Reimbursement Review

Etrasimod (Velsipity)

Sponsor: Pfizer Canada

Therapeutic area: Ulcerative colitis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance; UC = ulcerative colitis.

Introduction

Ulcerative colitis (UC) is a chronic form of inflammatory bowel disease (IBD) that affects the mucosal layer of the large intestine. It almost invariably involves the rectum and frequently extends continuously into the proximal colon.¹ UC is characterized by blood in the stool with mucus, frequent diarrhea, loss of appetite, and tenesmus (severe rectal cramp or spasm).² Extraintestinal manifestations may also occur, such as arthritis.³ About 10% to 15% of patients with UC experience an aggressive course.⁴ Relapse is common, with the cumulative risk of relapse being 70% to 80% at 10 years.⁴ UC has a considerable impact on patients’ health-related quality of life (HRQoL)^5,6 and their ability to perform their regular daily routines such as jobs or domestic chores,^7-10 and it impacts their caregivers and family, workplace, and community.¹¹ Although the risk of mortality from UC itself is low, the disease is associated with an increased risk of other complications (e.g., respiratory diseases, colorectal cancer, lymphoma, and skin cancer) that result in higher mortality compared with the general population.¹¹ The prevalence for UC in 2023 in Canada was estimated to be 414 per 100,000.¹² It is estimated that among the patients in Canada with UC, 32% to 46% have moderate disease and 13% to 14% have severe disease.¹³

The clinical expert consulted by CADTH pointed out that the treatment goals for patients with UC are to achieve rapid symptomatic relief and to induce and maintain clinical, serological, biomarker, and endoscopic remission in both the short and long-term. In patients with moderately to severely active UC, oral corticosteroids are typically the first-line therapy, but are used only for inducing remission due to their adverse effects.^14,15 Thiopurines (e.g., azathioprine, 6-mercaptopurine), 5-aminosalicylic acid (5-ASA), antitumour necrosis factor (anti-TNF) therapy, or vedolizumab can be used to maintain remission.^14,15 For patients for whom 5-ASAs, corticosteroids, or thiopurines are unable to induce or maintain remission or are not tolerated, advanced therapies are used.^14,15 Of note, most Canadian drug plans require a patient with moderately to severely active UC to have experienced failure of steroid tapering with azathioprine or 6-mercaptopurine before being eligible for a biologic. As such, advanced therapies are typically not used for first-line maintenance of steroid-induced remission.¹⁵ Under circumstances where medical therapy fails, colectomy (which is associated with risks of complications and additional procedures) may be required.¹¹ The clinical expert consulted by CADTH noted that early introduction of effective advanced therapy is important for patients’ benefit, particularly in avoiding repeated courses of corticosteroids, as recurrent use of corticosteroids to control UC symptoms is not ideal due to their multiple adverse effects. The clinical expert consulted by CADTH and the sponsor indicated there is limited robust evidence and thus no recent Canadian guidelines on the preferred sequencing (that is, which drug is optimally used first) for advanced therapies in UC.¹⁶

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of etrasimod (Velsipity) 2 mg tablet taken orally once daily in the treatment of adults with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, the Gastrointestinal (GI) Society and Crohn and Colitis Canada (CCC), provided input for this review. The GI Society’s input was informed by surveys conducted between 2015 and 2023 (N = 54 to 579), focus groups, and 1-to-1 interviews with patients with IBD. CCC’s input was compiled from 2 online surveys conducted in 2022. The first captured the experience of 354 patients with moderate to severe UC, and the second received responses from 4 patients with UC.

From the patient’s perspective, UC has a profound effect on daily life — physically, emotionally, and socially — at home, school, or in the workplace. Symptoms can be relentless, embarrassing, and scary. Sustained remission and/or treatment response is important. The concern of future flares — possibly worse than the last and occurring at unpredictable times — remains constant among patients with UC. Patients noted the most important aspects around UC management include having enough treatment options, having treatments that are well tolerated, and minimizing steroid use.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

The clinical expert noted that a significant portion of patients have disease that does not respond to the available advanced therapies, and some UC becomes refractory over time. The clinical expert indicated that multiple drug failures and ongoing progressive disease activity may lead to adverse consequences, including surgery to remove the entire colon. Moreover, there is a lack of available oral therapies, as most are delivered intravenously or subcutaneously.

The clinical expert indicated that a clear sequence of medications that is optimal for treating moderate to severe UC is not yet established. The clinical expert noted that in an outpatient context, etrasimod could be introduced early, in the course of 5-ASA failure, as it may induce remission and thus would not be reserved for patients for whom other drugs are contraindicated or other access limitations. The clinical expert noted that the evidence suggests the efficacy of etrasimod diminishes with more drug failures. Therefore, the clinical expert suggested that to optimize its efficacy, etrasimod should be considered for and administered to patients with UC earlier in their disease course.

The clinical expert indicated that patients with a confirmed pathologic or histologic diagnosis of moderate to severe UC are typically diagnosed by a gastroenterologist and, occasionally, by a surgeon in more rural parts of the country. Misdiagnosis is infrequent. The clinical expert noted that, although some clinical risk factors such as early age of onset (younger than 40 years), extensive colitis, and need for corticosteroids at diagnosis may be associated with a more complex course, there are currently no available predictors of disease response to a therapy (e.g., generic profile or available blood tests).

The clinical expert indicated the most important patient outcomes at various stages are as follows: first, in the short-term, clinical response is important to ensure patients are responding in terms of a reduction in symptoms, including extreme stool frequency, diarrhea, rectal bleeding, tenesmus, nighttime defecation, and urgency. Next, the main target in the intermediate term is symptom improvement or remission and the resolution of both blood-based (C-reactive protein) and stool-based biomarkers (fecal calprotectin). Finally, usually within 6 months, the goal is ideally to exhibit endoscopic healing or at least significant improvement. The clinical expert indicated that for UC, the goal of exhibiting histologic healing is not currently considered a robust accepted treatment target, although there is evidence to suggest histologic healing does predict improved outcomes; however, histologic healing is not used as a clinical target in routine clinical practice. The clinical expert also noted that etrasimod would not likely be used in an acute hospitalized setting for acute severe UC, as this is a unique context with standard of care, with IV anti-TNF alpha drugs used predominantly. The clinical expert noted that after the initiation of medication, a check-in within the first 1 to 2 weeks is essential to verify some clinical improvement. Another check-in around 4 to 6 weeks is appropriate, followed by a full assessment with blood work and stool studies completed at 12 weeks. It is preferred to have an endoscopic exam within 6 to 12 months of treatment initiation. The clinical expert indicated that treatment discontinuation of etrasimod should be considered in a manner similar to other advanced therapies for adults with moderate to severe UC, with factors that include:

• an inability to decrease the oral corticosteroid dose despite treatment with etrasimod (steroid dependence)

• the early recurrence of symptoms despite the full 12 weeks of initial therapy with etrasimod

• a persistent elevation of biomarkers, especially fecal calprotectin, and limited or no improvement of symptoms after 12 weeks of initial treatment with etrasimod

• evidence of persistent disease activity after initial therapy (12 weeks) or signs of progression during maintenance therapy based on endoscopy.

The clinical expert noted that the prescribing of etrasimod should be limited to gastroenterologists who treat IBD, with the exception of internal medicine physicians or surgeons in rural settings.

Clinician Group Input

One clinician group provided input, the Canadian IBD Interest Group, which is an assembly of gastroenterologists from across Canada with subspecialty expertise in IBD management. The group’s input was informed by 12 specialists.

In general, the input from the clinician group is in alignment with the input from the clinical expert consulted by CADTH. The clinician group noted that treatment for UC is influenced by disease severity and may involve medications, including oral and/or rectal 5-ASA, systemic corticosteroids, advanced biologics (adalimumab, infliximab, golimumab, vedolizumab, ustekinumab, mirikizumab), and advanced small-molecule drugs (tofacitinib, upadacitinib, ozanimod). The clinician group indicated there is a need for oral therapies that are well tolerated and provide durable disease control.

In alignment with input from the clinical expert consulted by CADTH, the clinician group anticipated that etrasimod is likely to be used as a first-line advanced therapy and could also be used in selected cases as a second- or third-line drug for UC treatment, based on several advantages of etrasimod, including its:

• oral delivery

• once-daily dosing regimen

• efficacy in all patient subgroups, including those with limited proctitis (the clinician group noted that the patients with UC with ulcerative proctitis have been excluded from previous clinical trials, but they represent up to 30% of the overall population with UC)

• favourable long-term safety compared with existing oral alternatives, including ozanimod, upadacitinib, and tofacitinib.

The clinician group noted that etrasimod would be unlikely to be used in patients with fulminant UC or who were hospitalized due to UC, as this therapy has not been evaluated in that setting. The clinician group noted that discontinuation with etrasimod could be considered when there is an inadequate clinical response (assessment of both symptoms and objective biomarkers of disease activity) within 12 to 16 weeks of treatment, or a significant adverse effect occurs.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for etrasimod:

• relevant comparators

• considerations for initiation of therapy

• considerations for continuation or renewal of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• care provision issues

• system and economic issues.

The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs. Refer to Table 4 for more details.

Clinical Evidence

Systematic Review

Description of Studies

The 2 multicentre, phase III, double-blind, randomized, placebo-controlled trials, ELEVATE UC 12 (N = 354) and ELEVATE 52 (N = 433) that were submitted by the sponsor compared etrasimod (2 mg daily oral) with placebo in patients with moderately to severely active UC. In both trials, randomization was done using a 2:1 ratio where patients received either etrasimod or placebo for 12 weeks and 52 weeks, respectively. Clinical remission was defined as patients having a stool frequency subscore of 0 (or a score of 1 with a ≥ 1 point decrease from baseline), a rectal bleeding subscore of 0, and an endoscopic score of 1 or less (excluding friability). These were the primary outcomes in both protocols. The key secondary outcomes were similar in both protocols, including endoscopic improvement, symptomatic remission, and mucosal healing. Corticosteroid-free clinical remission at week 52 and sustained clinical remission at both week 12 and week 52 were reported as the secondary outcomes in the ELEVATE UC 52 trial. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ) and compared (i.e., study drug versus placebo). Harms were also reported.

Patients in the trial populations had an approximate mean age of 40.5 years and a mean UC duration of 6.0 to 7.9 years. There were slightly more male (range, 53% to 63%) than female (range, 38% to 47%) patients. Most enrolled patients were white (range, 75% to 89%), followed by Asian, Black or African American, American Indian or Alaska Native, and multiple. At baseline, approximately 27% to 32% of the patients were receiving corticosteroid, and 78% to 84% were receiving oral 5-ASA. Approximately one-third of the enrolled patients reported prior use of at least 1 biologic or Janus kinase (JAK) inhibitor (JAKi) (range, 29% to 34%).^17-19

Efficacy Results

The key efficacy results from the ELEVATE UC 12 and ELEVATE UC 52 trials are summarized in Table 2 and listed in order from the most important to the least important outcomes, as suggested by the clinical expert consulted by CADTH. According to the statistical analysis plans for both trials,^19-21 the primary analysis of the efficacy end points was conducted in the full analysis set (FAS) among patients with a baseline modified Mayo score (MMS) of 5 to 9 (N = 334 in the ELEVATE UC 12 trial and N = 409 in the ELEVATE UC 52 trial).

Endoscopic Improvement

In both the ELEVATE UC 12 and ELEVATE UC 52 trials, a greater proportion of patients in the etrasimod group compared with the placebo group had endoscopic improvement at week 12 and week 52. The between-group common risk differences were 12.1% (95% confidence interval [CI], 3.0% to 21.2%; P = 0.009) in the ELEVATE UC 12 trial and 21.2% (95% CI, 13.0% to 29.3%; P < 0.001) in the ELEVATE UC 52 trial at week 12, and 26.7% (95% CI, 19.0% to 34.4%; P < 0.001) in the ELEVATE UC 52 trial at week 52. Greater between-group risk differences were observed for patients treated with etrasimod versus placebo in the subgroup of patients who were naive to any prior biologic or JAKi therapy compared with those who were not, and in the subgroup of patients who had received only 1 prior biologic or JAKi compared with those who had received more than 1 (no interaction P values were provided).

Mucosal Healing

At week 52, a greater proportion of patients in the etrasimod group (26.6%) compared with the placebo group (8.1%) had mucosal healing, with a between-group common risk difference of 18.4% (95% CI, 11.4% to 25.4%; P < 0.001) in the ELEVATE UC 52 trial.

Clinical Remission

In both pivotal trials, a greater proportion of patients in the etrasimod group compared with the placebo group had clinical remission at week 12 and week 52. The between-group common risk differences were 9.7% (95% CI, 1.1% to 18.2%; P = 0.026) in the ELEVATE UC 12 trial and 19.8% (95% CI, 12.9% to 26.6%; P < 0.001) in the ELEVATE UC 52 trial at week 12, and 25.4% (95% CI, 18.4% to 32.4%; P < 0.001) in the UC 52 trial at week 52.

Sustained Clinical Remission

A greater proportion of patients in the etrasimod group (17.9%) compared with the placebo group (2.2%) had sustained clinical remission at both week 12 and week 52, with a between-group common risk difference of 15.8% (95% CI, 10.7% to 21.0%; P < 0.001), based on the results from the ELEVATE UC 52 trial.

Corticosteroid-Free Clinical Remission

At week 52, a greater proportion of patients in the etrasimod group (32.1%) compared with the placebo group (6.7%) achieved clinical remission and were corticosteroid-free for at least 12 weeks, with a common risk difference of 25.4% (95% CI, 18.4% to 32.4%; P < 0.001). Similarly, at week 52, among the patients who were receiving oral corticosteroids for UC at baseline, a greater proportion of patients in the etrasimod group (31.0%) compared with the placebo group (7.5%) achieved clinical remission and were corticosteroid-free for at least 4 weeks, with a common risk difference of 23.1% (95% CI, 10.2% to 35.9%; P < 0.001).

Clinical Response

In both pivotal trials, a greater proportion of patients in the etrasimod group compared with placebo had clinical response with a between-group common risk difference of 21.2% (95% CI, 10.2% to 32.3%; P < 0.001) in ELEVATE UC 12 and 28.3% (95% CI, 18.5% to 38.0%; P < 0.001) in ELEVATE UC 52 at week 12 and 24.9% (95% CI, 15.8% to 34.1%; P < 0.001) in the UC 52 trial at week 52.

Symptomatic Remission

At week 52, a greater proportion of patients in the etrasimod group (43.4%) compared with the placebo group (18.5%) had mucosal healing, with a between-group common risk difference of 24.9% (95% CI, 16.2% to 33.6%; P < 0.001) in the ELEVATE UC 52 trial.

HRQoL Assessed With the IBDQ Total Score

In both pivotal trials, the IBDQ total scores in the etrasimod group showed patients experienced a greater increase in mean change from baseline compared with those in the placebo group at week 12 and week 52. The least squares (LS) mean differences between the 2 groups were 17.33 points (95% CI, 8.50 to 26.16; P < 0.001) in the ELEVATE UC 12 trial and 15.44 points (95% CI, 6.54 to 24.35; P < 0.001) in the ELEVATE UC 52 trial at week 12, and 17.70 points (95% CI, 6.64 to 28.76; P = 0.002) in the ELEVATE UC 52 trial at week 52.

Harms Results

The analysis of harms was conducted in the FAS among patients with a baseline MMS of 4 to 9 (N = 354 in the ELEVATE UC 12 trial and N = 433 in the ELEVATE UC 52 trial). Evidence from the pivotal trials showed etrasimod was generally safe and well tolerated.

Treatment-emergent adverse events (TEAEs) were experienced by approximately 47% of patients in the ELEVATE UC 12 study, and from 56% to 71% of patients in the ELEVATE UC 52 study. The most common TEAEs in the 2 pivotal trials were anemia (range, 6% to 10% across the different study groups), headache (2% to 8%), nausea (2% to 4%), UC (1% to 9%), and pyrexia (3% to 5%). In both trials, serious TEAEs occurred in approximately 2% to 7% of patients across the different treatment arms and were approximately similar between the 2 groups. The most frequently reported serious TEAEs and TEAEs leading to discontinuation of treatment in both trials was UC (not more than 2.5% across the study groups).

Across both trials, a greater proportion of patients in the etrasimod group reported cardiovascular-related adverse events of special interest (AESIs) than in the placebo group, whereas there was a greater proportion of patients in the placebo group experiencing infection-related AESIs than in the etrasimod group. No AESIs related to pulmonary disorders, macular edema, posterior reversible encephalopathy syndrome, or malignancy were reported in the ELEVATE UC 12 trial. Similar findings were demonstrated in the ELEVATE UC 52 trial, except for 1 patient (0.3%) in the etrasimod group who reported macular edema, and 1 patient in each treatment group (0.3% in the etrasimod group and 0.7% in the placebo group) who reported pulmonary disorders.

