Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies

Results

Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment (figure 2).

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Figure 2Trial profiles for patients in ELEVATE UC 52 (A) and ELEVATE UC 12 (B)

*The full analysis set comprised all randomly assigned patients (modified Mayo score 4–9) who received at least one dose of study treatment.

The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. A total of 265 (92%) patients in the etrasimod group and 124 (86%) patients in the placebo group completed the induction period and 161 (56%) patients and 46 (32%) patients, respectively, completed week 52. The most common reason for discontinuation in either study group during the induction period was withdrawal by the patient. The most common reason for discontinuation in either study group during the maintenance period was disease worsening (figure 2).
In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo, of whom 213 (89%) and 103 (89%), respectively, completed the trial. The most common reason for discontinuation in the induction period for patients in the placebo group was withdrawal by the patient and in the etrasimod group was adverse events. Baseline demographic and clinical characteristics were similar between the treatment groups in both trials (table 1). As reported by investigators during the screening period, 163 (38%) of 433 patients in ELEVATE UC 52 and 132 (37%) of 354 patients in ELEVATE UC 12 had previous biological or JAK inhibitor experience; however, based on subsequent evaluation of patient medication history, 129 (30%) of 433 patients in ELEVATE UC 52 and 118 (33%) of 354 patients in ELEVATE UC 12 had actual biological or JAK inhibitor experience.

Table 1Baseline demographic and clinical characteristics (full analysis set)

Data are mean (SD) or n (%). JAK=Janus kinase. MMS=modified Mayo score.

In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; figure 3A).

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Figure 3Coprimary endpoints of clinical remission at week 12 and at week 52 (A), key secondary and additional prespecified secondary endpoints at week 12 and week 52 (B), and key secondary and additional prespecified endpoints of sustained remission and corticosteroid-free remission at week 52 in ELEVATE UC 52 (C)

Patients with ulcerative colitis included those with a modified Mayo score of 5–9. *Significance is represented using unadjusted p values.

In ELEVATE UC 52, at week 12, significant improvements with etrasimod were observed versus placebo in the three key secondary endpoints of endoscopic improvement (96 [35%] of 274 patients vs 19 [14%] of 135 patients), symptomatic remission (126 [46%] of 274 patients vs 29 [21%] of 135 patients), and endoscopic improvement–histological remission (58 [21%] of 274 patients vs six [4%] of 135 patients; figure 3B). Additionally, in ELEVATE UC 52 at week 12, significant improvements with etrasimod compared with placebo were observed for the other prespecified secondary endpoint of clinical response (171 [62%] of 274 patients vs 46 [34%] of 135 patients; figure 3B).
At week 52, all key secondary efficacy endpoints were met, including sustained clinical remission (49 [18%] of 274 patients vs three [2%] of 135 patients) and corticosteroid-free remission with no use of corticosteroids for at least 12 weeks among all patients regardless of corticosteroid use at baseline (88 [32%] of 274 patients vs nine [7%] of 135 patients; figure 3C). Similar results for corticosteroid-free remission with no use of corticosteroids for at least 12 weeks were observed for patients with documented corticosteroid use at baseline (27 [31%] of 87 patients vs three [8%] of 40 patients). All patients with remission at week 52 were also corticosteroid free for at least 12 weeks.
Outcomes at week 12 and week 52 in ELEVATE UC 52 for the full analysis set of patients in the overall trial population and for the cohort that excluded patients with isolated proctitis, and subgroup analyses stratified by previous biological or JAK inhibitor exposure, are presented in the appendix (pp 33–39).
In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (figure 4A). In ELEVATE UC 12, at week 12, significant improvements with etrasimod compared with placebo were observed for the key secondary endpoints of endoscopic improvement (68 [31%] of 222 patients vs 21 [19%] of 112 patients), symptomatic remission (104 [47%] of 222 patients vs 33 [29%] of 112 patients), and endoscopic improvement–histological remission (36 [16%] of 222 patients vs ten [9%] of 112 patients; figure 4B). Additionally, at week 12, significant improvements with etrasimod compared with placebo were observed for the other prespecified secondary endpoint of clinical response (138 [62%] of 222 patients vs 46 [41%] of 112 patients; figure 4B).

