Reimbursement Review

Guselkumab (Tremfya)

Sponsor: Janssen Inc.

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 on Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Inflammatory bowel disease (IBD) is a group of diseases characterized by chronic recurrent, progressive inflammation of the gastrointestinal (GI) tract. There are 2 main types of IBD: Crohn disease (CD) and ulcerative colitis (UC). UC is a chronic disease characterized by inflammation and ulcers in the mucosal layer of the large intestine (colon), typically beginning at the rectum (anus), progressing upward and, in some cases, affecting the entire colon. 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. Patients with UC present with the following symptoms: blood in the stool with mucus, frequent diarrhea, loss of appetite, and tenesmus (strong urge to use the bathroom without necessarily having a bowel movement), in addition to abdominal pain, rectal bleeding, and weight loss. UC generally develops in young adulthood and persists throughout life, marked by periods of spontaneous remission and relapse. UC has a worldwide annual incidence rate of 1.2 to 20.3 cases per 100,000 people and a prevalence of 7.6 to 246.0 cases per 100,000 people. The prevalence for UC in Canada in 2023 was estimated to be 414 per 100,000. It is estimated that 32% to 46% of people in Canada with UC have moderate disease, and 13% to 14% have severe disease.

UC can be further classified in clinical practice based on severity: mild, moderate, or severe disease, depending on the specific index score used (Truelove and Witts Severity Index, Mayo score, or the Montreal classification). While most patients have a mild to moderate disease course, about 10% to 15% experience an aggressive course of UC. Relapse is common, with the cumulative risk of relapse being 70% to 80% at 10 years. Achieving endoscopic healing earlier may be associated with a reduced risk of future colectomy. The chronic nature of UC has a considerable impact on patients’ health-related quality of life (HRQoL), including psychological, physical, sexual, and social domains of HRQoL due to the chronicity of symptoms such as urgency and frequency and incontinence.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of guselkumab (Tremfya) 200 mg for induction, administered by IV infusion, followed by guselkumab 100 mg for maintenance, administrated by subcutaneous (SC) injection, for the treatment of adults with moderately to severely active UC.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient groups that responded to the call for input by Canada’s Drug Agency (CDA-AMC) and by the clinical experts consulted by CDA-AMC for the purpose of this review.

Patient Input

Two patient groups, Crohn’s and Colitis Canada and the Gastrointestinal Society, provided input for this review of guselkumab for the treatment of UC. The patient input from Crohn’s and Colitis Canada was gathered from an online survey conducted in 2022. The patient input from the Gastrointestinal Society was based on responses to questionnaires collected in 2024, 2023, 2022, 2020, 2018, and 2015, and 1 focus group conducted in 2022.

When asked what UC-related complications patients were experiencing currently or had experienced within the past year, the most frequently reported complications cited by respondents in the Crohn’s and Colitis Canada input were mental health and stress (65%), followed by joint inflammation and arthritis (51%), anal fissures and hemorrhoids (40%), anemia (33%), and skin conditions and malnutrition and weight loss, both of which were reported by around 30% of respondents. In the Gastrointestinal Society input, diarrhea, bowel urgency, incontinence, abdominal pain, fever, rectal bleeding, and nausea were reported by the respondents as the common symptoms of UC. Patients from the Gastrointestinal Society input added that sustained remission or treatment response was more important than relieving any 1 symptom.

In the 2020 and 2024 surveys conducted by the Gastrointestinal Society, 33% and 29% of respondents believed their IBD was not well controlled by their current medications. While the Gastrointestinal Society indicated that corticosteroids are helpful to reduce inflammation in moderate to severe cases, it also emphasized that these medications are appropriate for short-term treatment only because they are generally not well tolerated and can have potentially serious side effects. Half of the respondents in the Crohn’s and Colitis Canada input indicated that systemic steroids are or were a burden in the management of UC, particularly among those with moderate to severe forms of UC, and among women. According to patients in the Crohn’s and Colitis Canada input who indicated managing medication use is important, having enough treatment options, understanding side effects of treatment, and minimizing steroid use were the most important aspects in the management of UC. No patients from either patient group had experience with the drug under review.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