Critical Appraisal

Both trials used appropriate randomization methods, allocation concealment, randomization stratification, double-blind approaches, and statistical methods for the primary and key secondary outcomes. Both trials used the placebo as the comparator, and there is a lack of head-to-head direct evidence comparing etrasimod against other active pharmacotherapies that are relevant to clinical practice in Canada. It is notable that the FDA guidance to industry for conducting interventional trials in patients with UC²² encourages sponsors to use active treatments as controls. To align with the regulatory body’s guidance on moderate to severe UC²² that became available during or after the trials, the sponsor amended its statistical analysis plans and performed the primary efficacy analysis in the FAS of patients with a baseline MMS of 5 to 9 (excluding a total of 44 patients with a baseline MMS of 4 in the 2 trials),¹⁹ although the patients who were randomized were those with a baseline MMS of 4 to 9. In general, the CADTH review team and the clinical expert consulted by CADTH did not identify major issues with such a change in the efficacy analysis that would impact the study results, based on the patient characteristics that appeared to be reasonably balanced between the treatment groups, and the findings in the supplementary analyses of the same outcomes using the entire FAS for both studies were similar.

Some efficacy end points (e.g., MMS subscore of stool frequency and rectal bleeding, and the HRQoL outcome assessed with the IBDQ) were recorded and reported by patients. Although these subjective outcomes may be influenced by knowledge of treatment assignment, the double-blind design of the trials likely mitigated this risk. The CADTH review team noted that in the ELEVATE UC 52 trial, a higher proportion of patients in the placebo group (50.7%) discontinued the treatment due to disease worsening compared with the etrasimod group (27.3%) during the 52-week trial period. Withdrawal by patient as a reason for discontinuing the study or treatment was higher in the placebo group in both trials, except among those who discontinued from the ELEVATE UC 52 trial, where a higher percentage of patients treated with etrasimod discontinued the study by patient choice. Also, for the IBDQ total score at week 52 in the ELEVATE UC 52 trial, the missing data rate was higher in the placebo group than in the etrasimod group. There was no concrete evidence beyond these points that clearly showed unblinding due to patients’ inferences on treatment assignment based on symptom changes or the occurrence of other factors. Thus, the extent to which this could have affected the efficacy and HRQoL outcome results, particularly the outcomes at week 52, is unclear. Overall, no important imbalances in baseline patient characteristics, concomitant medications, or drop-outs of prognostic importance between the 2 study groups were identified. The overall concomitant use of systemic corticosteroids appeared similar between groups in each study, although the reported use of budesonide by patients was 3% to 6% more in the etrasimod groups versus the placebo groups in both studies. As well, more patients treated with etrasimod (5.9% and 3.5%) compared with placebo (1.7% and 1.4%) concurrently received immunomodulators. While these are notable differences, the relatively small percentages (< 10%) and small between-group differences (< 5%) mean these were unlikely to have been important confounders of the results in both trials. Overall, the statistical methods used in both trials were appropriate. The HRQoL assessed with the IBDQ (an efficacy-related outcome) at week 52 was most likely underpowered, as its outcome data were only available for fewer than half of the patients assessed with the IBDQ at baseline. The subgroup analyses were also likely underpowered to identify subgroup differences. An appropriate method for adjusting for multiplicity was used for the primary and secondary outcomes, but there was no multiplicity control for the subgroup analyses. The interaction P values for the subgroup analyses were not provided.

While the indication for etrasimod is for the treatment of moderately to severely active UC in adults, patients aged 16 to 80 years were eligible for both trials, yet a relatively small proportion of the enrolled patients (5.0% to 7.4%) were aged 65 years or older, and only 1 person in each study was younger than 18 years. No patients in the ELEVATE UC 12 trial and only 0.7% of the patients in the ELEVATE UC 52 trial were aged 75 years or older at baseline. These small population results limit the trial’s generalizability among older patients. The clinical expert consulted by CADTH noted the need for some caution when using etrasimod in patients who are 65 years and older because there is a higher likelihood of concomitant diseases and/or multiple medications (polypharmacy), as well as a higher potential for decreased hepatic, renal, cardiac, or pulmonary function. Patients in both trials were recruited from multiple countries, including Canada. The clinical expert did not raise any major concerns in the generalizability of the results of the trials to clinical practice in Canada, based on the eligibility criteria of patients, the demographic characteristics of the patients from the diversity aspect, and the etrasimod dose in the 2 trials. The clinical expert pointed out that the inclusion of patients with UC with isolated proctitis, a subgroup of patients with UC that is most often excluded from clinical trials, is helpful for clinical practice, contributing evidence for the efficacy and safety of etrasimod in this specific patient group. The clinical expert noted the importance of monitoring patients using biomarker examinations (e.g., fecal calprotectin) during treatment with etrasimod. The placebo-controlled period of the ELEVATE UC 52 trial was 1 year, which aligns with current regulatory guidance. However, given patients and clinicians often report the waning of treatment effect with advanced therapies for UC, longer-term comparative evidence on the durability of the effectiveness of etrasimod would be informative. The occurrence of some adverse events (AEs), especially rare ones, may take longer than 52 weeks to be identified. Longer-term follow-up to assess safety and a direct comparison between etrasimod versus other advanced therapies would be preferred.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^23,24 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

The selection of outcomes for the GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with the clinical expert, and input received from the patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: endoscopic improvement, mucosal healing, clinical remission, sustained clinical remission, corticosteroid-free clinical remission, clinical response, symptomatic remission, change in IBDQ, and serious TEAEs.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty-of-evidence assessment was the presence or absence of an important effect based on the minimal important difference (MID) thresholds identified in the literature for the IBDQ total score. The target of the certainty-of-evidence assessment was the presence or absence of an important effect, based on thresholds informed by the clinical expert consulted for this review, in terms of endoscopic improvement, mucosal healing, clinical remission, sustained clinical remission, corticosteroid-free clinical remission, clinical response, and symptomatic remission.

Findings from the ELEVATE UC 12 and ELEVATE UC 52 trials were considered together and summarized narratively per outcome because these studies were similar in population, interventions, design, and outcome measures.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for etrasimod versus placebo in adult patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment.

Long-Term Extension Studies

There are currently no results available from any long-term extension studies of etrasimod in moderately to severely active UC. One ongoing, single-arm, long-term open-label extension (OLE) study (ELEVATE UC OLE²⁵) of etrasimod 2 mg/day taken orally has an estimated primary completion date of February 6, 2027.

Indirect Comparisons

One indirect treatment comparison (ITC) was submitted by the sponsor to estimate the relative efficacy and safety of etrasimod versus advanced therapies for the treatment of adult patients with moderately to severely active UC.^26,27

Description of Studies

The trials included in the ITC enrolled adult patients with moderately to severely active UC and studied the following advanced therapies for these patients: adalimumab, infliximab, golimumab, tofacitinib, ustekinumab, vedolizumab, upadacitinib, mirikizumab, and ozanimod. Efficacy outcomes included clinical outcomes (remission and response) and safety outcomes (serious infections, serious adverse events [SAEs], any AE, and treatment discontinuations due to AEs), which generally aligned with the outcomes that were important to patients and clinicians.

Efficacy Results

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Table 2: Summary of Findings for Etrasimod Versus Placebo for Adults With Moderately to Severely Active UC

CI = confidence interval; ES = endoscopic score; FAS = full analysis set; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; LS = least squares; MID = minimal important difference; MMS = modified Mayo score; NR = not reported; RB = rectal bleed; RCT = randomized controlled trial; SE = standard error; SF = stool frequency; TEAE = treatment-emergent adverse event; UC = ulcerative colitis.

Note: The primary analysis of the efficacy end points was conducted in the FAS among patients with a baseline MMS of 5 to 9 (N = 334 in the ELEVATE UC 12 trial and N = 409 in the ELEVATE UC 52 trial). Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aEndoscopic improvement was defined as patients with an ES of ≤ 1 (excluding friability). An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome. Although the lower boundary of the 95% CI for the between-group difference in the ELEVATE UC 12 trial was 3%, which could be considered as a source of serious imprecision, this did not result in the level of certainty of the overall evidence for this outcome being rated down because the evidence from the ELEVATE UC 52 trial was also taken into consideration.

^bMucosal healing was defined as patients who have an ES of ≤ 1 (excluding friability) with histologic remission measured by a Geboes Index score < 2.0. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^cClinical remission was defined as patients who have an SF subscore of 0 (or a score of 1 with a ≥ 1 point decrease from baseline), an RB subscore of 0, and an ES ≤ 1 (excluding friability). An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 7.5% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome. Although the lower boundary of the 95% CI for the between-group difference in the ELEVATE UC 12 trial was 1.14%, which could be considered as a source of serious imprecision, this did not result in the level of certainty of the overall evidence for this outcome being rated down because the evidence from the ELEVATE UC 52 trial was also taken into consideration.

^dSustained clinical remission was defined as patients with an SF subscore of 0 (or a score of 1 with a ≥ 1-point decrease from baseline), an RB subscore of 0, and an ES of ≤ 1 (excluding friability) at both week 12 and week 52. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 10% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^eCorticosteroid-free for ≥ 12 weeks and achieved clinical remission at week 52 was defined as patients with an SF subscore of 0 (or a score of 1 with a ≥ 1-point decrease from baseline), an RB subscore of 0, and an ES of ≤ 1 (excluding friability), and who had not received corticosteroids for at least 12 weeks in the 40-week treatment period. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 7.5% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^fCorticosteroid-free for ≥ 4 weeks and achieved clinical remission at week 52 was defined as patients with an SF subscore of 0 (or a score of 1 with a ≥ 1-point decrease from baseline), an RB subscore of 0, and an ES of ≤ 1 (excluding friability), and who had not received corticosteroids for at least 4 weeks in the 40-week treatment period. Results of this outcome include those who were receiving oral corticosteroid for UC at baseline. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 7.5% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^gClinical response was defined as patients with a ≥ 2-point improvement and a ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RB subscore or an absolute RB subscore ≤ 1. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 10% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

^hSymptomatic remission was defined as patients with an SF subscore of 0 (or a score of 1 with a ≥ 1 point decrease from baseline) and an RB subscore of 0. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 10% between the groups was identified by the clinical expert consulted by CADTH as a threshold of clinical importance for this outcome.

ⁱThe level of evidence was rated down 1 level for serious imprecision. Based on the MID identified in the literature (≥ 15 points above placebo based on between-group data), the point estimate suggested little to no difference, and the 95% CI for the between-group difference crossed the MID threshold. The impact of missing outcome data was unclear (less than 10% of the patients in both the ELEVATE UC 12 and ELEVATE UC 52 trials had IBDQ results available at baseline) and no notable between-group imbalances in missing data were identified.

^jThe level of evidence was rated down 1 level for serious risk of bias and was rated down 1 level for serious imprecision. More than half of the patients with IBDQ results available at baseline did not respond at week 52, and there was a higher proportion of patients with missing data in the placebo group than in the etrasimod group. No sensitivity analyses were done to assess the impact of the missing data for this outcome. While the exact impact of such missing outcome data on the results is unclear, the CADTH review team considered that the risk of bias for this outcome was high. Based on the MID identified in the literature (≥ 15 points above placebo based on between-group data), the point estimate suggested little to no difference, and the 95% CI for the between-group difference crossed the MID threshold.

^kThe level of evidence was rated down 1 level for serious imprecision due to the small number of events.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52¹⁷ and sponsor’s submissions.^16,19

The networks of efficacy analyses were ██████ ██ █ ████ ████████ ████ ██████████ ███ █████ ████████ ██████ █ ██████ ██████████ ██████████ ███ ████ ███ ████████ ██████ █████ ██████████ █████████ █████ ████ ████████ ███ █████ ████ ██████████ ████ ██████████ █████████ █████████ ██████ ██████████ █████ ████ ██████████ █████████████ ██████ ██████████ ███ ████ ██████████ ██████████ ███████████ ███████ █████████ ██ ████████ ██ ██████████ ████ ███ ███████████ ████ █████ ████ ████ ███████████

Harms Results

Safety results among the overall and advanced therapy–naive trial population during the induction phase and maintenance phase ███ ████ ████ ███ ███ ███████ ███ ████ ███ ███████████ ██ █████████ ██████ █████ ████████ █████████ ███ ███ ██████ ███ ███ ████████ █████████ ████████████████ ███ ██ ████ ███ █████ ███ █████ ███████ █████ ███ ████████ █████████ ██ ██████████ ██ ███████████ ██ ██ █████ █ █████ ███ █ █████ ███ ████ █ ██ █████ ██ ███ ███████████ ██████ ████████ ████ ██████ ██████ ██ ███████████ ████ ███████ ██ █████ ███ █ ████ ███████ ████████ ██ ███ ████████████ ███ ███████████ ███████ ██████ █████████ ██ ███ ███████████ █████████████

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Critical Appraisal

The networks were sparsely populated with relatively few nodes centred around a single connection (placebo) in a star geometry. Furthermore, most closed loops were between different doses of individual drugs and, consequently, the evidence was essentially all indirect, increasing uncertainty in the estimates for each outcome, and the consistency assumption could not be assessed. Additionally, most nodes were informed by only 1 or 2 trials, increasing the chance the comparisons were underpowered, which impacted model selection and the types of adjustments that could be done. These factors mean there was imprecision in many of the estimates (as evidenced by relatively wide 95% credible intervals [CrIs] for many pairwise comparisons) and validating the key assumptions for the NMA is difficult, thereby increasing the uncertainty surrounding the results.

Overall, the clinical expert did not expect any major issues with the representativeness of the study populations enrolled in the RCTs included in the ITC in relation to those who may also be eligible for treatment with etrasimod in Canada. However, there was variability in patient characteristics (also potential treatment-effect modifiers) across the studies, such as for the definition of severity of UC based on Mayo score, disease duration, and concomitant medication use. It is also likely that there were differences in patients’ experience with previous treatments (number and type) and differences in eligibility criteria regarding intolerance to or failure of at least 1 of the conventional therapies or biologics, further introducing bias into the analysis. There was heterogeneity in the treatment regimens among treatments, the duration of the induction and maintenance phases, and the methods used for rerandomization into the maintenance phase. Moreover, the included studies used different definitions for the efficacy and safety outcomes, creating issues when analyzing efficacy and harms results.

The dissimilarity among patients, important heterogeneity across studies, and wide CrIs (in safety outcomes) made it challenging to draw definitive efficacy and safety conclusions as to whether etrasimod was superior or inferior to other advanced therapies, including ozanimod, in adult patients with moderately to severely active UC.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the pivotal and RCT evidence were identified for this review.

Conclusions

Two phase III, multicentre, double-blind RCTs evaluated the efficacy and safety of etrasimod compared with placebo in adults with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment. Compared with placebo at 12 and 52 weeks, etrasimod results in a clinically important increase in the proportion of patients who have endoscopic improvement, clinical remission, and clinical response. At 52 weeks, etrasimod results in a clinically important increase in the proportion of patients who have mucosal healing, sustained clinical remission, corticosteroid-free clinical remission in the overall population as well as in those who were receiving oral corticosteroids for UC at baseline, and symptomatic remission compared with placebo. Etrasimod likely results (at 12 weeks) or may result (at 52 weeks) in little to no difference in improvement in HRQoL based on the IBDQ, and likely results in little to no difference in the proportion of patients who have serious TEAEs at 12 weeks and 52 weeks compared with placebo. AEs were common but no particular concerns were identified beyond those noted in the product monograph or what is expected for sphingosine 1-phosphate (S1P) receptor modulators. However, the frequencies of AEs are based on relatively short observation periods and younger patient populations than would be included in real-world practice.

