.2
24.3
21.6
54.1
315.7 (61.5)
10.7 (5.9)
35.1
56.8
40.5
18.9
13.5
27.0
|
| Efficacy endpoints at Week 52 |
Endoscopic responseb [n/N (%)]
Treat-throughc
Responders onlyd
Clinical remission CDAIe [n/N (%)]
Treat-throughc
Responders onlyd
Clinical remission PRO2f [n/N (%)]
Treat-throughc
Responders onlyd
|
14.3 (6 / 42)
23.1 (6 / 26)
28.6 (12 / 42)
46.2 (12 / 26)
19.0 (8 / 42)
30.8 (8 / 26)
|
19.5 (8 / 41)
33.3 (8 / 24)
34.1 (14 / 41)
54.2 (13 / 24)
36.6 (15 / 41)
58.3 (14 / 24)
|
| Summary of safety (extension period) |
Any TEAE [n (%)]
Any serious TEAE [n (%)]
TEAEs leading to study treatment discontinuation [n (%)]
TEAEs leading to death [n (%)]
Most frequently reported TEAEsh [n (%)]
CD (worsening of/flare)
Headache
Arthralgia
COVID-19
TEAEs of special interesti [n (%)]
Severe infections (CTCAE ≥3) [n (%)]
Opportunistic infections [n (%)]
Ophthalmic herpes zosterl
Macular oedema [n (%)]
Cardiovascular events [n (%)]
1st degree AV block
2nd degree AV block, Mobitz type Im
Bradycardian
Hypertension
| 22 (78.6)
4 (14.3)
3 (10.7)
0
7 (25.0)
3 (10.7)
3 (10.7)
3 (10.7)
1 (3.6)j
0
0
0
0
1 (3.6)
0
| 33 (89.2)
7 (18.9)
6 (16.2)g
0
8 (21.6)
6 (16.2)
5 (13.5)
9 (24.3)
2 (5.4)k
1 (2.7)
0
2 (5.4)
0
0
1 (2.7)
|
aThiopurines/methotrexate and biologics were discontinued prior to randomisation.
bEndoscopic response defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD.
cAll randomised patients at baseline who received ≥1 dose of etrasimod (N=42 in the etrasimod 2 mg group; N=41 in the etrasimod 3 mg group).
dAll patients who were responderso at Week 14 (N=26 in the etrasimod 2 mg group; N=24 in the etrasimod 3 mg group).
eCDAI remission defined as CDAI <150.
fPRO2 remission defined as a PRO score <8.
gOne patient discontinued due to TEAE, which was deemed by the investigator as related to etrasimod 3 mg. All other TEAEs that led to discontinuation were related to CD.
hOccurred in >10% of patients in both etrasimod 2 mg and 3 mg groups.
iDefined as a subset of TEAEs that met the criteria of the sponsor’s medical review, and include cardiovascular events, macular oedema and infections.
jOne event of severe COVID-19.
kOne event of severe COVID-19 and one event of severe anal abscess.
lEvent had onset 10 days after the patient had discontinued etrasimod treatment and had started on monoclonal antibody treatment combined with prednisone for worsening CD. The event was assessed as unrelated to study treatment by the investigator.
mNo TEAEs of 2nd degree AV block, Mobitz type II or higher were reported.
nEvent was non-serious (Grade 1) and did not require intervention.
oResponders were required to achieve clinical response CDAI (clinical remission CDAI or ≥100-point decrease from baseline in CDAI) or endoscopic response.
AV, atrioventricular; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; COVID-19, coronavirus disease 2019; CTCAE, Common Terminology Criteria For Adverse Events; N, number of patients in group; n, number of patients; PRO, patient-reported outcome; PRO2, patient-reported outcome 2; QD, once daily; SD, standard deviation; SES-CD, Simple Endoscopic Score in Crohn’s Disease; TEAE, treatment-emergent adverse event. |
Conclusion
Both etrasimod doses remained well tolerated with no new safety signals. This non-placebo-controlled study suggests that etrasimod may be effective in moderately to severely active CD, with higher efficacy at the 3 mg dose. Placebo-controlled studies are ongoing.