The clinical experts indicated that the treatment goals for patients with moderately to severely active UC is to induce and maintain clinical and endoscopic remission. The experts noted that first-line therapy typically includes oral mesalamine (a 5-aminosalicylate [5-ASA]) plus corticosteroids, which is used for rapid achievement of clinical remission. Corticosteroids are not used in maintenance therapy and are avoided when used as a recurrent “rescue” medication, given the wide array of adverse effects common with their use. The experts noted that although mesalamine is effective for some patients, it is ineffective in those with more severe disease and, therefore, these patients require an alternative advanced therapy (ADT) to maintain remission. The experts noted that the challenge with currently available therapies for UC in Canada is that a portion of patients will not respond to ADT and, among the patients who experience an initial, most experience loss of response after a period of symptom relief. As such, in many patients, it is necessary to escalate the dose and try several types of therapy to maintain response and meet longer-term treatment goals. The clinical experts pointed out that multiple drug failures and ongoing progressive disease activity may lead to adverse consequences, including surgery to remove the entire colon. The experts noted there is also a gap in available oral therapies, as most current therapies are administered intravenously or subcutaneously. The clinical experts indicated that a clear sequence of medications that is optimal to treat moderate to severe UC is not yet established. In the clinical experts’ opinion, guselkumab should be available as a first-line treatment option, and experiencing failure with a previous therapy should not be a criterion for accessing the drug. The clinical experts indicated that the patients best suited for guselkumab would be those with moderately to severely active UC. The experts highlighted that patients would be identified based on clinical judgment and an examination that included a review of a patient’s history of symptoms, a biomarker evaluation, an endoscopic assessment, and a histopathological evaluation. The clinical experts indicated that in clinical practice, a combination of clinical scoring systems (e.g., full Mayo and partial Mayo scores), endoscopic outcomes, histopathological evaluation, and patient-reported HRQoL scores are used to determine whether a patient is experiencing a response or disease progression on treatment. The experts noted that patients starting a new ADT should have a clinical follow-up assessment within 14 to 16 weeks of initiating therapy. The clinical experts indicated that treatment with guselkumab should be discontinued if patients are primary nonresponders, and if patients experience disease progression (e.g., ongoing symptoms or symptom escalation) while on maintenance therapy.

Clinician Group Input

No clinician group input was received by CDA-AMC for this review.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC Reimbursement Review process. The following were identified as key factors that could potentially impact the implementation of a CDA-AMC recommendation for guselkumab:

• considerations for initiation of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy.

The clinical experts consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug programs (refer to Table 4).

Clinical Evidence

Systematic Review

Description of Studies

Two pivotal phase III double-blind randomized controlled trials (RCTs) submitted by the sponsor have been summarized in this report.