There is a data gap in the head-to-head direct evidence between etrasimod and other advanced therapies for moderately to severely active UC. Indirect evidence submitted by the sponsor ████████ ████ █████ ███ ██ ██ ██████████ ██████████ ██ ████████ ██ █████ ████████ ███████ █████████ ███ █████ ████████ █████████ ██████ █████████ ██ ███████████.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of etrasimod (Velsipity) 2 mg film-coated tablet taken orally once daily in the treatment of adults with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

Overview of the Condition

IBD is a group of diseases characterized by chronic recurrent, progressive inflammation of the GI tract.²⁸ There are 2 main types of IBD: Crohn disease (CD) and UC. UC is a chronic disease characterized by inflammation predominantly of the mucosal layer of the large intestine (colon) most often involving the rectum, and frequently extends continuously into the proximal colon.¹ The cause of UC remains uncertain, but a combination of genetic and environmental factors contributes to immune dysregulation and upregulation in response to micro-organisms in the GI tract.²⁹ UC is characterized by blood in the stool with mucus, frequent diarrhea, urgency, loss of appetite, and tenesmus (severe rectal cramp or spasm).² Although UC principally affects the GI tract, extraintestinal manifestations may also occur, such as arthritis.³ There is no notable difference in the frequency of UC among males and females.³⁰ Although the risk of mortality from UC itself is low, the disease is associated with an increased risk of other complications (e.g., respiratory diseases, colorectal cancer, lymphoma, and skin cancer) that result in higher mortality compared with the general population.¹¹ About 30% to 60% of patients with UC first present with isolated proctitis (involvement is limited to the rectum).^31,32 Patients with proctitis are more prone to proximal extension (i.e., more colon becomes involved in active disease), higher colectomy rates, an increased need for advanced therapy, and higher hospitalization rates than patients who start with extensive colitis.^31,33,34 Among patients with isolated proctitis who are untreated for 1 year, the relapse rate is between 47% and 86%.³⁵

While most patients have a mild or moderate disease course, about 10% to 15% experience an aggressive course of UC.⁴ Relapse is common, with a cumulative risk of relapse of 70% to 80% at 10 years.⁴ Achieving endoscopic healing earlier may be associated with a reduced risk of future colectomy.⁴ The chronic nature of UC has a considerable impact on a patient’s HRQoL, including psychological, physical, sexual, and social domains of HRQoL due to chronicity of symptoms such as urgency, frequency, and incontinence.^5,6 The medical and surgical treatments for UC (e.g., colectomies) and their potential accompanying complications can also negatively impact HRQoL and productivity.^7,36-39 Individuals with UC are at greater risk of comorbid anxiety, depression, and impaired social interactions.^5,6,40,41 Patients with UC frequently report fatigue and sleep disturbance as well as an inability to perform regular daily routines such as jobs or domestic chores.^7-10 Furthermore, the disease can impact the patient’s caregivers and family, workplace, and community.¹¹

Estimated Disease Prevalence

The prevalence of UC in Canada in 2023 was estimated to be 414 per 100,000.¹² It is estimated that 32% to 46% of patients in Canada with UC have moderate disease, and 13% to 14% have severe disease.¹³

Diagnosis of the Condition

Diagnosis of UC includes laboratory and stool testing to rule out bacterial, viral, or parasitic infection, as well as tests to rule out CD.^42,43 Endoscopic examination with a tissue biopsy is required to make a diagnosis of UC, combined with adjunctive clinical manifestations, a review of medical history, physical exams, laboratory tests, and histological and radiological examinations.^42-44 Tests are also conducted to assess the extent and severity of disease, with the endoscopic Mayo score reflecting disease severity, which is required to determine eligibility for reimbursement for certain treatments in Canada.⁴⁵

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and by clinical expert input. The following have been summarized and validated by the CADTH review team.

The clinical expert consulted by CADTH pointed out that the treatment goals for patients with UC are to achieve rapid symptomatic relief and to induce and maintain clinical, serological, biomarker, and endoscopic remission in both the short and long-term. Per the clinical practice guidelines, the primary goal for UC treatment is the improvement of symptoms, i.e., the induction of clinical remission (normal, nonbloody stools at a frequency of ≤ 3 per day).¹⁴ The ultimate goal for long-term management of UC is complete remission, involving both clinical remission and endoscopic remission with mucosal healing.¹⁴ Endoscopic remission is associated with decreased hospitalizations, decreased use of or freedom from corticosteroids, and a decreased need for colectomy.^46-49 The SPIRIT (Selecting End PoInts foR Disease-ModIfication Trials) consensus from the International Organization for the Study of Inflammatory Bowel Disease identified improvement in patients’ symptoms (e.g., reduction in stool frequency) and in HRQoL, prevention of disability, and reduction in UC-related morbidity (e.g., surgery, hospitalizations, disease extension, and GI and extraintestinal dysplasia or cancer) and mortality as key therapeutic goals.⁵⁰

Pharmacologic treatment is the mainstay of therapy for UC. Various drugs and drug classes are now available to treat UC. In patients with moderately to severely active UC, oral corticosteroids are typically the first-line therapy, but are used only for inducing remission due to their adverse effects.^14,15 In patients who respond to corticosteroids, thiopurines (e.g., azathioprine, 6-mercaptopurine) can be used to maintain remission.^14,15 Other recommendations include 5-ASA therapy in patients naive to 5-ASA drugs and to anti-TNF therapy or vedolizumab.¹⁴ However, most Canadian drug plans require a patient with moderately to severely active UC to have failed to respond steroid tapering using azathioprine or 6-mercaptopurine as a replacement before being eligible for a biologic. As such, advanced therapies are typically not used for first-line maintenance of steroid-induced remission.¹⁵

For patients for whom 5-ASAs, corticosteroids, or thiopurines are unable to induce or maintain remission or are not tolerated, advanced therapies are used. Anti-TNF therapy followed by vedolizumab was recommended for second- and third-line induction and maintenance of remission by the Toronto consensus guidelines in 2015 (which are the most recent Canadian guidelines for the treatment of UC).^14,15 However, clinical practice has evolved since then, with the introduction of new advanced therapies.⁴² The clinical expert consulted by CADTH noted that early introduction of effective advanced therapy is important for patient benefit, particularly for avoiding the adverse effects of recurrent or prolonged courses of steroids. The choice of which advanced therapy to prescribe is ideally a decision shared with the patient that considers the disease characteristics, comorbidities, and patient preferences as well as a given drug’s efficacy, safety, and mode of administration.¹⁶ Patients whose disease fails to respond or loses response, or who are intolerant to 1 advanced treatment would be offered a different one, potentially in a different medication class with a different mechanism of action.¹⁶ The clinical expert consulted by CADTH and the sponsor indicated there are limited extant data and no recent Canadian guidelines available to specifically guide the sequencing of advanced therapies in UC.¹⁶

Under circumstances where medical therapy fails to keep a patient’s UC in complete remission, colectomy (removal of all or part of the colon) may be required.¹¹ However, colectomy carries a risk of serious potential complications, including bleeding and infections,⁵¹ and physicians and surgeons work together closely to try to achieve disease control medically if at all possible. The clinical expert noted that emergent subtotal colectomy (taking the entire colon except for the rectum) remains a real and worrisome risk for patients with severe UC, which may be followed by additional surgical procedures, including the creation of an ileoanal pouch anastomosis. Either a temporary or permanent ileostomy requires specialized care and ostomy devices.⁵¹

Drug Under Review

Indication and Reimbursement Request

Etrasimod is indicated for the treatment of adult patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment.⁵² The sponsor’s reimbursement request is in line with the Health Canada indication.

Dosing and Administration

The recommended dosage is 2 mg taken orally once daily.⁵²

Mechanism of Action

Etrasimod is a highly selective S1P receptor modulator. The S1P receptor is involved in the regulation of multiple immune-inflammatory pathways, regulating lymphocyte egress from lymph nodes and into the blood.^53,54 S1P signals through 5 different receptor subtypes (S1P1, S1P2, S1P3, S1P4, and S1P5), where each receptor subtype has a different cell specificity.⁵⁵ Etrasimod exhibits selectivity to S1P1, S1P4, and S1P5 receptors, and minimal activation of S1P3 receptors, but has no activation of S1P2 receptors.^52,56,57

Main Comparators

Table 3 summarizes the key characteristics of etrasimod and the 9 other advanced therapies available in Canada for the treatment of patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment.

Table 3: Key Characteristics of Etrasimod and Main Comparators

6-MP = 6-mercaptopurine; AE = adverse event; b.i.d. = twice a day; CNS = central nervous system; CV = cardiovascular; DMARD = disease-modifying antirheumatic drug; IgG1 = immunoglobulin G1; IgG1k = immunoglobulin G1 kappa; IgG4 = immunoglobulin G4; IL = interleukin; ITC = indirect treatment comparison; JAK = Janus kinase; PRES = posterior reversible encephalopathy syndrome; S1P = sphingosine 1-phosphate; S1P1 = sphingosine 1-phosphate receptor subtype 1; SC = subcutaneous; TNF = tumour necrosis factor; TYK2 = tyrosine kinase 2; UC = ulcerative colitis.

Note: All the comparators in this table were included in the ITC as well as the pharmacoeconomic analyses. Adalimumab was included in the ITC, but it was not broken down by adalimumab biosimilars vs. the reference biologic drug. Infliximab was included in the ITC, but it was not broken down by infliximab biosimilars vs. the reference biologic drug. Tofacitinib was included in the ITC, but it was not broken down by tofacitinib generic vs. the reference biologic drug.

^aHealth Canada–approved indication.

Sources: Product monographs.^52,58-80

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient inputs received by CADTH have been included in the Stakeholder section of this report.

CADTH received 2 patient group input submissions, 1 from the GI Society and the other from CCC. The GI Society is a national charity that is committed to improving the lives of people with GI and liver conditions, supporting research, and advocating for appropriate patient access to health care. CCC is a national, volunteer-based health charity focused on finding treatments and improving the lives of people with CD and UC.

The GI Society collected patient input using a series of surveys conducted between 2015 and 2023 (N = 54 to 579), focus groups, and 1-to-1 interviews with patients with IBD. Patient input from CCC was compiled from 2 online surveys conducted in 2022. In the first survey, the number of respondents with moderate to severe UC was 354, and the second survey captured the experiences of 4 patients with UC.

Both patient groups noted that UC has a profound effect on daily life — physically, emotionally, and socially — at home, school, or in the workplace. Many patients surveyed by CCC revealed they hid aspects of their diagnosis from their friends, coworkers, and classmates. Nearly two-thirds (63%) of respondents agreed that their family and friends do not understand what they are going through. Patients noted that symptoms can be relentless, embarrassing, and scary. Based on the surveys conducted by CCC, the most frequently reported UC-related complications were mental health and stress (65%), joint inflammation and arthritis (51%), anal fissures and hemorrhoids (40%), anemia (33%), skin conditions (about 30%), and malnutrition and weight loss (about 30%). Patients stated that sustained remission and/or treatment response is more important than relieving any 1 symptom. The patients with UC expressed their constant concern that there would be future flares, possibly worse than the last and occurring at unpredictable times, which is disastrously disruptive.

Regarding current treatments for UC, it was noted that although there are several available options, most patients have difficulty obtaining remission or adequate symptom relief. Based on survey data from the GI Society, approximately a quarter (24%) of patients with IBD found available medications to be adequate, 56% found them to be only somewhat adequate, and 20% found them to be not at all adequate. About half of the patients (56%) surveyed by CCC believed that different treatment options could make them feel better. According to the input from CCC, although steroid use is an important part of symptom management for UC, patients reported not being particularly supportive of this treatment option and had concerns about side effects from systemic steroid use. Patient input from the GI Society emphasized the importance of having a variety of treatment options available because UC is a chronic disease and there is no cure. According to the patient input, a patient typically needs to change the type(s) of treatment when there is an inadequate response to the initial treatment. Patient respondents expressed a need for new and effective options to achieve mucosal healing and reduce the symptoms of UC. The input from CCC noted that patients seek any treatments that can relieve UC symptoms to protect their ability to work, study, and care for family. The patients interviewed by CCC noted the most important aspects around UC management include having enough treatment options, understanding side effects, and minimizing steroid use. Neither patient group was able to identify a patient to interview who had experience with etrasimod therapy.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of UC.

Unmet Needs

The clinical expert consulted by CADTH considered the symptomatic relief with clinical, serological, biomarker, and endoscopic remission through Health Canada–approved therapies that are effective at induction and during maintenance as the goals of UC treatment. The clinical expert noted several challenges among the currently available medical therapies for UC in Canada. First, a significant portion of patients will not respond to advanced therapy (most therapies exhibit endoscopic healing rates below 50% at 1 year). Second, it is common for patients who respond initially to lose response after a period of symptom relief. For those medications where a loss of response occurs, dose escalation is common. Therefore, in many patients with UC, multiple options, including increasing medication dosage and trying several types, are needed to maintain response and meet longer-term treatment goals. The clinical expert pointed out that multiple drug failures and ongoing progressive disease activity may lead to adverse consequences, including surgery to remove the entire colon. Finally, there is also a gap in available oral therapies, as most drugs used currently are administered intravenously or subcutaneously.

Place in Therapy

The clinical expert indicated that a clear sequence of medications that is optimal for treating moderate to severe UC is not yet established. The clinical expert noted that in an outpatient context, etrasimod (an S1P receptor modulator) could be introduced primarily in patients with moderate UC following the failure of a 5-ASA treatment. The clinical expert’s opinion was that etrasimod might be better placed earlier in treatment sequencing. The clinical expert noted the evidence suggests the efficacy of etrasimod may be lower when used after more drug failures, based on the subgroup results in patients in both etrasimod trials who had previously received more than 1 advanced therapy or who had experienced the failure of an anti-TNF treatment. Therefore, the clinical expert suggested that, to optimize efficacy, etrasimod should be considered for and administered to patients with UC earlier in their disease course. However, the clinical expert acknowledged that optimal sequencing of medications for moderate to severe UC is unclear across all available products, and the trials for etrasimod were not designed to specifically address the sequencing question.

Patient Population

The clinical expert described that patients with a confirmed pathologic or histologic diagnosis of moderate to severe UC are typically diagnosed by a gastroenterologist and sometimes, in more rural parts of the country, by a surgeon. Misdiagnosis is infrequent. The clinical expert noted that although some clinical risk factors such as early age of onset (younger than 40 years), extensive colitis, and need for corticosteroids at diagnosis may be associated with a more complex course, there are currently no available predictors of disease response to a therapy (e.g., generic profile or available blood tests). The clinical expert also noted that etrasimod would not likely be used in the acute, hospitalized setting for acute severe UC, as this is a unique context with standard of care with IV anti-TNF alpha drugs used predominantly.

Assessing the Response to Treatment

The clinical expert indicated that outcome assessments are guided by international recommendations regarding treatment goals for IBD, i.e., the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)-II guidelines published in 2021.⁸¹ The clinical expert indicated the outcomes that are most important for patients at various stages. First, in the short-term, early in the disease course, clinical response is important to ensure patients are responding in terms of their symptoms, including extreme stool frequency, diarrhea, rectal bleeding, nighttime defecation, and urgency. The relief of these symptoms is important for patients in terms of their daily function, return to work or school, and ability to sleep through the night. Next, the main intermediate-term target is symptom improvement or remission and resolution of both blood-based (C-reactive protein) and stool-based biomarkers (fecal calprotectin). Finally, usually within 6 months, the goal is ideally to exhibit endoscopic healing or at least significant improvement. The clinical expert indicated that for UC, the goal of exhibiting histologic healing is not currently considered a robust accepted treatment target, although there is evidence to suggest histologic healing does predict improved outcomes; however, it is not used as a clinical target in routine clinical practice. The clinical expert noted that after the initiation of medication, a check-in within the first 1 to 2 weeks is essential to verify some clinical improvement. Once an early response is established, another check-in at around 4 to 6 weeks is appropriate, followed by a full assessment with blood work and stool studies completed at 12 weeks. An endoscopic exam at between 6 and 12 months of treatment is preferred with etrasimod.

Discontinuing Treatment

The clinical expert indicated that the discontinuation of treatment with etrasimod should be considered in a manner similar to other advanced therapies for adults with moderate to severe UC, with factors that include:

• an inability to decrease the oral corticosteroid dose despite treatment with etrasimod (steroid dependence)

• the early recurrence of symptoms despite the full 12 weeks of initial therapy with etrasimod

• a persistent elevation of biomarkers, especially fecal calprotectin, and limited or no improvement of symptoms after 12 weeks of initial treatment with etrasimod

• evidence of persistent disease activity after initial therapy with etrasimod (12 weeks) or signs of progression during maintenance therapy based on endoscopy.

Prescribing Considerations

The clinical expert indicated that, ideally, the prescription of etrasimod should be limited to gastroenterologists who treat IBD (e.g., in the community or in academic centres); however, prescribing by expert internal medicine physicians or surgeons in rural settings would be an exception.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by the clinician group. The full original clinician group input received by CADTH has been included in the Stakeholder section of this report.

CADTH received 1 clinician group input submission from the Canadian IBD Interest Group, which is an assembly of gastroenterologists from across Canada with subspecialty expertise in IBD management. Input from the clinician group was based on a meeting in December 2023 among 12 clinicians (members of the group) to discuss UC treatment and review the literature and data from the etrasimod clinical development program.

Based on the input from the clinician group, the treatment goals for UC are in alignment with those of the clinical expert consulted by CADTH and include controlling symptoms as well as improving objective markers of disease activity, i.e., endoscopic assessment, histologic assessment, and biomarkers such as fecal calprotectin and serum C-reactive protein. The clinician group noted that treatment for UC is influenced by disease severity and may involve medications that include oral and/or rectal 5-ASA, systemic corticosteroids, advanced biologics (adalimumab, infliximab, golimumab, vedolizumab, ustekinumab, mirikizumab) and advanced small-molecule drugs (tofacitinib, upadacitinib, ozanimod). The clinician group pointed out that there is a need for oral therapies that are well tolerated and provide durable disease control.

The clinician group anticipated that etrasimod is likely to be used as a first-line advanced therapy and could also be used in selected cases as a second- or third-line drug for UC treatment, based on several potential advantages of etrasimod that, from their perspective, include:

• oral delivery

• a once-daily dosing regimen

• efficacy in all patient subgroups, including those with limited proctitis (the clinician group noted that the patients with UC with ulcerative proctitis have been excluded from previous clinical trials, but they represent up to 30% of the overall UC population)

• favourable long-term safety compared with existing oral alternatives, including ozanimod, upadacitinib, and tofacitinib.