References
1. D’Haens G et al. J Crohns Colitis 2023; 17: i764–i765.
Disclosure
GD, Advisor: AbbVie, Alimentiv, AstraZeneca, BI, BMS, Celltrion, Cosmo, Lilly, Galapagos, GSK, J&J, Pfizer, Polpharma, Prometheus, Takeda, Tillotts, and Ventyx. Speaker fees: AbbVie, BI, Celltrion, Lilly, J&J, Pfizer, Takeda, and Tillotts; MCD, Consulting fees: AbbVie, Abivax, Arena, AstraZeneca, BMS, Lilly, Galapagos, Genentech, Gilead, Janssen, Merck, Pfizer, Prometheus, Prometheus Laboratories, Sphyre, Takeda, and UCB. Shareholder/Royalties: Trellus Health. Directorship/Ownership interest: Trellus Health. LPB, Consulting fees: AbbVie, Abivax, Alimentiv, Alma Bio, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillotts, Viatris, Vifor, Vectivbio, Ventyx, and Ysopia. Grants: Celltrion, Fresenius Kabi, and Takeda. Lecture/speaker bureau: AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genetech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillotts, Viatris, and Vifor; SD, Lecture/speaker fees: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda. Consulting/advisory fees: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, BI, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, J&J, MSD, Mundi, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor. Directorship/Ownership: Gastroenterology and Endoscopy. BES, Consulting fees: AbbVie, Abivax, Adiso, Agomab, Alimentiv, Amgen, AnaptysBio, Arena, Artugen, AstraZeneca, Biora, BI, Boston, BMS, Calibr, Celgene, Celltrion, ClostraBio, Enthera, Equillium, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech/Roche, Gilead, GSK, Gossamer Bio, Index, Innovation, Janssen, Kaleido, Kallyope, Lilly, Merck, Mobius Care, Morphic, MRM Health, Nexus, Nimbus Discovery, Odyssey, Palisade Bio, Pfizer, Progenity, Prometheus, Prometheus Laboratories, Protagonist, Q32 Bio, Rasayana, Sun, Surrozen, Takeda, Target RWE, Teva, Theravance, TLL, TR1X, Union, and Ventyx. Speaking fees: AbbVie, Abivax, BMS, Janssen, Lilly, Pfizer, and Takeda. Research grants: BMS, Janssen, Pfizer, and Takeda. Stock and Stock options: Ventyx. Other support: Abivax, BMS, Lilly, Janssen, Pfizer, and Takeda. AY, Consulting fees: AbbVie, Arena, BMS, Pfizer, and Takeda. Lecture fees: AbbVie and BMS. MVC, Grant support: BMS, Janssen, Pfizer, and Novartis. Consulting fees: AbbVie, Arena, BMS, Celltrion, Fresenius Kabi, Janssen, Lilly, Medtronic, Pfizer, Prometheus, and Takeda. Speaker fees: AbbVie, BMS, Janssen, Lilly, Medtronic, Pfizer, and Takeda. IM, DB, AM, MK, LVC, GG, HT, CS, Shareholder and employee: Pfizer; LVC Shareholder and employee: BMS; SS, Lecture/speaker fees: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Falk, Fresenius, Janssen, MSD, Pfizer, and Takeda. Consulting/advisory fees: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Takeda, Theravance, and Ventyx. BF, Senior Scientific Director: Alimentiv. Speaker fees: AbbVie, Janssen, and Takeda. Consulting/advisory board: AbbVie, AbolerIS, AgomAB, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Atomwise, Avoro Capital Advisors, BioJamp, Biora, BI, Boxer, Celgene/BMS, Celsius, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge Bio, Hot Spot, Index, Imhotex, Immunic, JAKAcademy, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Play to Know AG, Progenity, Prometheus and Diagnostics, Protagonist, PTM, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx, VHSquared Ltd, Viatris, Ysios, Ysopia, and Zealand. Shareholder: Gossamer; SV, Lecture/speaker fees: AbbVie, Dr. Falk, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, and Tillotts. Consulting/advisory fees: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, BI, Celgene, CVasThera, Dr Falk, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, J&J, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundi, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts AG, and Zealand. Grant/research support: AbbVie, Galapagos, Janssen, MSD, Pfizer, and Takeda.