The QUASAR induction (N = 701) and maintenance (N = 568) studies met the inclusion criteria for the systematic review conducted by the sponsor. The objective of the induction study was to assess the efficacy and safety of guselkumab 200 mg IV as induction therapy versus matching placebo administered at weeks 0, 4, and 8 in adults with moderately to severely active UC. The study enrolled patients who have experienced an inadequate response or are unable to tolerate conventional therapy (i.e., 6-mercaptopurine, azathioprine, or corticosteroids) or ADT (i.e., tumour necrosis factor [TNF] antagonists, vedolizumab, or tofacitinib). Patients were required to have a modified Mayo score (MMS) of 4 to 9, a Mayo rectal bleeding score of 1 or more, and a Mayo endoscopy subscore of 2 or more. Patients were eligible for the maintenance study if they had experienced a clinical response to guselkumab or placebo treatment at weeks 12 or 24. The objective of the maintenance study was to assess the efficacy and safety of the guselkumab SC injection maintenance regimens (100 mg or 200 mg) versus matching placebo in patients who achieved clinical response with guselkumab IV induction. Patients received guselkumab 200 mg every 4 weeks, guselkumab 100 mg every 8 weeks, or placebo every 4 weeks starting at week 0 through week 44. In general, the approved Health Canada indication and reimbursement request aligned with both study populations, except that the indication is not limited to patients who have experienced an inadequate response or are unable to tolerate conventional therapy or ADT. The outcomes most relevant to the CDA-AMC review included the primary outcome of clinical remission, and secondary outcomes of endoscopic healing, clinical response and maintenance of clinical response, corticosteroid-free clinical remission (maintenance only), and Inflammatory Bowel Disease Questionnaire (IBDQ) remission, a disease-specific HRQoL measure defined as an IBDQ score of 170 or greater. For both studies, the key baseline characteristics were generally balanced between treatment groups. Patients in the induction study were predominantly white (72.5%) and male (56.9%). The median age was 39.0 years (range, 18 to 79 years), and the majority of patients were from Eastern Europe (42.2%), followed by rest of world (37.5%) and Asia (20.3%). The mean duration of disease was 7.5 years, and the mean baseline MMS was 6.9, with 64.5% of patients with severely active disease (i.e., MMS 7 to 9) and 47.8% presenting with extensive disease. At baseline, 43.1% of patients were taking corticosteroids, 20.8% were taking immunomodulatory drugs, and 72.5% were taking oral 5-ASAs, with generally similar proportions of patients across the treatment groups. Among all patients, 93.2% experienced an inadequate response or intolerance to corticosteroids and/or 6-mercaptopurine or azathioprine or experienced corticosteroid dependence. Overall, 49.1% of patients had a history of experiencing ADT failure (i.e., treatment with an anti–TNF alpha, vedolizumab, or tofacitinib) and 50.9% had a history of experiencing ADT nonfailure. At induction baseline for the patients in the maintenance study, 40% were taking corticosteroids and 22.2% were taking immunomodulatory drugs (6-mercaptopurine, azathioprine, or methotrexate), 57.7% did not have a history of experiencing an inadequate response or intolerance to ADT (of these, 94.2% were naive to ADT), and 42.3% had experienced a prior inadequate response or intolerance to ADT. At maintenance baseline, the mean MMS was 2.5; 34.2% of patients were in clinical remission and 39.1% achieved endoscopic healing.

Efficacy Results

For the induction study, the primary analysis of efficacy outcomes was conducted in the FAS, which included patients with a baseline MMS of 5 to 9 who had received at least 1 (partial or complete) dose of the study intervention. For the maintenance study, the primary analysis of efficacy outcomes was performed in the randomized FAS among treated patients who had an MMS of 5 to 9 at induction baseline. The following results are from the primary analyses.

Clinical Remission (Primary Outcome)

A greater proportion of patients in the guselkumab group (22.6%) compared with the placebo group (7.9%) achieved clinical remission at week 12, with an estimated adjusted between-group difference of 14.9% (95% confidence interval [CI], 9.9 to 19.9; P value < 0.001). The results for clinical remission were consistent across the 2 prespecified ADT-related subgroups of interest (i.e., patients who were ADT-naive versus those who had experienced ADT failure) and were in favour of guselkumab compared with placebo, with an adjusted between-group difference of 20.0% (95% CI, 11.6 to 28.3) and 8.8% (95% CI, 3.4 to 14.3), respectively.

A greater proportion of patients in the guselkumab 100 mg (45.2%) and guselkumab 200 mg (50.0%) groups compared with the placebo group (18.9%) achieved clinical remission at week 44, with an estimated adjusted between-group difference of 25.2% (95% CI, 16.4 to 33.9; P value < 0.001) and 29.5% (95% CI, 20.9 to 38.1; P value < 0.001), respectively. The results for clinical remission were consistent across the prespecified ADT-related subgroups of interest (ADT-naive versus failure of ADT) in favour of guselkumab 100 mg and 200 mg compared with placebo, with an adjusted between-group difference of 24.3% (95% CI, 12.0, 36.5) and 28.8% (16.5% to 41.1), respectively.

Endoscopic Healing

A greater proportion of patients in the guselkumab group (26.8%) compared with the placebo group (11.1%) had endoscopic healing at week 12, with an estimated adjusted between-group difference of 16.0% (95% CI, 10.5 to 21.4; P value < 0.001). The results for clinical remission were consistent across the prespecified subgroups of interest, ADT-naive and failure of ADT, in favour of guselkumab compared with placebo (data not shown).