The clinician group noted that etrasimod would be unlikely to be used in patients with fulminant UC or who were hospitalized due to UC, as this therapy has not been evaluated in that setting. The clinician group pointed out that discontinuation with etrasimod can be considered when there is an inadequate clinical response (assessment of both symptoms and objective biomarkers of disease activity) within 12 to 16 weeks of treatment, or a significant adverse effect occurs.

In alignment with the input from the clinical expert consulted by CADTH, the clinician group anticipated that etrasimod will be prescribed by physicians experienced in the management of UC, most often by gastroenterologists or general internists with specific training and experience. The clinician group indicated that etrasimod would be administered at home and, for the rare patients who require first-dose monitoring, its administration should be under supervision in an ambulatory clinic setting.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

5-ASA = 5-aminosalicyclic acid; AE = adverse event; AV = atrioventricular; CBC = complete blood count; CDEC = Canadian Drug Expert Committee; CRP = C-reactive protein; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; JAK = Janus kinase; LFT = liver function test; LOI = letter of intent; MD = medical doctor; RSV = respiratory syncytial virus; S1P = sphingosine 1-phosphate; UC = ulcerative colitis.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of etrasimod (2 mg taken orally once daily) in the treatment of adult patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment. The focus will be placed on comparing etrasimod with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of etrasimod is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes the sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence. There were no long-term extension studies (section 2) nor additional studies to address important gaps in the systematic review evidence (section 4) submitted by the sponsor.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• 2 pivotal placebo-controlled RCTs

• 1 NMA.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

ELEVATE UC 12 and ELEVATE UC 52 are pivotal phase III RCTs evaluating the safety and efficacy of etrasimod for moderately to severely active UC when administered for 12 weeks (ELEVATE UC 12 trial) and 52 weeks (ELEVATE UC 52 trial).

ELEVATE UC 12 Trial

ELEVATE UC 12 (N = 354) was a multicentre, randomized, placebo-controlled, double-blind study. The primary objective of the ELEVATE UC 12 trial was to assess the efficacy of etrasimod in clinical remission at week 12 in patients with moderately to severely active UC. The ELEVATE UC 12 trial consisted of a 28-day screening period, a 12-week randomized treatment period, and 2-week and 4-week follow-up periods. At the end of the 12-week treatment period, patients underwent efficacy and safety assessments and were evaluated for clinical response or remission. At the end of the 12-week treatment period, patients had the choice to enter the OLE study (ELEVATE OLE) if they met the eligibility criteria. Patients who did not participate in the ELEVATE OLE study had follow-up visits at weeks 2 and 4 after the last dose of the study treatment. A study design flow diagram of the ELEVATE UC 12 trial is outlined in Figure 1.

Table 5: Details of Studies Included in the Systematic Review

5-ASA = 5-aminosalicylic acid; AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BP = blood pressure; CD = Crohn disease; ECG = electrocardiogram; EIM = extraintestinal manifestation; ES = endoscopic score; HR = heart rate; JAK = Janus kinase; MMS = modified Mayo score; NHI = Nancy histological index; OLE = open-label extension; RB = rectal bleeding; RHI = Robarts histopathology index; SF = stool frequency; TEAE = treatment-emergent adverse event; TMS = total Mayo score; UC = ulcerative colitis; ULN = upper limit of normal.

^aInadequate response, loss of response, and intolerance are defined as: 1) Inadequate response: Signs and symptoms of persistently active disease despite a history of completing a dosing regimen; 2) Loss of response: Recurrence of symptoms of active disease during treatment following prior clinical benefit (discontinuation despite clinical benefit does not qualify as treatment failure or patient being intolerant to UC biologic therapy); 3) Intolerance: Including, but not limited to, infusion- or injection-related reaction, demyelination, congestive heart failure, infection, or any other related AE that led to a reduction in dose or discontinuation of the medication.

^bAdequate hematological function defined by white blood cell count ≥ 3.5 × 10⁹/L with ANC ≥ 1.5 × 10⁹/L, lymphocyte count ≥ 0.8 × 10⁹/L, platelet count ≥ 100 × 10⁹/L, and hemoglobin ≥ 8 g/dL.

^cAdequate hepatic function defined by a total bilirubin level ≤ 1.5 × ULN range and AST and ALT levels ≤ 2.0 × ULN. Patients with an isolated total bilirubin elevation and normal AST and ALT diagnosed with Gilbert syndrome could participate.

^dAdequate renal function defined by an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m² by the Chronic Kidney Disease Epidemiology Collaboration equation at screening.

^eSevere extensive colitis as evidenced by physician judgment that the patient is likely to require hospitalization for medical care or surgical intervention of any kind for UC (e.g., colectomy) within 12 weeks following randomization; current evidence of fulminant colitis, toxic megacolon, or recent history (within last 6 months) of toxic megacolon or bowel perforation; and previous total or partial colectomy.

^fHave any of the following conditions or receiving treatments that may affect cardiovascular function: myocardial infarction, unstable angina, stroke or transient ischemic attack, decompensated heart failure requiring hospitalization or Class III or IV heart failure ≤ 6 months before or during the screening period; history or presence of second-degree or third-degree atrioventricular block, sick sinus syndrome, or periods of asystole for > 3 seconds without a functional pacemaker; history or presence of recurrent symptomatic bradycardia or recurrent cardiogenic syncope; screening or week 0 (day 1) prerandomization vital sign readings (taken in the sitting position) showing an HR < 50 bpm, or systolic BP < 90 mm Hg, or diastolic BP < 55 mm Hg. The taking of vital signs may be repeated up to 3 times during a visit to confirm abnormal readings; screening or week 0 (day 1) prerandomization ECG with a PR interval > 200 ms or Fridericia’s corrected QT interval (QTcF) ≥ 450 ms in males or ≥ 470 ms in females; start, stop, change, or planned change in dosage of any antiarrhythmic drug (class I to IV) ≤ 1 week before screening or within 1 week before or after randomization.

^gA 40-week maintenance treatment period with a treat-through design.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52¹⁷ and the sponsor’s summary of clinical evidence.¹⁶

Patients were enrolled across 407 sites in 39 countries, including 2 sites in Canada. Eligible patients were randomized in a 2:1 ratio to receive either blinded etrasimod at a dose of 2 mg (n = 238) or matching placebo (n = 116) for 12 weeks of treatment. Patients in the ELEVATE UC 12 trial were centrally assigned to randomized study treatment using an interactive web response system. Randomization was stratified by previous biologic or JAKi therapy exposure (yes or no), baseline corticosteroid use (yes or no), and baseline disease activity (MMS of 4 to 6 or 7 to 9). The ELEVATE UC 12 study was completed on December 7, 2021.

Figure 1: Study Design of the ELEVATE UC 12 Trial

OLE = open-label extension.

Source: Clinical Study Report for ELEVATE UC 12.¹⁸

ELEVATE UC 52 Trial

ELEVATE UC 52 (N = 433) was a multicentre, randomized, placebo-controlled, double-blind study. The primary objective of the ELEVATE UC 52 trial was to assess the efficacy of etrasimod in clinical remission after 12 and 52 weeks of treatment in patients with moderately to severely active UC. The ELEVATE UC 52 trial comprised a 28-day screening period and a 12-week induction treatment period followed by a 40-week maintenance treatment period with a treat-through design (i.e., patients continued their double-blind study treatment), and 2-week and 4-week follow-up periods for patients who did not enrol in the ELEVATE OLE study. At the end of the 12-week treatment period, patients underwent efficacy and safety assessments and were evaluated for clinical response or remission as well as UC disease worsening. Patients who experienced disease worsening after 12 weeks of treatment and met the predefined eligibility criteria could participate in the ELEVATE OLE study. Patients who did not meet disease worsening criteria, including those achieving clinical response or clinical remission at week 12, continued into the 40-week treatment period and continued their double-blind treatment (per the treat-through design). Patients who either experienced disease worsening during the 40-week treatment period or completed all study procedures at week 52 had the choice to enrol into the ELEVATE OLE study if they met the predefined eligibility criteria. Patients who did not participate in the ELEVATE OLE study had follow-up visits at weeks 2 and 4 after the last dose of the study treatment. A study design flow diagram of the ELEVATE UC 12 trial is outlined in Figure 2.

Patients were enrolled across 315 sites in 37 countries, including 1 site in Canada. Eligible patients were randomized in a 2:1 ratio to receive either a blinded etrasimod oral tablet at a dose of 2 mg (n = 289) or a matching placebo (n = 144) for up to 52 weeks of treatment. Patients were centrally assigned to randomized study treatment using an interactive web response system. Randomization was stratified by previous exposure to a biologic or JAKi therapy (yes or no), baseline corticosteroid use (yes or no), and baseline disease activity (MMS of 4 to 6 or 7 to 9). The ELEVATE UC 52 study was completed on February 22, 2022.

Figure 2: Study Design of the ELEVATE UC 52 Trial

OLE = open-label extension; UC = ulcerative colitis.

Source: Clinical Study Report for the ELEVATE UC 52 trial.¹⁷

Populations

Inclusion and Exclusion Criteria

In both the ELEVATE UC 12 and ELEVATE UC 52 studies, eligible patients were aged 16 to 80 years and had moderately to severely active UC. Active UC was confirmed by endoscopy with rectal involvement equal to or greater than 10 cm. Moderate to severe UC was defined as an MMS of 4 to 9, which included an endoscopic subscore of 2 or greater, and a rectal bleeding subscore of 1 or greater. Patients had to be diagnosed with UC at least 3 months before the study screening period. Patients also had to have demonstrated an inadequate response, loss of response, or an intolerance to at least 1 conventional therapy (e.g., corticosteroid, thiopurines) or a biologic or JAKi therapy (e.g., anti-TNF alpha antibodies) approved for the treatment of UC. Inadequate response to at least 1 conventional biologic or JAKi therapy was defined as having signs and symptoms of persistently active disease despite a history of completing a dosing regimen. Loss of response was defined as recurrence of symptoms of active disease during treatment following prior clinical benefit (discontinuation despite clinical benefit does not qualify as treatment failure or the patient being intolerant to UC biologic therapy). Intolerance was defined as including, but not limited to, infusion-related or injection-related reactions, demyelination, congestive heart failure, infection, or any other related AE that led to a reduction in dose or discontinuation of the medication. Patients with isolated proctitis (less than 10 cm rectal involvement) at baseline who met other eligibility criteria could enrol in both studies, with enrolment capped at 15% of total patients.

Patients were excluded from both the ELEVATE UC 12 and ELEVATE UC 52 studies if they had severe extensive colitis, a diagnosis of CD or indeterminate colitis, or the presence or history of a fistula consistent with CD, or a diagnosis of microscopic colitis, ischemic colitis, or infectious colitis. Patients were excluded from both studies if they previously received 3 or more biologic drugs, 2 or more biologics and a JAKi approved for the treatment of UC, or any S1P receptor modulator. Patients who had a clinically relevant cardiac condition (a history of myocardial infarction, stroke, or second-degree or third-degree atrioventricular block), a history of opportunistic infections, macular edema, or a history of or currently active primary or secondary immunodeficiency were also excluded from both the ELEVATE UC 12 and ELEVATE UC 52 studies.

Interventions

Study treatment for both the etrasimod and placebo groups consisted of 1 tablet taken once daily by mouth for a period of 12 weeks in the ELEVATE UC 12 trial, and 52 weeks in the ELEVATE UC 52 trial.

Starting with the week 12 assessment in both studies, patients whose disease had not improved or had worsened compared with baseline could be eligible to participate in the ELEVATE OLE study provided their endoscopic score was 2 or greater and they met 1 of the following eligibility criteria:

• a rectal bleeding subscore of 2 or greater at 2 time points at least 7 days and no more than 14 days apart

• rectal bleeding plus stool frequency subscores of 4 or greater at 2 time points at least 7 days and no more than 14 days apart

• a rectal bleeding subscore of 2 or greater, or rectal bleeding plus stool frequency subscores of 4 or greater (in any order) at 2 time points at least 7 days and no more than 14 days apart.

Concomitant Medications

The following concomitant UC therapies were permitted in both the ELEVATE UC 12 and ELEVATE UC 52 studies; however, these products could not be started during screening or during the treatment period in patients who were not already receiving them:

• immunosuppressive drugs, such as oral azathioprine or 6-mercaptopurine had to be discontinued at least 2 weeks before randomization

• oral 5-ASA compounds, provided the dose had been stable for at least 2 weeks immediately before randomization

• oral corticosteroid therapy (prednisone at a stable dose of 20 mg/day or less, budesonide at a stable dose of 9 mg/day or less, or an equivalent steroid), provided the dose had been stable for the 4 weeks immediately before the screening endoscopy assessment

• probiotics (e.g., Culturelle, Saccharomyces boulardii) provided the dose had been stable for the 2 weeks immediately before randomization.

During the 12-week treatment period in both studies, patients were to maintain their stable baseline corticosteroid dose.

In the ELEVATE UC 52 trial, following the week 12 assessment, corticosteroids were tapered for patients entering the 40-week treatment period. The recommended tapering schedule for oral corticosteroids (other than budesonide extended-release tablets) was as follows:

• Dose of prednisone or equivalent is greater than 10 mg/day: Taper daily dose by 5 mg/week until receiving 10 mg/day, and then continue tapering at 2.5 mg/week until 0 mg/day.

• Dose of prednisone or equivalent is 10 mg/day or less: Taper daily dose by 2.5 mg/week until 0 mg/day.

Live vaccines and medications that were expected to cause clinically important drug–drug interactions (e.g., moderate or strong inhibitors of CYP2C8 or CYP2C9) were prohibited during the ELEVATE UC 12 and ELEVATE UC 52 studies.

Outcomes

A list of efficacy end points assessed in the Clinical Study Reports for the ELEVATE UC 12 and ELEVATE UC 52 trials is provided in Table 6, followed by descriptions of the outcome measures. The summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review, according to the clinical expert consulted by CADTH, and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. The proportion of patients with serious TEAEs was also assessed using GRADE.

Efficacy Outcomes

The ELEVATE UC 12 and ELEVATE UC 52 trials investigated the same outcomes at either week 12 only (ELEVATE UC 12 trial) or both week 12 and week 52 (ELEVATE UC 52 trial). Sustained clinical remission at both weeks 12 and 52 was investigated only in the ELEVATE UC 52 study.

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

GRADE = Grading of Recommendations Assessment, Development and Evaluation; IBDQ = Inflammatory Bowel Disease Questionnaire; NA = not applicable; UC = ulcerative colitis.

^aStatistical testing for these end points was adjusted for multiple comparisons (i.e., Hochberg procedure was used to adjust for multiple comparisons).

^bThe results of this outcome among the patients who were receiving corticosteroids for UC at baseline were included in the GRADE assessment.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52¹⁷ and the sponsor’s summary of clinical evidence.¹⁶

A description of the efficacy outcome measures and their measurement properties that were used in both the ELEVATE UC 12 and ELEVATE UC 52 trials are presented in Table 7.

Endoscopic Improvement

Endoscopic improvement was defined as achieving an endoscopic subscore of 0 or 1, excluding friability.

Mucosal Healing

Mucosal healing was defined as achieving an endoscopic subscore of 1 or less, with histologic remission measured by a Geboes Index score of less than 2.

The Geboes Index score assesses features associated with histological inflammation in UC.^83,84 This histologic grading system evaluates all aspects of mucosal injury seen in UC, including crypt architecture, lamina propria chronic inflammation, lamina propria eosinophils, lamina propria neutrophils, intraepithelial neutrophils, crypt destruction, and surface epithelial injury.

Clinical Remission

Clinical remission was the primary end point in the ELEVATE UC 12 trial at week 12 and in the ELEVATE UC 52 trial at weeks 12 and 52. Clinical remission was based on the MMS as opposed to the total Mayo score (TMS). The MMS excludes the Physician’s Global Assessment to reduce subjectivity in the assessment, in accordance with the regulatory guidance for trials in UC.^22,85 Clinical remission was defined as:

• a stool frequency subscore of 0 or 1 with at least a 1-point decrease from baseline

• a rectal bleeding subscore of 0

• an endoscopic subscore of 0 or 1.

Regulatory guidance^22,85 has indicated that the presence of any friability is not consistent with clinical remission, which requires an endoscopic subscore of 0 or 1. To align with this guidance, the endoscopic score was increased to 2. Scoring of the MMS subscores is further detailed in Table 7.

Rectal bleeding and stool frequency subscores were from patient-derived assessments and were captured in an e-diary that was recorded in real time and not subject to change. The rectal bleeding subscore reports the most severe amount of blood passed by rectum in a 24-hour period. The stool frequency subscore reflects the number of stools in a 24-hour period relative to the normal number of stools for that individual. The total number of stools passed in a 24-hour period was recorded by the patient in a daily e-diary. On visits when MMS was calculated, these subscores were derived using the scores from the last 3 consecutive days of diary entries or 4 nonconsecutive days within 7 days before the assessment date. Otherwise, the rectal bleeding and stool frequency subscores were considered missing and the patient was considered a nonresponder.

