S1083 Etrasimod for Moderately to Severely Active Crohn’s Disease: Results From the Extension Period of a Phase 2 Study

Introduction: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P) 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, randomized, double-blind study. Methods: Adults (18–80 years) who completed the 14-week (W) induction phase (data reported previously1) were eligible for the 52W extension period. Patients receiving etrasimod 3 mg during induction continued this treatment within the extension period, regardless of response. Etrasimod 2 mg responders at W14 continued treatment during the extension period, while nonresponders were re-randomized (1:1) to etrasimod 2 or 3 mg (Figure 1). Two analyses were performed based on 2 approaches for patients entering extension: treat-through (TT; outcomes reported for all randomized patients regardless of W14 response) and responders only (RO; outcomes reported for W14 responders only). Both used non-responder imputation. The primary endpoint was the achievement of endoscopic response (defined by endoscopic remission or ≥ 50% decrease in SES-CD) at Week 52; other endpoints included the achievement of clinical remission based on CDAI (< 150) and based on PRO2 (< 8) at Week 52 (Table 1). Treatment-emergent adverse events (TEAEs) were reported for the safety set (Figure 1). Results: Patient disposition and baseline characteristics are shown in the Table 1 and Figure 1. 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 W52 (Table 1). Among W14 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 W52 (Table 1). Most TEAEs were mild or moderate. Nine TEAEs led to discontinuation; 1 was deemed treatment-related (Table 1). No deaths or TEAEs of macular edema or malignancies were reported. 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. Reference: 1. D’Haens G et al. Journal Crohns Colitis 2023; 17: i764–i765.Figure 1.: Patient disposition in the extension period. The safety set (all randomized patients who received ≥ 1 dose) for the 3 mg group in the extension period included 37 patients (34 patients treated with 3 mg during IND and EXT, 2 patients treated with etrasimod 2 mg at IND who were re-randomized to 3 mg during EXT, and one patient that received placebo [randomized to placebo per a previous amendment of the study protocol, the patient was excluded in summary analyses of efficacy and safety]). The safety set for the 2 mg group includes 28 patients. Patients who completed 66 weeks of treatment in Substudy A were eligible to enroll in long-term extension (SS4 LTE). [a]One patient received placebo during the IND period and etrasimod 3 mg QD during the EXT period. [b]Two patients treated with etrasimod 2 mg QD during the IND period were nonresponders and were re-randomized to the 3 mg QD treatment group. These patients were counted as nonresponders in the 2 mg group in the TT design. EXT, extension; IND, induction; N, number of patients in group; n, number of patients; QD, once daily; SS4 LTE, substudy 4 long-term extension; TEAE, treatment-emergent adverse event; TT, treat-through. Table 1. - Baseline demographics and clinical characteristics of patients entering the extension period, proportions of patients achieving efficacy endpoints at W52, 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 41.8 (12.8) 41.6 (14.2) Sex, female (%) 53.6 43.2 Extent of disease (%) Ileal disease 17.9 24.3 Colonic disease 39.3 21.6 Ileocolonic disease 42.9 54.1 Baseline CDAI, mean (SD) 338.6 (81.2) 315.7 (61.5) Baseline SES-CD, mean (SD) 12.3 (7.3) 10.7 (5.9) Baseline systemic corticosteroids (%) 39.3 35.1 Prior use of thiopurines/methotrexatea (%) 46.4 56.8 Number of prior biologicsa (%) 0 50.0 40.5 1 21.4 18.9 2 10.7 13.5 ≥ 3 17.9 27.0 Efficacy endpoints at W52 Endoscopic responseb [n / N (%)] Treat-throughc 14.3 (6 / 42) 19.5 (8 / 41) Responders onlyd 23.1 (6 / 26) 33.3 (8 / 24) Clinical remission CDAIe [n / N (%)] Treat-throughc 28.6 (12 / 42) 34.1 (14 / 41) Responders onlyd 46.2 (12 / 26) 54.2 (13 / 24) Clinical remission PRO2f [n / N (%)] Treat-throughc 19.0 (8 / 42) 36.6 (15 / 41) Responders onlyd 30.8 (8 / 26) 58.3 (14 / 24) Summary of safety (extension period) Any TEAE [n (%)] 22 (78.6) 33 (89.2) Any serious TEAE [n (%)] 4 (14.3) 7 (18.9) TEAEs leading to study treatment discontinuation [n (%)] 3 (10.7) 6 (16.2)g TEAEs leading to death [n (%)] 0 0 Most frequently reported TEAEsh [n (%)] CD (worsening of / flare) 7 (25.0) 8 (21.6) Headache 3 (10.7) 6 (16.2) Arthralgia 3 (10.7) 5 (13.5) COVID-19 3 (10.7) 9 (24.3) TEAEs of special interesti [n (%)] Severe infections (CTCAE ≥ 3) [n (%)] 1 (3.6)j 2 (5.4)k Opportunistic infections [n (%)] Ophthalmic herpes zosterl 0 1 (2.7) Macular edema [n (%)] 0 0 Cardiovascular events [n (%)] 1st degree AV block 0 2 (5.4) 2nd degree AV block, Mobitz type Im 0 0 Bradycardian 1(3.6) 0 Hypertension 0 1 (2.7) aThiopurines/methotrexate and biologics were discontinued prior to randomization.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 randomized 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 W14 (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 edema, 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 2 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 version 5.0; IV, intravenous; N, number of patients in group; n, number of patients; 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; W, Week.

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