A greater proportion of patients in the guselkumab 100 mg (49.5%) and guselkumab 200 mg (51.6%) groups compared with the placebo group (18.9%) had endoscopic healing at week 44 of the maintenance study, with an estimated adjusted between-group difference of 29.5% (95% CI, 20.7 to 38.3; P value < 0.001) and 31.1% (95% CI, 22.5 to 39.8; P value < 0.001), respectively.

Clinical Response

Overall, 77.2% (n = 325) of patients achieved a clinical response at week 12 or week 24. Among the patients who were not in clinical response at week 12 with IV guselkumab and received SC guselkumab treatment (n = 125), 55.2% (n = 69) achieved a clinical response at week 24. A greater proportion of patients in the guselkumab 200 mg group (61.5%) compared with the placebo group (27.9%) experienced clinical response at week 12, with an estimated adjusted between-group difference of 33.8% (95% CI, 26.9 to 40.7; P value < 0.001).

A greater proportion of patients in the guselkumab 100 mg (77.7%) and guselkumab 200 mg (74.7%) groups compared with the placebo group (43.2%) continued to experience clinical response at week 44, with an estimated adjusted between-group difference of 33.6% (95% CI, 24.5 to 42.7; P value < 0.001) and 30.7% (95% CI, 21.5 to 40.0; P value < 0.001), respectively.

Corticosteroid-Free Clinical Remission

A greater proportion of patients in the guselkumab 100 mg (45.2%) and guselkumab 200 mg (48.9%) groups compared with the placebo group (18.4%) achieved clinical remission and were corticosteroid-free at week 44 of the maintenance study, with an estimated adjusted between-group difference of 25.7% (95% CI, 17.0 to 34.5; P value < 0.001) and 29.0% (95% CI, 20.5 to 37.6; P value < 0.001), respectively.

HRQoL Measured by IBDQ-Defined Remission

A greater proportion of patients in the guselkumab group (51.3%) compared with the placebo group (29.6%) achieved IBDQ remission at week 12, with an estimated adjusted between-group difference of 21.9% (95% CI, 14.9 to 29.0; P value < 0.001).

A greater proportion of patients in the guselkumab 100 mg (64.4%) and guselkumab 200 mg (64.2%) groups compared with the placebo group (37.4%) achieved IBDQ remission at week 44 of the maintenance study, with an estimated adjusted between-group difference of 26.3% (95% CI, 16.8 to 35.7; P value < 0.001) and 25.9% (95% CI, 16.5 to 35.4; P value < 0.001), respectively.

Subgroup and Sensitivity Analyses of Key Secondary Outcomes

For both studies, the results for endoscopic healing, clinical response, corticosteroid-free clinical remission (maintenance only), and IBDQ remission were consistent across the prespecified ADT-related subgroups of interest (ADT-naive and failure of ADT) in favour of guselkumab compared with the placebo group (data not shown). For both studies, the results of the sensitivity analyses were consistent with the those of the primary analyses.

Harms Results

In the induction study, 49.4% and 49.3% of patients reported at least 1 treatment-emergent adverse event (TEAE) in the guselkumab and placebo groups, respectively. Over the 12-week treatment period, the most frequently reported TEAEs in the guselkumab and placebo groups were anemia (5.0% and 6.8%, respectively), COVID-19 (5.0% and 4.3%), headache (3.1% and 2.9%), and colitis ulcerative (2.4% and 8.2%). Of these TEAEs, a numerically higher proportion of UC was reported in patients taking placebo. In the maintenance study, 64.5%, 70.0%, and 68.2% of patients reported at least 1 TEAE in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups, respectively. Over the 44-week treatment period, the most frequently reported TEAEs in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups were UC (9.1%, 13.2%, and 29.7%, respectively) and COVID-19 (12.9%, 9.5%, and 14.1%). Of these TEAEs, a numerically higher proportion of colitis ulcerative was reported in patients taking placebo. In the induction study, 2.9% and 7.1% of patients reported at least 1 serious TEAE in the guselkumab and placebo groups, respectively. In the maintenance study, 2.7%, 6.3%, and 0.5% of patients reported at least 1 serious TEAE in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups, respectively. In the induction study, 1.7% and 3.9% of patients reported at least 1 TEAE leading to discontinuation of treatment in the guselkumab and placebo groups, respectively. In the maintenance study, 3.8%, 2.6%, and 6.8% of patients reported at least 1 TEAE leading to discontinuation of treatment in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups, respectively. In the induction study, 1 and 2 deaths were reported in the guselkumab and placebo groups, respectively. There were no deaths reported in the maintenance study. In the induction study, the incidence of notable TEAEs, which included infections and serious infections, were similar between groups. Infections were reported in approximately 15% of patients and serious infections were reported in approximately less than 1% of patients in both groups. In the maintenance study, the incidence of notable infections and serious infections was also similar between groups. Infections were reported in approximately 32% of patients in all groups, and serious infections were reported in approximately 1% of patients in the guselkumab groups and 0 patients in the placebo group. No cases of active tuberculosis were reported in either study.