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Figure 4The primary endpoint of clinical remission at week 12 (A) and key secondary and additional prespecified secondary endpoints at week 12 (B) in ELEVATE UC 12

Patients with ulcerative colitis included those with a modified Mayo score of 5–9. *Significance is represented using unadjusted p values.

Outcomes at week 12 in ELEVATE UC 12 for the full analysis set of patients in the overall trial population and for the cohort that excluded patients with isolated proctitis, and subgroup analyses stratified by previous biological or JAK inhibitor exposure are presented in the appendix (pp 40–43).
A greater proportion of patients treated with etrasimod had symptomatic remission compared with those treated with placebo by week 2 in ELEVATE UC 52 and week 4 in ELEVATE UC 12 (figure 5). Patients in the etrasimod group showed decreases in rectal bleeding and stool frequency subscores as early as week 2 in both trials (appendix pp 56–59). A greater proportion of patients treated with etrasimod had endoscopic normalisation compared with patients treated with placebo at week 12 in both trials and week 52 in ELEVATE UC 52 (appendix p 44). Decreases in faecal calprotectin (appendix pp 60–61) and high-sensitivity C-reactive protein levels (appendix pp 62–63) were also observed in those treated with etrasimod versus those treated with placebo in both trials.

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Figure 5Symptomatic remission over time in ELEVATE UC 52 (A) and ELEVATE UC 12 (B) (non-responder imputation)

Patients with ulcerative colitis included those with a modified Mayo score of 5–9. *p≤0·05; data based on Cochran-Mantel-Haenszel analysis of the full analysis set (all randomly assigned patients who received at least one dose of study drug) and non-responder imputation. Significance is represented using nominal two-sided p values to test the hypothesis of the risk difference for etrasimod minus placebo being 0, based on the estimated common risk difference using Mantel-Haenszel weights.

Consistent with the proposed mechanism of action, mean lymphocyte counts in patients treated with etrasimod decreased to around 50% of those at baseline by week 2 and were maintained throughout the treatment periods of ELEVATE UC 52 and ELEVATE UC 12 (appendix p 45). Among the small proportion of patients in the etrasimod group who completed either study and did not continue treatment in the open-label extension study (n=31), absolute lymphocyte counts returned to the normal range within 2 weeks in 15 (83%) of 18 patients after 52 weeks of treatment in ELEVATE UC 52 and ten (77%) of 13 patients after 12 weeks of treatment in ELEVATE UC 12.
Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and in 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12 (table 2). Exposure-adjusted safety values were consistent between treatment groups in both studies (appendix pp 46–47). Most events were considered mild or moderate. In the etrasimod groups, 12 (4%) of 289 patients in ELEVATE UC 52 and 13 (5%) of 238 patients in ELEVATE UC 12 permanently discontinued study treatment because of treatment-emergent adverse events, compared with seven (5%) of 144 patients and one (1%) of 116 patients in the placebo groups of ELEVATE UC 52 and ELEVATE UC 12, respectively (table 2). The proportion of patients who had serious adverse events was low and similar across etrasimod and placebo groups in both studies (20 [7%] of 289 patients in the etrasimod group vs nine [6%] of 144 patients in the placebo group in ELEVATE UC 52; six [3%] of 238 patients in the etrasimod group vs two [2%] of 116 patients in the placebo group in ELEVATE UC 12). The most frequently reported adverse events (in ≥1% of patients) included anaemia, headache, and worsening of ulcerative colitis or ulcerative colitis flare. In both studies, overall infections, serious infections, and opportunistic infections (ie, tuberculosis and cytomegalovirus infection) were similar between the treatment groups. Across both trials, four patients had herpes zoster events (two patients treated with etrasimod in ELEVATE UC 52; and two patients treated with placebo in ELEVATE UC 12; table 2). These events were considered either mild or moderate, were localised, and did not lead to discontinuation from the study.