Endoscopy images were reviewed by a local endoscopist and central laboratory reader. In the case of a score discrepancy, a second read by a central adjudication reader was performed. The endoscopic subscore reports the worst appearance of the mucosa on flexible sigmoidoscopy or colonoscopy on a 4-point scale. Endoscopy was performed during screening at week 12 and week 52. Biopsies were obtained at each endoscopy to support assessment of the histopathology end points.

For patients who have had pancolitis for more than 8 years or patients who have had left-sided colitis for more than 12 years without a surveillance colonoscopy within 12 months of baseline, a colonoscopy and biopsies were performed at screening in accordance with the local standard of care to rule out dysplasia. Any adenomatous polyps were to be removed before a patient’s first dose of the study treatment.

Sustained Clinical Remission

Sustained clinical remission was defined as achieving clinical remission at both weeks 12 and 52 and was assessed in the ELEVATE UC 52 trial only.

Corticosteroid-Free Clinical Remission

Corticosteroid-free clinical remission was defined as achieving clinical remission at week 52 and no corticosteroid use for 12 or more weeks before week 52. This outcome was assessed in the ELEVATE UC 52 trial only. The proportion of patients who had not received corticosteroids for at least 4 weeks immediately before week 52 and achieved clinical remission at week 52 was also reported as another end point in the ELEVATE UC 52 trial.

Clinical Response

Clinical response was defined as a decrease of at least 2 points and at least 30% from baseline in MMS, and a decrease of at least 1 point from baseline in the rectal bleeding subscore, or an absolute rectal bleeding subscore of 0 or 1.

Symptomatic Remission

Symptomatic remission was defined as achieving a stool frequency subscore of 0 (or a subscore of 1 with at least a 1-point decrease from baseline) and a rectal bleeding subscore of 0.

Inflammatory Bowel Disease Questionnaire Total Score

The IBDQ was used to assess disease-specific HRQoL in the ELEVATE UC 12 trial at week 12 and the ELEVATE UC 52 trial at week 52. The IBDQ consists of a 32-item list, subdivided into 4 dimensions, including systemic symptoms, bowel symptoms, emotional function, and social function. Total scores range from 32 to 224, with a higher score indicating a better HRQoL. The IBDQ has been shown to have good internal consistency and test–retest reliability and shown to be responsive to change in IBD.^86-88 Available studies have suggested that an improvement of 30 points from baseline or an improvement of at least 15 points or greater above placebo may constitute an MID.^89-94

Harms Outcomes

Harms were assessed using monitoring of AEs, clinical laboratory findings, 12-lead electrocardiographs, physical examinations, vital signs, pulmonary function tests, ophthalmoscopy, and optical coherence tomography.

AEs were predefined and reported in both the ELEVATE UC 12 and ELEVATE UC 52 studies, including AEs, serious TEAEs, TEAEs leading to discontinuation, death, and TEAEs of special interest, including progressive multifocal leukoencephalopathy, cardiovascular events, macular edema, pulmonary disorders, infections, and liver injury.

Table 7: Summary of Outcome Measures and Their Measurement Properties

CD = Crohn disease; ES = endoscopic score; HRQoL = health-related quality of life; IBD = inflammatory bowel disease; IBDQ = Inflammatory Bowel Disease Questionnaire; ICC = intraclass correlation; MID = minimal important difference; MMS = modified Mayo score; OR = odds ratio; PGA = Physician’s Global Assessment; RB = rectal bleed; SE = standard error; SF = stool frequency; SIBDQ = Short Inflammatory Bowel Disease Questionnaire; UC = ulcerative colitis; WPAI = Work Productivity and Activity Impairment.

Protocol Amendments

Several amendments were made to the protocols for the ELEVATE UC 12 and ELEVATE UC 52 trials. The major changes included amending the terminology of the first stratification factor, from patients having experienced failure with previous biologic or JAKi therapy to patients being naive to such therapy at study entry; modifying the documentation of response to prior UC therapy as “an adequate response to, loss of response to, or intolerance to prior therapy”; and modifying eligibility criteria (e.g., list of prior therapy failures or nonresponse, contraception use, cardiovascular disease history, and prior therapy washout period). An exclusion criterion was modified to having received treatment with at least 3 biologic drugs or at least 2 biologics plus a JAKi approved for treatment of UC, and the washout period for methotrexate was changed from within 16 weeks to 8 weeks of screening. Experiencing an AE and noncompliance with the protocol or study treatment were added as reasons for treatment discontinuation, and an update was made to define adequate hepatic function as having alanine aminotransferase and aspartate aminotransferase levels that are twice the upper limit of normal or less (reduced from 3 times the upper limit of normal or less). The final amendment of the study protocol was dated February 22, 2021, for the ELEVATE UC 12 trial (version 3; patients were enrolled between September 2020 and August 2021), and December 22, 2020, for the ELEVATE UC 52 trial (version 4; patients were enrolled between June 2019 and January 2021).¹⁹

Changes to Statistical Analysis

On January 22, 2022, the primary analysis set for the efficacy end points was updated to the FAS in patients with an MMS of 5 to 9 at baseline, and the subgroup definition related to MMS score was updated accordingly. The sponsor noted that the change in the FAS was made to align with the changes to FDA guidance²² received after the study protocols were finalized. The revised FDA guidance states that, “For clinical trials for drugs intended to treat moderately to severely active UC: patients should have a score of 5 to 9 on the MMS, including an endoscopy subscore of at least 2.” The sponsor also noted that the statistical analysis plan for both pivotal trials was finalized on January 19, 2022, when early draft guidance was available from the FDA.²² This change excluded approximately 44 patients who had a baseline MMS of 4 from the primary efficacy analysis. The full FAS (patients with a baseline MMS of 4 to 9) was used in supplementary analyses of efficacy end points and safety assessment.

Statistical Analysis

The statistical analysis of the efficacy end points in the pivotal trials assessed in this Clinical Review Report is summarized in Table 8.

Sample Size and Power Calculation

ELEVATE UC 12 Trial

In the ELEVATE UC 12 trial, based on a 2-group Fisher exact test, a 1-sided significance level of 0.025, and a randomization ratio of 2:1, a total of 330 patients (220 patients in the etrasimod group and 110 patients in the placebo group) were required to achieve at least 90% power to detect a difference of 12.5% in the primary end point of clinical remission between the etrasimod (18.5%) and placebo (6.0%) groups.

ELEVATE UC 52 Trial

Based on a 2-group Fisher exact test, a 1-sided significance level of 0.025, and a randomization ratio of 2:1, a total of 420 patients (280 patients in the etrasimod group and 140 patients in the placebo group) were required to achieve 93.4% power to detect a difference of 13.5% in the primary end point of clinical remission at week 52 between the etrasimod (23.5%) and placebo (10.0%) group. With this sample size, there was 96% power to detect a difference of 12.5% in the other primary end point of clinical remission at week 12, assuming a placebo rate of 6.0%. The lower bound of overall power for the coprimary end points (i.e., clinical remission at weeks 12 and 52) was at least 90%; since the coprimary end points were expected to be at least moderately positively correlated, the actual overall power to reject both null hypotheses was likely greater than 90%.

Statistical Testing

The primary efficacy analysis in the ELEVATE UC 12 and ELEVATE UC 52 trials was performed for the FAS and a baseline MMS score of 5 to 9. All primary and key secondary end points were statistically analyzed using a Cochran-Mantel-Haenszel test, stratified by naive to biologic or JAKi therapy at study entry (yes or no), baseline corticosteroid use (yes or no), and baseline disease activity (MMS of 4 to 6 or 7 to 9). Reported randomization stratum was used in the model. The analysis results were presented as the number and proportion of responders in the treatment groups, difference in proportions and 95% CI, and odds ratio and 95% CI. Risk differences in the end points between the etrasimod and placebo groups were calculated using the Wilson score method.

Change from baseline in an MMS was summarized by visit using descriptive statistics (n, mean, standard deviation [SD], median, minimum, and maximum), and also using a mixed model for repeated measures (MMRM) adjusted for naive to biologic or JAKi therapy at study entry (yes or no), baseline corticosteroid use (yes or no), baseline disease activity (MMS of 4 to 6 or 7 to 9), treatment, visit, treatment by visit interaction, a covariate of the corresponding baseline MMS, and a random patient effect. LS means, standard errors, CIs, and P values by visit were reported. For HRQoL measurements (i.e., the Short Form [36] Health Survey), comparisons were made using MMRM analysis, adjusted for naive to biologic or JAKi therapy at study entry (yes or no), baseline corticosteroid use (yes or no), baseline disease activity (MMS of 4 to 6 or 7 to 9), treatment, visit, treatment by visit interaction, a covariate of the corresponding baseline MMS, and a random patient effect.

Multiple Comparisons and Multiplicity

ELEVATE UC 12 Trial

To control for multiplicity for the primary and key secondary end points, the familywise type I error was controlled at a fixed 2-sided significance level of 0.05 using the parallel gatekeeping procedure, that is, the truncated Hochberg procedure. First, the whole significance level of 0.05 was spent on testing the primary end point. Only if the primary null hypothesis was rejected at the significance level could testing proceed for the 3 key secondary end points. Any key secondary end point that failed to be significant at the significance level was considered exploratory. All other end points were evaluated without multiplicity adjustment (Figure 3).

ELEVATE UC 52

To control for multiplicity for the primary and key secondary end points, the familywise type I error was controlled at a fixed 2-sided significance level of 0.05 using the parallel gatekeeping procedure, i.e., traditional Hochberg and truncated Hochberg procedures. First, the whole significance level was spent on testing coprimary end points (clinical remission at weeks 12 and 52). This study was considered an overall success only if both of the primary null hypotheses were rejected, each at the significance level (as coprimary hypotheses). The study was considered a partial success if only 1 of the 2 primary null hypotheses were rejected. Only if both of the primary null hypotheses were rejected could testing proceed for the 8 key secondary end points. Any key secondary end point using this method to control multiplicity that failed to be significant at the significance level was considered exploratory. All other end points were evaluated without multiplicity adjustment (Figure 4).

Subgroup Analyses

The following subgroups, planned a priori in the statistical analyses plans, aligned with the subgroups identified as relevant by the clinical expert consulted by CADTH for this review: extent of disease (left-sided colitis or proctosigmoiditis, pancolitis, or isolated proctitis based on the electronic case report form), isolated proctitis based on central read (yes or no), prior UC treatment with oral 5-ASA only (yes or no), prior UC treatment failure of oral 5-ASA only (yes or no), naive to biologic or JAKi therapy at study entry (yes or no), prior UC treatment failure with an anti-TNF alpha (yes or no), and number of prior biologic or JAKi therapies (1 or > 1), among others. Only the subgroups identified as relevant are reported herein. Subgroup analyses were done only for the FAS population with a baseline MMS of 4 to 9. Subgroup analyses were not powered to detect differences between treatment groups. No interaction P value was provided for the subgroup analyses.

Figure 3: Gatekeeping Procedure Summary for the ELEVATE UC 12 Trial

F1 = family 1; F2 = family 2, F3 = family 3.

Source: Clinical Study Report for ELEVATE UC 12.¹⁸

Sensitivity Analyses

The following sensitivity analyses were implemented to explore different approaches to handle missing data: multiple imputation under missing at random, tipping point analysis, multiple imputation with copy reference under missing not at random, and multiple imputation under missing at random or using a nonresponder imputation. In this hybrid imputation, a multiple imputation approach was used to handle endoscopy data that were missing due to the impact of the COVID-19 pandemic, and a nonresponder imputation was used for data that were missing for reasons other than the impact of the COVID-19 pandemic. All sensitivity analyses were performed in the FAS among patients with an actual baseline MMS of 5 to 9.

Figure 4: Gatekeeping Procedure Summary for the ELEVATE UC 52 Trial

F1 = family 1; F2 = family 2, F3 = family 3.

Source: Clinical Study Report for ELEVATE UC 52.¹⁷

Missing Data

In the ELEVATE UC 12 and ELEVATE UC 52 trials, all patients who had missing data during the study were considered nonresponders in the analysis of all efficacy end points at any subsequent time points, including those who:

• discontinued the study due to a lack of efficacy or an AE related to UC

• initiated a rescue medication for UC

• had an increase in the dose of their existing UC medication over baseline levels

• had undergone a rescue medical procedure (e.g., colectomy, ileostomy, or sigmoidectomy).

Rescue medications included any exposure after the first dose of the study drug, including biologics with immunomodulatory properties (e.g., anti-TNF alpha antibodies), nonbiologic medicines with immunomodulatory properties (e.g., immunosuppressant drugs), 5-ASA compounds, systemic glucocorticoids, and topical glucocorticoids. Rescue medical procedure included any exposure after the first dose of the study drug, including leukocyte apheresis, other apheresis, and plasma exchange. If the medication or procedure was used in the follow-up period, then it was not considered to be a rescue therapy. The impact of rescue therapy use in the analysis was timing-dependent, e.g., if a patient started a rescue therapy between the outcome assessments at week 12 and week 52, then it could have a potential impact on the end point analysis at week 52 but would have no impact on the end point assessment at week 12.

In the main analysis of the continuous or scored end points, such as biomarker measures, urgency, numerical rating scale (NRS), abdominal pain NRS, and HRQoL measures, patients with missing data were handled using observed cases only or using an MMRM.

Supplementary Analyses

In the ELEVATE UC 12 and ELEVATE UC 52 trials, supplementary analyses of the primary and key secondary end points were conducted using the FAS of patients with a baseline MMS of 4 to 9, the modified FAS (with data as observed), and the per-protocol set in patients with a baseline MMS of 5 to 9.

Table 8 summarizes the statistical analysis for each outcome reported in the systemic review for the ELEVATE UC 12 and ELEVATE UC 52 trials.

Table 8: Statistical Analysis of Efficacy End Points: ELEVATE UC 12 and ELEVATE UC 52 Trials

CR = copy reference; FAS = full analysis set; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; JAK = Janus kinase; MAR = missing at random; MMRM = mixed model for repeated measures; MMS = modified Mayo score; MNAR = missing not at random; NA = not applicable; NRI = nonresponder imputation.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52.¹⁷ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Analysis Populations

The ELEVATE UC 12 and ELEVATE UC 52 trials used the same definitions for the different analysis sets (Table 9).

Table 9: Analysis Populations of the ELEVATE UC 12 and ELEVATE UC 52 Trials

BAS = biomarker analysis set; FAS = full analysis set; mFAS = modified full analysis set; MMS = modified Mayo score.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52.¹⁷ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Results

Patient Disposition

Patient disposition for the ELEVATE UC 12 and ELEVATE UC 52 trials among the overall population of randomized patients is summarized in Table 10.

ELEVATE UC 12 Trial

Of the 606 patients screened in the ELEVATE UC 12 trial, 252 patients (41.6%) failed screening. The main reasons for screening failure included failure to meet eligibility criteria (37.0%) and withdrawal by patient (2.5%). In the ELEVATE UC 12 trial, 238 patients were randomized to the etrasimod arm and 116 patients were randomized to the placebo arm. A total of 38 patients (10.7%) discontinued from the study. The most common reasons for study discontinuation included withdrawal by patient (4.0%), AE (2.5%), and physician decision (1.7%).

Study treatment discontinuation occurred in 24 patients (10.1%) in the etrasimod group and 11 patients (9.5%) in the placebo group. The most common reasons for treatment discontinuation in the etrasimod and placebo groups included AE (4.6% and 0.9%, respectively), withdrawal by patient (2.1% and 5.2%, respectively), physician decision (1.3% and 1.7%, respectively), and lack of efficacy (1.3% and 0%, respectively). A total of 214 patients (89.9%) in the etrasimod group and 105 patients (90.5%) in the placebo group completed the study treatment.

ELEVATE UC 52 Trial

Of the 821 patients screened in the ELEVATE UC 52 trial, 388 patients (47.3%) failed screening. The main reasons for screening failures included failure to meet eligibility criteria (41.0%) and withdrawal by patient (2.3%). In the ELEVATE UC 52 trial, 289 patients were randomized to the etrasimod arm and 144 patients were randomized to the placebo arm. A total of 226 patients (52.2%) discontinued the study. The most common reasons for study discontinuation included disease worsening (35.1%), withdrawal by patient (7.9%), and AE (3.5%).

Study treatment discontinuation occurred in 123 patients (42.6%) in the etrasimod group and 98 (68.1%) in the placebo group. The most common reasons for treatment discontinuation in the etrasimod and placebo groups included disease worsening (27.3% and 50.7%, respectively), withdrawal by patient (5.9% and 6.9%, respectively), AE (3.5% in both groups), and lack of efficacy (2.4% and 2.8%, respectively). A total of 166 patients (57.4%) in the etrasimod group and 46 patients (31.9%) in the placebo group completed the study treatment.

In both the ELEVATE UC 12 and ELEVATE UC 52 trials, patient disposition among those with a baseline MMS of 5 to 9¹⁹ was similar to the overall data presented in Table 10.