Critical Appraisal

Both the induction and maintenance studies were randomized, double-blind, placebo-controlled, parallel-group trials. Randomization and allocation concealment for both studies were performed using appropriate methodology via an interactive web response system. Randomization stratification was prespecified and was based on relevant prognostic factors, i.e., whether ADT had failed previously, region, and concomitant use of corticosteroids at baseline for the induction study, and clinical remission status at maintenance baseline, concomitant use of corticosteroids at maintenance baseline, and induction treatment for the maintenance study. Overall, the baseline demographic and disease characteristics appeared to be reasonably balanced between treatment groups in both studies. For the induction study, patients were eligible and enrolled if they had a baseline MMS of 4 to 9, and those with a baseline MMS of 4 were capped at 5% or less. However, according to the sponsor, the statistical analysis plan was amended per “health authority request” (on April 26, 2022, after patient enrolment) for the primary efficacy and safety analyses to include randomized and treated patients with a baseline MMS of 5 to 9. As a result, a total of 34 patients with a baseline MMS of 4 were excluded from the FAS primary efficacy and safety analyses, which could have compromised randomization. In general, the CDA-AMC review team and the clinical experts consulted by CDA-AMC did not consider this exclusion to have an important impact on study results because the patient characteristics appeared to be balanced between the treatment groups, and the findings of the supplementary analyses that included those with an MMS of 4 were consistent with the primary analyses. Overall, the statistical methods used in both studies were appropriate. The studies were powered sufficiently for primary and key secondary outcomes between the treatment groups. The subgroup analyses were 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 IBDQ remission and the subgroup analyses. The sponsor noted that based on feedback from the FDA, IBDQ remission was not included in the US-specific hierarchal testing procedure. Rates of study discontinuation were generally low in both studies and similar between groups although, in the induction study, the rate in the placebo group (12.9%) was higher than the guselkumab group (5.5%), mostly attributed to withdrawal by patients. Nonresponder imputation was used for missing data in the primary analysis, and preplanned sensitivity analyses were done under different assumptions, which were considered appropriate by the CDA-AMC review team.

In general, the study populations align with the approved Health Canada indication and reimbursement request, except that the indication is not limited to patients who have experienced an inadequate response or an ability to tolerate ADT or conventional therapy. The clinical experts did not consider the broader indication to affect the generalizability of the findings from the induction and maintenance studies. The dosing and administration of guselkumab were consistent with the approved product monograph. According to the clinical experts, the patient eligibility criteria and baseline characteristics of both studies were generalizable to adults with moderately to severely active UC in the Canadian setting. There were 8 and 6 patients from Canada included in the induction and maintenance studies, respectively. There was a relatively high rate of unsuccessful screenings in the induction study (269 out of 1,005 patients were screened out), mainly due to not meeting eligibility criteria. The clinical experts did not regard this as a factor that might influence the generalizability of the studies’ results. The studies included outcomes that were important to patients and clinicians, including clinical remission, clinical response, corticosteroid-free clinical remission, and HRQoL.

GRADE Summary of Findings and Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform the deliberations of the CDA-AMC expert committee, and a final certainty rating was determined as outlined by the GRADE Working Group.