Table 2Summary of adverse events and most frequent adverse events

Data are n (%). The most frequent adverse events were defined as those that occurred in ≥3% of etrasimod-treated patients and those that occurred as a greater rate in the etrasimod group versus the placebo in either study. Data were not exposure adjusted.

Adverse events of special interest were similar between the two trials (table 2). No malignancies were reported in either trial. Elevated liver enzymes were reported in both trials, with a higher incidence in the etrasimod treatment groups. No patients met Hy’s Law criteria for elevated liver enzymes or bilirubin in either study. Two patients discontinued treatment in ELEVATE UC 52 because of increased alanine aminotransferase, one of whom had a history of primary sclerosing cholangitis, and the other had all transaminase tests less than 3 times the upper limit of normal (appendix pp 48–49). Bradycardia or sinus bradycardia was identified as a sponsor-designated adverse event of special interest if the heart rate was less than 40 beats per min, there were associated symptoms (eg, lightheadedness), or the event led to study discontinuation. Across both trials, nine events of bradycardia or sinus bradycardia were reported in patients receiving etrasimod—four in ELEVATE UC 52 and five in ELEVATE UC 12; no events were reported in patients receiving placebo. Of these nine events, five met the criteria for sponsor-designated adverse events of interest. Eight of the nine events were first reported on day 1 and the remaining event was reported on day 2. Two of the events of bradycardia were symptomatic (accompanied by mild or moderate dizziness) and led to study discontinuation; both events resolved without the need for pharmacological intervention. Of the seven asymptomatic events, all were reported on day 1, and three of the patients who had these events discontinued the study. One of the three asymptomatic patients who discontinued the trial had both bradycardia and asymptomatic atrioventricular block second-degree Mobitz type I on day 1. Two additional patients had asymptomatic atrioventricular block on day 1; both events were first degree (one of the two patients was discontinued). One of the atrioventricular block first-degree events was reported as an adverse event before the first study drug dose and did not change 4 h after the dose. All three events of atrioventricular block resolved without administration of interventional treatment. No atrioventricular block second-degree Mobitz type II or higher events were reported in either trial. There were no serious events of bradycardia or atrioventricular block, and no patients had a nadir heart rate less than 40 beats per min (appendix pp 50–55). 13 patients across both trials had hypertension, but none of these events led to study interruption or discontinuation.

Across both trials, three patients had macular oedema: one patient in the etrasimod group of ELEVATE UC 52 who discontinued because of the event; one patient in the placebo group of ELEVATE UC 12 who continued without study treatment interruption; and one patient in the etrasimod group of ELEVATE UC 12 (who had a preceding moderate adverse event of uveitis) and continued without study treatment interruption. All events of macular oedema resolved.

All authors meet the International Committee of Medical Journal Editors criteria for authorship for this Article, take responsibility for the integrity of the work as a whole, were involved in drafting and critical review of the manuscript, and approved the final version for submission. WJS, SV, LP-B, MCD, JP, BES, GD, SD, and BGF conceived and designed the study. AY, TR, FB, MC, DCW, and SSc did the research. WJS, SV, LP-B, MCD, JP, SSc, SSl, FC, KS, CJR, AY, MC, DCW, BES, GD, SD, MG, and BGF analysed the data. KS and CJR accessed and verified the underlying data. All authors had full access to the data, were involved in drafting the manuscript and its revisions, made the decision to submit the manuscript for publication, and vouch for the accuracy and completeness of the data and fidelity of the trials to the protocols.