Baseline Characteristics

A summary of baseline patient demographics, disease characteristics, and medication history in the pivotal trials is shown in Table 11. These characteristics are limited to those considered most relevant to this review or might affect the outcomes or interpretation of the study results.

Table 10: Summary of Patient Disposition From the Studies Included in the Systematic Review

FAS = full analysis set; MMS = modified Mayo score; OLE = open-label extension.

^aPatients with a baseline MMS of 5 to 9 were considered for the primary analysis of efficacy end points in the ELEVATE UC 12 and ELEVATE UC 52 trials.

^bPatients with a baseline MMS of 4 were not included in the primary analysis of efficacy end points in the ELEVATE UC 12 and ELEVATE UC 52 trials.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52.¹⁷ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Table 11: Summary of Baseline Characteristics From Studies Included in the Systematic Review — FAS and Baseline MMS of 5 to 9

5-ASA = 5-aminosalicylic acid; BMI = body mass index; ES = endoscopic score; FAS = full analysis set; JAK = Janus kinase; MMS = modified Mayo score; RB = rectal bleeding; SD = standard deviation; SF = stool frequency; TNF = tumour necrosis factor; UC = ulcerative colitis.

^aAs reported by investigators during screening.

^bThis row represented the number of patients (%) who were naive to biologics at the baseline of the study.

Source: Sponsor’s additional information.¹⁹

ELEVATE UC 12 Trial

The study population in the ELEVATE UC 12 trial had a mean age of 40.5 years (SD = 13.47 years), and 94.6% of the study population was aged between 18 and 64 years. A total of 195 patients (58.4%) were male, and 139 patients (41.6%) were female. The majority of patients were white (75.7%), followed by Asian (19.2%), American Indian or Alaska Native (1.8%), Black or African American (1.2%), multiple (0.3%), and unknown (1.8%). In the ELEVATE UC 12 trial, 55.4% of patients were from eastern Europe and 8.7% of patients were from North America.¹⁹ The mean baseline MMS in both the etrasimod and placebo groups was 6.7 (SD = 1.1), and the mean disease duration was 7.2 years (SD = 6.5) in the etrasimod group and 7.9 years (SD = 7.4) in the placebo group. Baseline corticosteroid and 5-ASA use in the etrasimod and placebo groups was present in 27.0% and 28.6% of patients, and 84.2% and 81.3% of patients, respectively. In terms of prior UC therapies, the proportion of patients in the etrasimod and placebo groups reporting prior use of biologics was 33.3% and 33.9%, respectively. The proportion of patients in the etrasimod and placebo groups reporting prior use of at least 1 biologic or JAKi was 33.3% and 33.9%, respectively. The proportion of patients reporting prior anti-TNF failure and baseline corticosteroid use was similar between treatment groups (9.5% and 8.9% of patients in the etrasimod and placebo groups, respectively). The proportion of patients reporting prior failure of anti-TNF therapy and no baseline corticosteroid use was 12.2% in the etrasimod group and 12.5% in the placebo group. No information was reported for the proportion of patients with failure of 5-ASA therapy. Overall, the baseline characteristics were well balanced between treatment arms.

ELEVATE UC 52 Trial

The study population in the ELEVATE UC 52 trial had a mean age of 40.6 years (SD = 14.1), and 93.2% of the study population was aged between 18 and 64 years. The median age in the etrasimod group was higher than in the placebo group. A total of 224 patients (54.8%) were male and 185 patients (45.2%) were female. There was a larger proportion of males in the placebo group than in the etrasimod group. The majority of patients were white (89.0%), followed by Asian (6.8%), Black or African American (2.2%), American Indian or Alaska Native (1.0%), and unknown (1.0%). In the ELEVATE UC 52 trial, 61.6% of patients were from eastern Europe and 18.6% of patients were from North America.¹⁹ The mean baseline MMS was 6.9 (SD = 1.0) and 6.8 (SD = 1.0) in the etrasimod and placebo groups, respectively. The mean disease duration was 7.6 years (SD = 8.1) in the etrasimod group and 6.0 years (SD = 5.6) in the placebo group. Baseline corticosteroid use in the etrasimod and placebo groups was present in 31.8% and 29.6% of patients, respectively; baseline 5-ASA use was present in 78.1% and 77.8% of patients, respectively. In terms of prior UC therapies, the proportion of patients in the etrasimod and placebo groups reporting prior use of at least 1 biologic was 29.2% and 31.1%, respectively. The proportion of patients reporting prior anti-TNF failure and baseline corticosteroid use was similar between treatment groups: 4.7% in the etrasimod group and 5.9% in the placebo group. The proportion of patients reporting prior failure of anti-TNF therapy and no baseline corticosteroid use was 12.0% in the etrasimod group and 15.6% in the placebo group. No information was reported for the proportion of patients with failure of 5-ASA therapy. Overall, the baseline characteristics were well balanced between treatment arms.

Concomitant Medications for UC

Concomitant medication use in the ELEVATE UC 12 and ELEVATE UC 52 studies is summarized in Table 12. Concomitant medication use for UC was generally similar across treatment groups in the pivotal trials. A total of 91.5% of patients in the ELEVATE UC 12 trial and 88.5% of patients in the ELEVATE UC 52 trial received at least 1 concomitant medication for UC during the trial. The most common concomitant medications were drugs for antidiarrheals, intestinal anti-inflammatory or anti-infective drugs, and corticosteroids for systematic use.

Table 12: Summary of Concomitant Medications in the ELEVATE UC 12 and ELEVATE UC 52 Trials — Safety Analysis Set

NR = not reported; UC = ulcerative colitis.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52¹⁷ and sponsor’s additional information.¹⁹ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Exposure to Study Treatments

Treatment exposure from the pivotal trials is summarized in Table 13.

ELEVATE UC 12 Trial

Treatment exposure time was similar between the etrasimod and placebo groups: 12.1 weeks (SD = 3.0) and 12.2 weeks (SD = 2.8), respectively. In the ELEVATE UC 12 trial, the proportion of patients who had at least 12 weeks of treatment exposure was similar in the etrasimod and placebo groups (85.3% and 84.5%, respectively). Treatment compliance was also similar across groups.

ELEVATE UC 52 Trial

Treatment exposure time was higher in the etrasimod group (38.0 weeks; SD = 19.3) compared with the placebo group (27.5 weeks; SD = 18.9). In the ELEVATE UC 52 trial, the proportion of patients who had 12 to 26 weeks of treatment exposure was 28.0% and 50.0% in the etrasimod and placebo groups, respectively. Fewer patients had a treatment exposure of at least 52 weeks, with a greater proportion in the etrasimod group (45.7%) than in the placebo group (27.8%). Treatment compliance was similar across groups.

Table 13: Summary of Patient Exposure in the ELEVATE UC 12 and ELEVATE UC 52 Trials — Safety Analysis Set

NA = not applicable; SD = standard deviation.

Note: Percentages are based on the number of patients in the analysis set.

^aExposure for the entire treatment period was calculated as (end date of study treatment minus start date of study treatment plus 1) divided by 7.

^bOverall compliance is calculated as total number of tablets taken divided by total number of tablets expected during the treatment period.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52¹⁷ and the sponsor’s summary of clinical evidence.¹⁶

Treatment Modifications

Table 14 summarizes the treatment modifications in the ELEVATE UC 12 and ELEVATE UC 52 trials.

ELEVATE UC 12 Trial

A total of 7 patients (2.9%) in the etrasimod group and 5 patients (4.3%) in the placebo group had at least 1 treatment interruption, mostly due to AEs (2.5% and 3.4% in the etrasimod and placebo groups, respectively). Treatment overdoses were reported in 2 patients (0.6%).

ELEVATE UC 52 Trial

A total of 35 patients (12.1%) in the etrasimod group and 12 patients (8.3%) in the placebo group had at least 1 treatment interruption, mostly due to AEs (6.9% and 4.2% in the etrasimod and placebo groups, respectively). Treatment overdose was reported in 1 patient (0.3%) in the etrasimod group.

Table 14: Study Treatment Modifications in the ELEVATE UC 12 and ELEVATE UC 52 Trials — Safety Analysis Set

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52.¹⁷ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Protocol Deviations

Protocol deviations in the pivotal trials for the full FAS population are summarized in Table 15.

In the ELEVATE UC 12 trial, a total of 54 patients (22.7%) in the etrasimod group and 22 patients (19.0%) in the placebo group had at least 1 important protocol deviation. The most frequent protocol deviations in the etrasimod and placebo groups were study procedure (13.4% and 7.8%, respectively), eligibility and entry criteria (4.2% and 3.4%, respectively), visit schedule (2.5% and 3.4%, respectively), and laboratory assessment (4.2% and 1.7%, respectively). A total of 10 protocol deviations (2.8%) were impacted by the COVID-19 pandemic.

In the ELEVATE UC 52 trial, a total of 150 patients (51.9%) in the etrasimod group and 76 patients (52.8%) in the placebo group had at least 1 important protocol deviation. The most frequent protocol deviations in the etrasimod and placebo groups were study procedure (29.8 and 29.2%, respectively), laboratory assessment (17.6% and 13.2%, respectively), eligibility and entry criteria (5.5% and 6.9%, respectively), and visit schedule (5.2% and 4.9%, respectively). A total of 61 protocol deviations (14.1%) were impacted by the COVID-19 pandemic.

Table 15: Summary of Important Protocol Deviations From the Pivotal Studies

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52.¹⁷ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Efficacy

A summary of the key efficacy results is shown in Table 16. The primary analysis of the efficacy end points was conducted in the FAS among patients with a baseline MMS of 5 to 9.

Endoscopic Improvement

ELEVATE UC 12 Trial

In the ELEVATE UC 12 trial, a greater proportion of patients in the etrasimod group (30.6%) compared with the placebo group (18.8%) had endoscopic improvement at week 12, with a common risk difference of 12.1% (95% CI, 3.0% to 21.2%; P = 0.009).

In the subgroups identified as relevant by the clinical expert consulted by CADTH — including the extent of disease (proctosigmoiditis or left-sided colitis, pancolitis, and proctitis), isolated proctitis, prior UC treatment with oral 5-ASA only, prior UC treatment failure of oral 5-ASA only, and prior UC treatment failure of anti-TNF — more patients achieved endoscopic improvement at week 12 with etrasimod than with placebo (Appendix 1 Detailed Outcome Data[REMOVED REF FIELD]). There was a greater between-group difference for patients treated with etrasimod versus placebo in the subgroup of patients who were naive to biologic or JAKi therapy at baseline (18.9%; 95% CI, 7.9% to 29.8%) than those who were not (5.6%; 95% CI, −10.13% to 21.2%). There was a greater between-group difference for patients treated with etrasimod versus placebo in the subgroup of patients who had received 1 prior biologic or JAKi therapy (−4.13%; 95% CI, −25.6% to 17.3%) than the patients who had received more than 1 prior biologic or JAKi therapy (13.3%; 95% CI, −10.2% to 36.8%).¹⁹

ELEVATE UC 52 Trial

In the ELEVATE UC 52 trial, a greater proportion of patients in the etrasimod group (35.0%) compared with the placebo group (14.1%) had endoscopic improvement at week 12, with a common risk difference of 21.2% (95% CI, 13.0% to 29.3%; P < 0.001). A greater proportion of patients in the etrasimod group (37.2%) compared with the placebo group (10.4%) had endoscopic improvement at week 52, with a common risk difference of 26.7% (95% CI, 19.0% to 34.4%; P < 0.001).

In the prespecified subgroups — including the extent of disease (proctosigmoiditis or left-sided colitis, pancolitis, and proctitis), isolated proctitis, prior UC treatment of oral 5-ASA only, prior UC treatment failure of oral 5-ASA only, and prior UC treatment failure of anti-TNF — more patients achieved endoscopic improvement at weeks 12 and 52 on etrasimod than on placebo (Appendix 1 Detailed Outcome Data, Figure 9 and Figure 10). For patients treated with etrasimod versus placebo, there were greater between-group differences at baseline in the subgroup of patients who were naive to biologic or JAKi therapy, with a between-group difference of 22.1% at week 12 (95% CI, 12.1% to 32.2%) and 26.8% at week 52 (95% CI, 17.3% to 36.4%) compared with patients who were not naive to such therapy, with between-group differences of 16.5% (95% CI, 3.9% to 29.2%) at week 12 and 23.5% (95% CI, 11.1% to 35.9%) at week 52. There were greater between-group differences for patients treated with etrasimod versus placebo in the subgroup of patients who had received 1 prior biologic or JAKi therapy, with a between-group difference of 24.2% (95% CI, 9.3% to 39.0%) at week 12 and 24.8% (95% CI, 7.9% to 41.8%) at week 52, whereas the between-group difference among patients who had received more than 1 prior biologic or JAKi therapy was 7.7% (95% CI, −12.6% to 28.0%) at week 12 and 7.7% (95% CI, −12.6% to 28.0%) at week 52.¹⁹

Mucosal Healing

ELEVATE UC 12 Trial

In the ELEVATE UC 12 trial, a greater proportion of patients in the etrasimod group (16.2%) compared with the placebo group (8.9%) had mucosal healing at week 12, with a common risk difference of 7.4% (95% CI, 0.5% to 14.4%; P = 0.036).

ELEVATE UC 52 Trial

In the ELEVATE UC 52 trial, a greater proportion of patients in the etrasimod group (21.2%) compared with the placebo group (4.4%) had mucosal healing at week 12, with a common risk difference of 16.9% (95% CI, 10.8% to 23.0%; P < 0.001). A greater proportion of patients in the etrasimod group (26.6%) compared with the placebo group (8.1%) had mucosal healing at week 52, with a common risk difference of 18.4% (95% CI, 11.4% to 25.4%; P < 0.001).

For mucosal healing, only the outcome results at week 52 were considered important for informing the deliberations of CADTH’s expert committee and were assessed using GRADE.

Clinical Remission

ELEVATE UC 12 Trial

A greater proportion of patients in the etrasimod group (24.8%) compared with the placebo group (15.2%) achieved clinical remission at week 12, with a common risk difference of 9.7% (95% CI, 1.1% to 18.2%; P = 0.026).

ELEVATE UC 52 Trial

A greater proportion of patients in the etrasimod group (27.0%) compared with the placebo group (7.4%) achieved clinical remission at week 12, with a common risk difference of 19.75% (95% CI, 12.9% to 26.6%; P < 0.001). A greater proportion of patients in the etrasimod group (32.1%) compared with the placebo group (6.7%) achieved clinical remission at week 52, with a common risk difference of 25.4% (95% CI, 18.4% to 32.4%; P < 0.001).

Sustained Clinical Remission

ELEVATE UC 52 Trial

At both weeks 12 and 52, a greater proportion of patients in the etrasimod group (17.9%) compared with the placebo group (2.2%) achieved sustained clinical remission, with a common risk difference of 15.8% (95% CI, 10.7% to 21.0%; P < 0.001).

Corticosteroid-Free Clinical Remission

ELEVATE UC 52 Trial

At week 52, 32.1% of patients in the etrasimod group and 6.7% of patients in the placebo group achieved clinical remission and were corticosteroid-free for at least 12 weeks, with a common risk difference of 25.4% (95% CI, 18.4% to 32.4%; P < 0.001). At week 52 and among the overall patient population, 32.1% of patients in the etrasimod group and 6.7% of patients in the placebo group achieved clinical remission and were corticosteroid-free for at least 4 weeks, with a common risk difference of 25.1% (95% CI, 18.1% to 32.1%; P < 0.001). At week 52 among the patients who were receiving oral corticosteroids for UC at baseline, 27 patients (31.0%) in the etrasimod group and 3 patients (7.5%) in the placebo group achieved clinical remission and were corticosteroid-free for at least 4 weeks, with a common risk difference of 23.1% (95% CI, 10.2% to 35.9%; P < 0.001).

Clinical Response

ELEVATE UC 12 Trial

At week 12, a greater proportion of patients in the etrasimod group experienced clinical response compared with the placebo group (62.2% and 41.1%, respectively), with a common risk difference of 21.2% (95% CI, 10.2% to 32.3%; P < 0.001).

ELEVATE UC 52 Trial

At week 12, a greater proportion of patients in the etrasimod group had a clinical response compared with the placebo group (62.4% and 34.1%, respectively), with a common risk difference of 28.3% (95% CI, 18.5% to 38.0%; P < 0.001). At week 52, 48.2% of patients in the etrasimod group and 23.0% of patients in the placebo group had a clinical response, with a common risk difference of 24.9% (95% CI, 15.8% to 34.1%; P < 0.001). At both weeks 12 and 52, a greater proportion of patients in the etrasimod group had a clinical response compared with the placebo group (44.9% and 18.5%, respectively), with a common risk difference of 26.2% (95% CI, 17.5% to 34.8%; P < 0.001).

Symptomatic Remission

ELEVATE UC 12 Trial

A greater proportion of patients in the etrasimod group (46.8%) compared with the placebo group (29.5%) achieved symptomatic remission at week 12, with a common risk difference of 17.5% (95% CI, 6.8% to 28.2%; P = 0.001).