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer 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 reference points for the certainty-of-evidence assessment for clinical remission, endoscopic healing, clinical response and maintenance of clinical response, corticosteroid-free clinical remission, and HRQoL measured via IBDQ remission were set according to the presence or absence of an important effect based on thresholds informed by the clinical experts consulted for this review.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• remission and response (clinical remission, endoscopic healing, clinical response and maintenance of clinical response, and corticosteroid-free clinical remission)

• HRQoL outcome (IBDQ remission).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for guselkumab versus placebo.

Table 2: Summary of Findings for Guselkumab vs. Placebo for Patients With Moderately to Severely Active Ulcerative Colitis — Induction and Maintenance Studies

CI = confidence interval; FAS = full analysis set; IBDQ = Inflammatory Bowel Disease Questionnaire; NA = not applicable; RCT = randomized controlled trial; SC = subcutaneous; vs. = versus.

Notes: 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.

^aFor clinical remission, clinical response, and IBDQ remission, between-group absolute risk differences of 7.5% and 10% (75 and 100 fewer or more events per 1,000 patients) at 12 and 44 weeks, respectively, were clinically important, according to the clinical experts. The point estimate and entire CI exceeded the threshold.

^bFor endoscopic healing at 12 weeks, the clinical experts could not determine a minimal important difference, so the target of the certainty appraisal was any effect. The point estimate and entire CI exceeded the null in favour of guselkumab.

^cFor endoscopic healing at 44 weeks, a between-group absolute risk difference of 10% (100 fewer or more events per 1,000 patients) was clinically important, according to the clinical experts. The point estimate and entire CI exceeded the threshold.

^dFor corticosteroid-free clinical remission at 44 weeks, a between-group absolute risk difference of 15% (150 fewer or more events per 1,000 patients) was clinically important, according to the clinical experts. The point estimate and entire CI exceeded the threshold.

Sources: QUASAR induction and maintenance Clinical Study Reports.^1,2 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Comparisons

One network meta-analysis (NMA) was submitted by the sponsor to inform the pharmacoeconomic model and fill gaps in the comparative evidence for other treatments of interest for moderately to severely active UC.

Description of Studies

The sponsor undertook a feasibility assessment to ascertain the extent of clinical heterogeneity across the trials identified in the systematic literature review. Trial design characteristics, patient eligibility criteria, baseline patient characteristics, outcome characteristics (i.e., definitions and methods of reporting outcomes), and placebo response were considered sources of clinical heterogeneity and explored in the feasibility assessment. Based on the feasibility assessment, an NMA was used for the outcomes of clinical remission and clinical response for induction and maintenance treatments (1-year analysis). The NMA assessed the induction and maintenance treatment effects of guselkumab versus adalimumab, infliximab, tofacitinib, upadacitinib, mirikizumab, vedolizumab, etrasimod, ozanimod, and ustekinumab for the treatment of adults with moderately to severely active UC. Some comparators were not relevant to Canadian public payers (e.g., risankizumab, filgotinib) and have therefore been excluded from the Clinical Review. A Bayesian NMA was conducted as the primary analysis of outcomes using an ordinal regression model to estimate odds ratios (ORs) and 95% credible intervals (CrIs). Random-effects NMA results were summarized for both induction and maintenance therapy based on 2 distinct patient populations: those who had experienced the failure of ADT and those who had not experienced ADT failure. The model fit of the induction results was adjusted by a baseline response due to placebo, but it was not possible to fit the same model in the maintenance phase (1-year analysis); therefore, the results presented are unadjusted.

Efficacy Results

The results for clinical remission at induction in the ADT nonfailure population did not favour any particular treatment (i.e., 95% CrIs crossed the null), and the results for the ADT failure population favoured upadacitinib versus guselkumab 200 mg. For clinical remission at maintenance in the ADT nonfailure population, the results favoured guselkumab 200 mg versus adalimumab and golimumab, and the results for the ADT failure population showed no difference between treatments. The results for clinical response at induction in the ADT nonfailure population favoured guselkumab 200 mg versus golimumab and adalimumab, and the results for the ADT failure population favoured guselkumab versus adalimumab. For clinical response at maintenance in the ADT nonfailure population, the results favoured guselkumab 100 mg and 200 mg versus adalimumab, and the results for the ADT failure population showed no difference between treatments.