Declaration of interests

WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Gilead Sciences, GSK, Janssen, Lilly, Pfizer, Prometheus Laboratories, Seres Therapeutics, Shire Pharmaceuticals, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Allakos, Amgen, Arena Pharmaceuticals, AstraZeneca, Atlantic Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, ClostraBio, Forbion, Galapagos, Genentech (Roche), GSK, Gossamer Bio, Index Pharmaceuticals, Iota Biosciences, Janssen, Lilly, Morphic Therapeutics, Novartis, Oppilan Pharma (now Ventyx Biosciences), Pfizer, Pharm Olam, Polpharma, Progenity, Prometheus Biosciences, Protagonist Therapeutics, PTM Therapeutics, Seres Therapeutics, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Vedanta Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Gastrosciences, Xencor, and Zealand Pharmaceuticals; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (now Ventyx Biosciences), Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Gastrosciences; and is Chief Medical Officer at Ventyx Biosciences. SV reports grants from AbbVie, J&J, Pfizer, Galapagos, and Takeda; and has received consulting or speaking fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MRM Health, Mundipharma, MSD, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand Pharma. LP-B reports consulting fees from AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharma, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, 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, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, and Abivax; grants from Takeda, Fresenius Kabi, and Celltrion; and lecture or speaker fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, and Medac. MCD reports consulting fees from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus Labs, and Takeda; and is founder and a shareholder of Trellus Health. JP reports consulting fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GSK, Janssen, Mirum, Morphic, Nestle, Origo, Pandion, Progenity, Pfizer, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann; speaker fees from AbbVie, Biogen, Ferring, Janssen, Pfizer, and Takeda; and research funding from AbbVie and Pfizer. AY reports consulting fees from Takeda, Prometheus Labs, Arena Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau fees from Bristol Myers Squibb. TR served on advisory boards or speaker panels for Gilead, AbbVie, Arena Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Gossamer, Intercept, Janssen, Eli Lilly, Pfizer, Prometheus, and Takeda. FB reports grant or research support from AbbVie, Amgen, Janssen, and Takeda; honoraria from AbbVie, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, MSD, Pfizer, Sandoz, and Takeda; and was on speakers bureaus for AbbVie, Arena Pharmaceuticals, Ferring, Galapagos, Janssen, MSD, Pfizer, and Takeda. SSc has been a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, GSK, Gilead, I-MAB Biopharma, Janssen, Lilly, Merck, Novartis-Sandoz, Pfizer, Protagonist, Takeda, and Theravance. FC was a previous employee and stockholder of Arena Pharmaceuticals at the time of research. SSl, KS, CJR, and MG are employees and stockholders of Arena Pharmaceuticals, a wholly-owned subsidiary of Pfizer Inc. MC has been a speaker for AbbVie, Janssen, Medtronic, Pfizer, Bristol Myers Squibb, and Takeda; and has served as a consultant for AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Medtronic, Pfizer, Lilly, Prometheus, and Takeda. DCW has received consulting or speaker honoraria from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Janssen, Lilly, Pfizer, and Takeda. BES reports consulting fees from Abivax, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Entera, Evommune, Galapagos, Genentech, Gilead Sciences, GSK, Gossamer Bio, Index Pharmaceuticals, Inotrem, Innovation Therapeutics, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, Miro Bio, Morphic Therapeutics, MRM Health, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Surrozen, Takeda, Teva, TLL Pharmaceutical, USWM Enterprises, and Viela Bio; speaking fees from Abivax, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; and grant or research support from Janssen. GD has been a consultant for AbbVie, AgomAb, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GSK, Gossamer Bio, Pfizer, Immunic, J&J, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist; and has received speakers bureau fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Pfizer, Bristol Myers Squibb, and Takeda. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor; and payment for expert testimony from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda. BGF has been a consultant for AbbVie, Admirx, AgomAb Therapeutics, Applied Molecular Transport, Arena Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Ferring, Galapagos, Galen Atlantica, Genentech-Roche, Gilead, Gossamer Pharma, GSK, F Hoffmann-La Roche, Janssen, Morphic Therapeutics, OM Pharma, Pandion Therapeutics, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Sanofi, Seres Therapeutics, Surrozen, Takeda, Theravance, TiGenix, Tillotts, and Zealand Pharma; has received speaker bureau fees from AbbVie, Janssen, and Takeda; served on the scientific advisory board for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Bristol Myers Squibb, Genentech, Roche, Janssen, Novartis, Origo BioPharma, Pfizer, Prometheus, Takeda, Tillotts Pharma, Teva, Progenity, Index, and GSK; is a stockholder of Gossamer Pharma; and is an employee of Western University and Alimentiv.

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