ELEVATE UC 52 Trial

At week 12, a greater proportion of patients in the etrasimod group (46.0%) compared with the placebo group (21.5%) achieved symptomatic remission at week 12, with a common risk difference of 24.6% (95% CI, 15.5% to 33.6%; P < 0.001). At week 52, 43.4% of patients in the etrasimod group and 18.5% of patients in the placebo group achieved symptomatic remission, with a common risk difference of 24.9% (95% CI, 16.2% to 33.6%; P < 0.001).

For symptomatic remission, only the outcome results at week 52 were considered important for informing the deliberations of CADTH’s expert committee and were assessed using GRADE.

Based on the results from the ELEVATE UC 12 and ELEVATE UC 52 trials, in the prespecified subgroups — including the extent of disease (proctosigmoiditis or left-sided colitis, pancolitis, and proctitis), isolated proctitis, prior UC treatment of oral 5-ASA only, prior UC treatment failure of oral 5-ASA only, and prior UC treatment failure of anti-TNF — more patients on etrasimod than on placebo had mucosal healing and clinical remission at week 12 and week 52. In both studies, the results of the prespecified subgroup analyses were consistent with the primary analysis results at weeks 12 and 52 for sustained clinical remission, corticosteroid-free clinical remission, clinical response, and symptomatic remission.^16,19

In the ELEVATE UC 12 and ELEVATE UC 52 trials, the results of sensitivity analyses of endoscopic improvement, mucosal healing, clinical remission, and symptomatic remission were consistent with the primary analysis results at weeks 12 and 52.

HRQoL Assessed With the IBDQ Total Score

ELEVATE UC 12 Trial

At week 12, in the IBDQ total score, patients in the etrasimod group experienced a mean change of 45.5 points from baseline compared with a change of 30.4 points in the placebo group, with an LS mean difference between groups of 17.3 (95% CI, 8.5 to 26.2; P < 0.001).

ELEVATE UC 52 Trial

At week 12, in the IBDQ total score, patients in the etrasimod group experienced a mean change of 44.3 points from baseline compared with a change of 26.7 points in the placebo group, with an LS mean difference between groups of 15.44 (95% CI, 6.5 to 24.4; P < 0.001). At week 52, in the IBDQ total score, patients in the etrasimod group experienced a mean change of 66.6 points from baseline compared with a change of 52.5 points in the placebo group, with an LS mean difference between groups of 17.7 (95% CI, 6.6 to 28.8; P = 0.002).

Table 16: Summary of Key Efficacy Results of the ELEVATE UC 12 and ELEVATE UC 52 Trials — FAS and a Baseline MMS of 5 to 9

CI = confidence interval; ES = endoscopic score; FAS = full analysis set; IBDQ = Inflammatory Bowel Disease Questionnaire; JAK = Janus kinase; LS = least squares; MMRM = mixed model for repeated measures; MMS = modified Mayo score; NA = not applicable; RB = rectal bleeding; SD = standard deviation; SE = standard error; SF = stool frequency; UC = ulcerative colitis.

Note: Percentages are based on the number of patients in the analysis set.

^aDefined as patients with an ES of ≤ 1 (excluding friability).

^bEstimates are from a Cochran-Mantel-Haenszel test stratified by naive to biologic or JAK inhibitor therapy at study entry (yes or no), baseline corticosteroid use (yes or no), and baseline disease activity (MMS of 4 to 6 or 7 to 9). Ratio is for etrasimod over placebo. Difference (%) is for etrasimod minus placebo and is based on estimated common risk difference using the Cochran-Mantel-Haenszel weights.

^cDefined as patients who have an ES of ≤ 1 (excluding friability) with histologic remission measured by a Geboes Index score of < 2.0.

^dDefined as patients who have an SF subscore of 0 (or 1 with a ≥ 1 point decrease from baseline), RB subscore of 0, and ES of ≤ 1 (excluding friability).

^eDefined as patients with an SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline), RB subscore of 0, and ES of ≤ 1 (excluding friability) at both week 12 and week 52.

^fDefined as patients with an SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline), RB subscore of 0, ES of ≤ 1 (excluding friability), and who have not received corticosteroids for ≥ 12 weeks in the 40-week treatment period.

^gDefined as patients with an SF subscore of 0 (or 1 with a ≥ 1 point decrease from baseline), RB subscore of 0, ES of ≤ 1 (excluding friability), and who have not received corticosteroids for ≥ 4 weeks in the 40-week treatment period.

^hDefined as patients with a ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RB subscore or an absolute RB subscore ≤ 1.

ⁱDefined as patients with an SF subscore of 0 (or 1 with a ≥ 1 point decrease from baseline) and an RB subscore of 0.

^jIBDQ scores and change from baseline were reported using a modified FAS and an actual baseline MMS of 5 to 9.

^kEstimates are from an MMRM model for change from baseline with a covariate for baseline score, and factors for naive to biologic or JAK inhibitor therapy at study entry (yes or no), baseline corticosteroid use (yes or no), baseline disease activity (MMS 4 to 6 or 7 to 9), treatment, visit, and treatment by visit interaction.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52¹⁷ and sponsor’s additional information.¹⁹ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Harms

A summary of harms reported in the safety analysis sets in the ELEVATE UC 12 and ELEVATE UC 52 trials is provided in Table 17.

Adverse Events

In the ELEVATE UC 12 trial, 47.1% and 46.6% of patients reported a TEAE in the etrasimod and placebo groups, respectively. During the 12 weeks of treatment in the ELEVATE UC 12 trial, the most common TEAEs in the etrasimod and placebo groups were anemia (5.9% and 6.9%, respectively), headache (4.6% and 1.7%, respectively), nausea (4.2% and 1.7%, respectively), UC (3.8% and 0.9%, respectively), pyrexia (3.4% and 2.6%, respectively), and arthralgia (1.7% and 2.6%, respectively). A total of 2.5% and 1.7% of patients in the etrasimod and placebo groups, respectively, reported serious TEAEs.

Table 17: Summary of Harms Results in the ELEVATE UC 12 and ELEVATE UC 52 Trials — Safety Analysis Set

AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; NR = not reported; SMQ = Standardised MedDRA Query; SOC = system organ class; TEAE = treatment-emergent adverse event.

Note: TEAEs are defined as any AE that started or worsened in severity on or after the first dose of the study treatment. Terms are coded using MedDRA Version 24.1. Percentages are based on the number of patients in the analysis set. AE categories are sorted in order of decreasing total frequency in the etrasimod treatment group and then sorted within the category in order of decreasing frequency of the subcategory and preferred term. Severe infections are defined as events in the “Infections and Infestations” MedDRA SOC, with severity reported as grade 3 (severe), grade 4 (life-threatening), or grade 5 (death). Opportunistic infections (narrow) are based on an SMQ. Patients are counted only once per summarization level.

Sources: Clinical Study Reports for ELEVATE UC 12¹⁸ and ELEVATE UC 52.¹⁷ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

In the ELEVATE UC 52 trial, 71.3% and 56.3% of patients reported a TEAE in the etrasimod and placebo groups, respectively. Over 52 weeks of treatment in the ELEVATE UC 52 trial, the most common TEAEs in the etrasimod and placebo groups were anemia (8.3% and 9.7%, respectively), headache (8.3% and 4.9%, respectively), UC (7.6% and 9.0%, respectively), COVID-19 infection (6.9% and 6.3%, respectively), dizziness (5.2% and 0.7%, respectively), and pyrexia (4.8% and 4.2%, respectively).

Serious Adverse Events

In the ELEVATE UC 12 trial, 2.5% and 1.7% of patients reported serious TEAEs in the etrasimod and placebo groups, respectively. The most common serious TEAEs in the etrasimod and placebo groups included UC (1.3% and 0%, respectively), abdominal pain (0% and 0.9%, respectively), and anemia (0% and 0.9%, respectively).

In the ELEVATE UC 52 trial, 6.9% and 6.3% of patients reported serious TEAEs in the etrasimod and placebo groups, respectively. The most common serious TEAEs in the etrasimod and placebo groups included UC (2.1% in both groups), anemia (0.7% in both groups), and COVID-19 pneumonia (0.3% and 0.7%, respectively).

Withdrawals Due to Adverse Events

In the ELEVATE UC 12 trial, 5.5% and 0.9% of patients withdrew from the trial due to an AE in the etrasimod and placebo groups, respectively. In the ELEVATE UC 52 trial, 4.2% and 4.9% of patients withdrew from the trial due to a TEAE in the etrasimod and placebo groups, respectively. In both the ELEVATE UC12 and ELEVATE UC 52 studies, UC was the most common reason for withdrawal (not more than 2.5% across the study groups).

Mortality

No deaths were reported in either the ELEVATE UC 12 or ELEVATE UC 52 trial.

Notable Harms

In the ELEVATE UC 12 trial, 3.4% of patients in the etrasimod group experienced cardiovascular events compared with 1.7% of patients in the placebo group. In the ELEVATE UC 12 trial, in the etrasimod and placebo groups, liver injury was reported in 1.3% and 0% of patients, respectively, and infections were reported in 0.8% and 1.7% of patients, respectively. No AESIs in the categories of pulmonary disorders, macular edema, posterior reversible encephalopathy syndrome, progressive multifocal leukoencephalopathy, or malignancy were reported in the ELEVATE UC 12 trial.¹⁸ Of note, 1 patient in the etrasimod group and 1 patient in the placebo group reported AEs of macular edema. Neither of these were identified as AESIs per the definition of macular edema by preferred term, which is confirmed by an increase in central foveal thickness of 40 μm or greater or a central foveal thickness of 40 μm or greater, with associated symptoms and clinically significant abnormal findings.¹⁸

In the ELEVATE UC 52 trial, 4.2% of patients in the etrasimod group experienced cardiovascular events compared with 0% of patients in the placebo group. In the ELEVATE UC 52 trial, in the etrasimod and placebo groups, liver injury was reported in 1.4% of patients in both groups, and infections were reported in 2.8% and 4.9% of patients, respectively. In the ELEVATE UC 52 trial, 1 patient (0.3%) in the etrasimod group and no patients (0%) in the placebo group reported macular edema. There were no AESIs of posterior reversible encephalopathy syndrome, progressive multifocal leukoencephalopathy, or malignancy reported during the ELEVATE UC 52 study.¹⁷

Critical Appraisal

Internal Validity

Based on the CADTH review team’s assessment, randomization in both the ELEVATE UC 12 and ELEVATE UC 52 trials was performed using an appropriate methodology with adequate allocation concealment, i.e., an interactive web response system. Randomization stratification was prespecified and was based on relevant prognostic factors, i.e., naive to biologic or JAKi therapy at study entry (yes or no), baseline corticosteroid use (yes or no), and baseline disease activity (MMS of 4 to 6 or 7 to 9). For both pivotal trials, patients who had a baseline MMS of 4 to 9 were eligible and enrolled in the studies; however, while safety outcomes were presented in the FAS of patients with a baseline MMS of 4 to 9 (i.e., among all patients who were randomized), a primary efficacy analysis was performed in the FAS of patients with a baseline MMS of 5 to 9, in accordance with the trials’ statistical analysis plans.^17-21 As a result, in the 2 trials, a total of 44 patients (20 of 354 patients in the ELEVATE UC 12 trial and 24 of 433 patients in the ELEVATE UC 52 trial) with a baseline MMS of 4 were excluded from the primary efficacy analysis, which might compromise randomization.¹⁹ According to the sponsor, this amendment to the statistical analysis plan (i.e., changing the FAS to comprise patients with an actual baseline MMS of 4 to 9 to patients with an MMS of 5 to 9) for both trials was made in January 2022 to align with the regulatory body’s feedback on what is considered a moderate to severe UC population, which was outlined in the FDA draft guidance (Ulcerative Colitis: Developing Drugs for Treatment — Guidance for Industry)²² but which became available after the finalization of study protocols and the initiation of patients recruitment (ELEVATE UC 12 enrolled patients between September 2020 and August 2021, and ELEVATE UC 52 enrolled patients between June 2019 and January 2021). In general, the CADTH review team and the clinical expert consulted by CADTH did not identify any major issues with excluding patients with a baseline MMS of 4 for the efficacy analysis that would impact the study results, based on the patient characteristics that appeared to be reasonably balanced between the treatment groups, and given the similar findings in the supplementary analyses of the same outcomes that used the entire FAS for both studies.

In both trials, the double-blind approaches that masked participants as well as investigators (including the outcome assessors) regarding treatment allocation, from the time of random assignment until the time of unblinding per the study protocols, were appropriate. The study drugs were identical in physical appearance and packaging. Some efficacy end points (clinical remission and the related outcomes, clinical response, and symptomatic remission) were composite outcomes that included MMS subscores for stool frequency and rectal bleeding, which were recorded and reported by patients. The HRQoL outcome that was assessed with the IBDQ was also a patient-reported measure. Although these subjective (components of) outcomes may be influenced by knowledge of treatment assignment, the double-blind design of the trials likely mitigated this risk. The CADTH review team noted that in the ELEVATE UC 52 trial, a higher proportion of patients in the placebo group discontinued the treatment due to disease worsening (50.7%) compared with the etrasimod group (27.3%) during the 52-week trial period. Withdrawal by patient as a reason for discontinuing the study or treatment was higher in the placebo group in both trials, except among those who discontinued the study in the ELEVATE UC 52 trial, where a higher percentage of patients treated with etrasimod discontinued the study by patient choice. Also, for the IBDQ total score at week 52 in the ELEVATE UC 52 trial, the rate of missing data was higher in the placebo group than in the etrasimod group. There was no concrete evidence beyond these points that clearly showed unblinding due to patients’ inferences on treatment assignment based on symptom changes or the occurrence of other factors. Thus, the extent to which this could have affected the efficacy and HRQoL outcome results, particularly the outcomes at week 52, is unclear.

Both the ELEVATE UC 12 and ELEVATE UC 52 trials used placebo as the comparator instead of an advanced therapy for UC that is relevant to clinical practice in Canada. The clinical expert consulted by CADTH pointed out that relevant pharmacotherapies for patients with moderately to severely active UC in clinical practice in Canada include adalimumab, golimumab, infliximab, mirikizumab, ozanimod, tofacitinib, upadacitinib, ustekinumab, and vedolizumab. The sponsor submitted evidence regarding comparative effectiveness, which is summarized in the ITC section of this report. It is notable that the FDA guidance to industry for conducting interventional trials in patients with UC²² encourages sponsors to use active treatments as controls.

Overall, the baseline demographic and disease characteristics appeared to be reasonably balanced between the etrasimod and placebo groups in the ELEVATE UC 12 and ELEVATE UC 52 trials. At baseline, 29.2% to 33.9% of the patients across the different groups in the 2 trials reported the use of at least 1 prior biologic or JAKi; the percentages were similar between groups within the studies. The clinical expert did not identify any important imbalance in the baseline characteristics of prognostic importance between the 2 groups within each study.

In the ELEVATE UC 12 and ELEVATE UC 52 trials, most patients received 1 or more concomitant drugs for UC, including antidiarrheals, intestinal anti-inflammatory or anti-infective drugs (mainly mesalazine), corticosteroids for systemic use, and immunosuppressants, among others. The overall concomitant use of systemic corticosteroids appeared similar between groups in each study, although the reported use of budesonide by patients was 3% to 6% higher in the etrasimod groups versus the placebo groups in both studies (Table 12). As well, more patients treated with etrasimod (5.9% and 3.5%) compared with placebo (1.7% and 1.4%) received immunomodulators concurrently. While these are notable differences, the relatively small percentages (< 10%) and small between-group differences (< 5%) mean these differences were unlikely to have been important confounders of the results in both trials.

Overall, the statistical methods used in both trials were appropriate. The trials were powered on their primary and key secondary end points for comparison between the treatment groups. The HRQoL assessed with the IBDQ (an efficacy-related outcome) at week 52 was most likely underpowered, as its outcome data were only available for fewer than half of those with an IBDQ result assessed at baseline. The subgroup analyses were also likely underpowered to identify subgroup differences. An appropriate method for adjusting for multiplicity was used for the primary and secondary outcomes, but there was no multiplicity control for the subgroup analyses. The interaction P values for subgroup analyses were not provided.

In the ELEVATE UC 52 trial, the rates of treatment discontinuation (42.6% in the etrasimod group and 68.1% in the placebo group) and study discontinuation (44.3% in the etrasimod group and 68.1% in the placebo group) were high, mainly due to disease worsening and withdrawal by patients. Nonresponder imputation was used per FDA guidance for missing data in the base case; as well, supportive preplanned sensitivity analyses were done under different assumptions (missing at random, missing not at random). Nonresponder imputation is generally conservative, but it assumes that missing data occur randomly and are unrelated to unobserved variables. However, this assumption is often unrealistic and, if violated, the imputed values may be biased, especially when differences between groups are pronounced.⁹⁷ However, appropriate methods (e.g., tipping point and multiple imputation) for the sensitivity analyses were used. These analyses confirmed that the results of the trial remained robust to the differential discontinuations between groups.

External Validity

While the indication for etrasimod is for the treatment of moderately to severely active UC in adults, patients aged 16 to 80 years were eligible for the ELEVATE UC 12 and ELEVATE UC 52 trials, yet a relatively small proportion of the enrolled patients were aged 65 years or older (5.0% to 7.4% across the different groups in both trials) and 1 person in each study was younger than 18 years. No patients in the ELEVATE UC 12 trial and only 0.7% of the patients in the ELEVATE UC 52 trial were aged 75 years or older at baseline. These small populations limit the trials’ generalizability among older patients. The clinical expert consulted by CADTH noted that clinicians would be cautious about using etrasimod in patients aged 65 years and older because there is a higher likelihood of comorbidity and/or multiple medications (polypharmacy), as well as a higher potential for decreased hepatic, renal, cardiac, or pulmonary function.

Patients in the ELEVATE UC 12 and ELEVATE UC 52 trials were recruited from multiple countries, including Canada. Approximately 9% of patients in the ELEVATE UC 12 trial and 19% of patients in ELEVATE UC 52 were from North America. The majority of patients enrolled in these trials (55% to 62% across the treatment groups) were from eastern Europe. Also, there were relatively high rates of screening failure in both the ELEVATE UC 12 (41.6%) and ELEVATE UC 52 (47.3%) trials, mainly due to failure to meet eligibility criteria. The clinical expert did not regard these failures as factors that might essentially influence the generalizability of the studies’ results. The clinical expert noted that the eligibility criteria for patients in both trials generally aligned with the diagnosis standard and treatment indication for moderately to severely active UC in clinical settings, and the demographic characteristics of the patients from a diversity aspect in the 2 trials were mostly in line with the patients seen in clinical practice in Canada. Moreover, the clinical expert pointed out that the inclusion of patients with UC with isolated proctitis (< 10 cm rectal involvement) with a limitation of not more than 15% of the total number of the included patients (which is a subgroup of patients with UC that is most often excluded from clinical trials), is helpful for clinical practice, contributing evidence for the efficacy and safety of etrasimod in this specific patient group.

The clinical expert considered the recommended dosage for etrasimod (2 mg taken orally once daily) to be adequate and reasonable for clinical practice in Canada. The clinical expert pointed out the importance of monitoring patients using biomarker examinations (e.g., fecal calprotectin) during treatment with etrasimod.

The trials included outcomes that were important to patients, including sustained clinical remission, corticosteroid-free clinical remission, symptomatic remission, and HRQoL. These outcomes, together with other outcomes reported in this review (i.e., endoscopic improvement, mucosal healing at the longer follow-up time point, and clinical response) were considered appropriate by the clinical expert and the clinician group. The placebo-controlled period of the ELEVATE UC 52 trial was 1 year, which aligns with current regulatory guidance. However, given that patients and clinicians often report a waning of treatment effect with advanced therapies for UC, longer-term comparative evidence on the durability of the effectiveness of etrasimod would be informative, especially in the context of a health technology assessment on comparative effectiveness for purposes of reimbursement. Likewise, the occurrence of some AEs, especially rare ones, may take longer than 52 weeks to be identified. Longer-term follow-up to assess safety and a direct comparison between etrasimod with other advanced therapies would be preferred.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^23,24

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty-of-evidence assessment was the presence or absence of an important effect based on thresholds (MIDs) identified in the literature for the IBDQ total score. The target of the certainty-of-evidence assessment was the presence or absence of an important effect based on thresholds informed by the clinical expert consulted for this review for endoscopic improvement, mucosal healing, clinical remission, sustained clinical remission, corticosteroid-free clinical remission, clinical response, and symptomatic remission.

For the GRADE assessments, findings from the ELEVATE UC 12 and ELEVATE UC 52 trials were considered together and summarized narratively per outcome because these studies were similar in population, interventions, design, and outcome measures.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for etrasimod versus placebo in adult patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Description of Studies

There are currently no results available from any long-term extension studies of etrasimod in moderately to severely active UC.

The sponsor did note there is an ongoing, single-arm, long-term extension study (ELEVATE UC OLE²⁵) that evaluates the safety and efficacy of etrasimod in patients with moderately to severely active UC who previously received double-blind treatment (etrasimod 2 mg/day or placebo) during inclusion in 1 of the phase III or phase II double-blind, placebo-controlled parent studies.¹⁶ These studies include but are not limited to ELEVATE UC 52 (APD334 to 301/NCT03945188),⁹⁸ ELEVATE UC 12 (APD334 to 302/NCT03996369),⁹⁹ and GLADIATOR UC (APD334 to 210/NCT04607837).¹⁰⁰ The ELEVATE UC OLE trial includes patients aged 16 to 80 years with study locations in 39 countries, including Canada (Toronto and Montreal).²⁵ The estimated primary completion date for the ELEVATE UC OLE trial is February 6, 2027.²⁵ It is anticipated that this trial will ultimately provide up to 8 years of efficacy and safety follow-up data for etrasimod in adult patients with moderately to severely active UC.¹⁶

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Objectives for the Summary of Indirect Evidence

In the absence of direct head-to-head trials evaluating the comparative efficacy and safety of etrasimod versus relevant comparators for moderately to severely active UC in adult patients, the sponsor submitted a systematic review with an NMA. The sponsor-conducted NMA was used to inform the sponsor-submitted economic model for etrasimod.

Description of Indirect Treatment Comparison

The sponsor submitted 1 NMA that comprises the ██████ ███ █████████ ████ ███ ███ ████████████████████ ██████ ███ ██ ██ ████████ ████████████ ███ █████ ███████████ ████████████ ██████ ███ ██ ██ ██████ █████ ███████ █ ██████████ ███████ █████████ █████████ ████████ █████████████████ ███ ███ █████████ ██ ████████ ████ ████████ ██ ██████ ██████ ██ █████ ██ █████████ ████████ █████ ████████.^26,27,101

Indirect Treatment Comparison Design

Objectives

The objective of the sponsor-submitted NMA was to evaluate the relative efficacy and safety of etrasimod versus relevant advanced therapies for moderately to severely active UC in adults.

Study Selection Methods

The NMA followed the guidelines published by the National Institute for Health and Care Excellence (NICE) in NICE DSU [Decision Support Unit] Technical Support Document 2.¹⁰² A systematic literature search was conducted in November 2022 and updated in August 2023 for the submission to CADTH to identify RCTs. Multiple electronic databases, including MEDLINE, Embase, and the Cochrane Library, were searched, supplemented with searches of conference proceedings and other sources to identify evidence available from RCTs on the efficacy and safety of interventions used to treat moderate to severe UC.¹⁰³ Study selection from the initial literature search was conducted by 2 independent reviewers and data extraction was also conducted independently by 2 reviewers. Study selection criteria are summarized in Table 18. The quality of the selected studies was assessed by 2 independent reviewers using the NICE checklist.¹⁰³ A single reviewer was involved in study selection, data extraction, and quality appraisal, with an independent reviewer overseeing quality checks at each stage following the updated literature search.

The NMA made comparisons between etrasimod versus infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, filgotinib, upadacitinib, mirikizumab, and ozanimod.²⁶

Table 18: Study Selection Criteria and Methods for ITC Submitted by the Sponsor

AE = adverse event; EMA = European Medicines Agency; EU = European Union; ITC = indirect treatment comparison; MMS = modified Mayo score; NICE = National Institute of Health and Care Excellence; NIH = National Institutes of Health; NMA = network meta-analysis; RCT = randomized controlled trial; SC = subcutaneous; TLR = targeted literature review; TMS = total Mayo score; UC = ulcerative colitis.

^aNot given daily; given on specific weeks.

^bBased on dose weight of patient at the time of dosing.

^cThe initial induction dose for children and adolescents is 80 mg.

^dSuggested dose for patients with renal impairment.

^eMirikizumab was included in the Canadian NMA only.

^fOutcomes were not assessed in the Canadian base-case analyses.

Sources: Sponsor-submitted NMAs.^{26,27,101,114}

ITC Analysis Methods

Statistical Model

The NMAs were conducted under a Bayesian framework¹⁰² using a Markov chain Monte Carlo, in accordance with NICE technical support documents.^102,115 Placebo was selected as the reference treatment for all analyses.²⁶ Results were generated using both random-effects and fixed-effects models when possible and compared for goodness of fit to the data, calculated as the total residual deviance.²⁶ The fixed-effects models were the most appropriate model approach in the majority of cases.²⁶ Typically, only 1 study informed each comparison and, as a result, it was inappropriate to use random-effects models. The deviance information criterion (DIC) was reported for both models to inform the model fit, with lower values of DIC indicating a better model fit. Typically, differences of 5 for the DIC would be considered an important difference.²⁶ The multinomial approach was the preferred analysis approach where outcomes were correlated, as it allows for the inclusion of all available information and ensures coherence across the outcomes. This approach was applied where appropriate and possible. The probit link function was used for the multinomial modelling.¹⁶

Prior Distribution

Since the test-specific baselines, 𝜇𝑖, are regarded as nuisance parameters (i.e., they are estimated in the model but are not of interest), they were given vague priors, where 𝜇𝑖 is asymptotic to 𝒩(0, 10⁴).²⁶ Furthermore, under the consistency assumptions of the NMA and the assumption that consistency equations can be written generally as 𝑑_{𝑡𝑖1,𝑡𝑖𝑘} = 𝑑_{1,𝑡𝑖𝑘} − 𝑑_1,𝑡𝑖1, the parameters 𝑑₁₂ and 𝑑₁₃ were given vague prior distributions: 𝒩 (0, 10⁴).²⁶ These noninformative priors applied to both the fixed-effects and the random-effects models.²⁶ In addition, the random-effects model required priors for the variance of parameters 𝛿𝑖,𝑘.²⁶ A vague prior was set for its SD: 𝑠𝑑 is asymptotic to 𝒰niform (0, 5).²⁶ This prior was adjusted where necessary to improve model convergence.²⁶ In addition, for the meta-regression coefficient, a vague prior was given, 𝒩 (0, 10⁴). For the ordinal category cut-offs, a vague prior was also used, 𝒰niform(0, 2).²⁶

Model Selection

As mentioned, as only 1 study informed each comparison, it was inappropriate to use random-effects models.²⁶ A fixed-effects model was the most appropriate model approach in the majority of cases.²⁶ Where possible, results were generated using both random-effects and fixed-effects models and compared for goodness of fit to the data, calculated as the total residual deviance.²⁶ The DIC, a measure of model fit, was reported for both models, with lower values of DIC indicating a better model fit (typically differences of 5 would be considered an important difference ).¹⁶

Assessment of Homogeneity

Homogeneity was assessed by performing a pairwise meta-analysis for each comparison informing the network (e.g., etrasimod versus placebo) or, if there were multiple studies informing the comparison, using the I² statistic and the P value from the chi-square test to assess potential heterogeneity.^26,101 This type of analysis may provide more robust comparisons against these comparators and give an indication of the potential for bias across the standard NMAs due to the concomitant use of medications.²⁶

The level of significance used was 0.1, since the chi-square statistic is typically underpowered. To interpret the I² value, the following was used:¹¹⁶

• 0% to 40%: Might not be important.

• 30% to 60%: May represent moderate heterogeneity.

• 50% to 90%: May represent substantial heterogeneity.

• 75% to 100%: Considerable heterogeneity.

The trials included in the NMA were carefully assessed for possible sources of heterogeneity in a feasibility assessment in collaboration with experts in either UC or in the statistical or economic component of the development of these analyses.²⁶ Feedback, which was obtained through a sponsor-conducted virtual advisory board meeting, was sought on the potential sources of heterogeneity in the patient and study characteristics of the included studies, treatments, and analysis approaches.²⁶

Assessment of Inconsistency

Given the structure of the network and the structure for any closed loop, all nodes are linked by the same trial; no inconsistencies were expected. Nonetheless, to test the consistency assumption, an unrelated mean effects (UME) model was implemented for the primary analyses (global [AL] analyses AL1 to AL9, fixed-effects models without baseline risk adjustment).¹¹⁷ Primary NMA models and inconsistency models (UME models) were compared according to the recommendations of Daly et al. (2022).¹¹⁸

Construction of Nodes

All nodes were connected by the same trial.²⁶ The analyses did not pool doses or regimens.²⁶

Outcomes

Clinical efficacy outcomes analyzed include:

• clinical response

• clinical remission

• sustained clinical response among induction responders

• sustained clinical remission among induction responders.

The safety outcomes analyzed include:

• serious infections

• SAEs

• overall AEs

• treatment discontinuations due to AEs.

No preplanned outcomes were excluded or not analyzed.¹⁶

Of note, there were differing definitions of the outcomes used across trials due to the scales used, i.e., the TMS or the MMS. Where a trial reported both the TMS and the MMS, the TMS was used, given that the TMS was reported more frequently.²⁶ The MMS was used for the ELEVATE trials since this was the primary outcome measure.⁸²

Analyses

The primary analyses conducted are summarized in Table 19. Trials with a maintenance phase of less than 38 weeks were excluded to align with the primary efficacy analyses, and only trials from the overall population were included, so trials that were “naive only” were excluded.²⁶ Parts of studies or entire studies were excluded from the review because their doses were outside the range authorized by the European Medicines Agency.²⁶

The population of biologics- and JAKi-naive, biologics-naive, TNF inhibitor (TNFi)-naive, and TNFi- and biologics-naive patients is referred to as the advanced therapy–naive population. The population of biologics- and JAKi-exposed, biologics-exposed, and/or TNFi-exposed patients is referred to as the advanced therapy–experienced population.²⁶

Table 19: Summary of Main Analyses for ITC Submitted by the Sponsor

AE = adverse event; ITC = indirect treatment comparison.

Note: Global analyses are labelled AL, while analyses conducted for Canada are labelled CA. Global analyses that included only treat-through trials are labelled TT. Analyses conducted for Canada include mirikizumab as a comparator, which was not included in the global analyses.

^aThis analysis was not included in the Canadian model.

Sources: Sponsor-submitted network meta-analyses.^26,101

Subgroup Analysis

The focus of this analysis was on the biologics-naive (i.e., advanced therapy–naive) and biologics-exposed (i.e., advanced therapy–exposed or –experienced) subgroups, since there was precedent to split the population due to prior treatment being an effect modifier. Consideration was also given to other subgroups and the overall population.²⁶

Sensitivity Analysis

A summary of the sensitivity analyses conducted is presented in Table 20. No sensitivity analyses were conducted for the Canadian base-case analyses.¹¹⁹ Several sensitivity analyses were conducted for the global analyses to test assumptions of the data generated by the ELEVATE trials.²⁶

Sensitivity analyses SA1 to SA4 were performed to investigate the robustness of the primary analyses by using TMS outcomes instead of MMS outcomes for the ELEVATE trials, as most trials included in the networks report outcomes using the TMS rather than the MMS, despite the general conclusion that there is a strong correlation between the 2 score measures.

Sensitivity analyses SA5 to SA8 used the FAS in the ELEVATE trials. In the primary analyses, the population in the ELEVATE trials was restricted to patients who had an MMS of between 5 and 9, as this aligned with the definition that other trials have used to define moderately to severely active UC. The FAS population from the ELEVATE trials with a baseline MMS of 4 to 9 was used to examine the impact of including patients with less severe disease.

As only failure and no-failure data were available for upadacitinib and there were no therapy–naive or therapy–exposed data available during the time of the analysis, sensitivity analyses SA9 to SA12 were run, excluding upadacitinib from the network to assess the impact. Upadacitinib failure data were used for sensitivity analyses SA5 to SA12 rather than exposure data, as this was the only data available at the time of the analysis.

To assess the impact that studies with Asian-only populations have on the analyses, sensitivity analyses SA13 and SA14 were conducted and applied only to analysis networks that included these studies (AL1 and AL3).

Sensitivity analyses SA15 to SA18 were conducted to assess the impact of stratifying patients in the ELEVATE trials by biologic status only because most trials included in the analysis networks stratified patients by prior biologic status at baseline rather than prior biologic or JAKi treatment status.

The main analyses included trials with maintenance periods of at least 38 weeks; however, there were several trials with shorter maintenance periods, particularly infliximab trials. Sensitivity analysis SA19 was conducted to investigate the impact of including trials with a shorter maintenance period. Sensitivity analysis treat-through trial 1 (SATT1) also assessed the impact of including treat-through trials with a shorter maintenance period.

In the main safety analyses, only the overall (mixed advanced therapy–naive and advanced therapy–exposed) populations in the trials were included; however, there were several trials that included only advanced therapy–naive populations. These trials were included in sensitivity analyses SA24 to SA28 to investigate the impact of the included trials and comparators on outcomes.

Two trials, Sandborn (2012) and VISIBLE 1,^120,121 were excluded from the main efficacy analyses, as they reported only 1 of the 2 efficacy outcomes for the multinomial model. The trials were included in sensitivity analyses SA29 to SA32, with the additional assumption that the cut-offs for the missing categories (in the multinomial model) were sampled from the distribution informed by other trials.

Summary of ITC Analysis Methods

The ITC analysis methods are summarized in Table 21.

Table 20: Summary of Sensitivity Analyses for ITC Submitted by the Sponsor