There were several notable sources of heterogeneity for potential effect modifiers across the included studies. These included trial design characteristics, patient eligibility criteria, baseline patient characteristics, and definitions and methods of reporting outcomes. In addition, beyond the induction phase, the sponsor noted that although placebo is a common comparator across the majority of the included trials, placebo groups across re-randomized studies may not be equivalent due to variation in the treatments received during the preceding induction phase. The magnitude and direction of potential bias due to the heterogeneity of the outcome estimates cannot be predicted.

Harms Results

Harms were not assessed in the NMA.

Critical Appraisal

The methods used to conduct the systematic literature review and NMA were prespecified with an a priori protocol and used appropriate criteria to search databases, select studies, extract data, and assess the risk of bias of the included studies. Selection bias is expected to be low, given the comprehensiveness of the searches and methods for study selection. The NMA included relevant outcomes identified by the CDA-AMC team (clinical remission and clinical response); however, clinical and patient-relevant outcomes, such as endoscopic healing, corticosteroid-free clinical remission, HRQoL, and harms, were not included in the comparisons. The majority of comparators within the evidence network were informed by a single study, resulting in a star-shaped network and limiting certainty in the assumptions of the analysis.

Heterogeneity was noted across the studies, and while the meta-regression random-effects model accounts for some source of heterogeneity, there is a risk of the exchangeability assumption being validated. Specifically, potential effect modifiers across the included studies that could not be controlled for. Identified variables of concern included trial design characteristics, patient eligibility criteria, baseline patient characteristics, and outcome characteristics (i.e., definitions and methods of reporting outcomes). Variations in placebo effect estimates across the studies support these concerns about heterogeneity as well as concerns about possible violations of the assumptions of transitivity for the NMA. In addition, beyond the induction phase, the sponsor noted that although placebo is considered to be a common comparator across the majority of included trials, placebo arms across re-randomized trials may not be equivalent due to variation in the treatments received during the preceding induction phase. In particular, carryover effects observed due to previous treatments are likely to vary based upon treatment mechanism, potentially constituting a substantial source of cross-trial heterogeneity, which is evidenced in part by variations in baseline risk across included trials.

The specified model, while referred to as ordinal regression, is a multinomial regression that removes correlations between the outcomes of response and remission and estimates an OR for each outcome individually against no response or remission. Furthermore, the model structures the data such that the response outcome used a definition that is different from the one used in the clinical trial setting, where it is defined as response without remission. This redefinition introduces a core issue in that the response outcome is defined conditionally on a separate outcome that can occur at a future date; thus, whether an improvement in response rate due to treatment is a benefit or a harm becomes unclear. Ultimately, the interpretation of the ordinal ORs when the model assumptions are violated can create a misleading impression of how the outcomes and treatments are related. Due to the limitations in the NMA, the relative treatment effects of guselkumab versus other relevant comparators is uncertain and there is no conclusive evidence of a preferred treatment, based on the reported results.

Studies Addressing Gaps in the Evidence From the Systematic Review

No additional studies were submitted by the sponsor.

Conclusions

Evidence from 2 phase III double-blind RCTs (QUASAR induction and maintenance studies) reported on outcomes that were important to both patients and clinicians. The studies showed a high certainty of evidence that treatment with guselkumab results in a clinically meaningful increase in clinical remission, endoscopic healing, clinical response and maintenance of clinical response, corticosteroid-free clinical remission (maintenance only), and HRQoL via IBDQ remission at 12 weeks (induction therapy) and 44 weeks (maintenance therapy) compared with placebo in adults with moderately to severely active UC. Although the approved Health Canada indication is for a population that is broader than the patient populations enrolled in the studies (i.e., patients who had experienced an inadequate response or were unable to tolerate ADT or conventional therapy), the clinical experts consulted by CDA-AMC did not consider the indication to affect the generalizability of the findings. No new safety signals were identified, and the safety of guselkumab was consistent with the known safety profile of the drug. Due to limitations of the indirect treatment comparison (ITC), mostly attributed to the heterogeneity across studies, no conclusions can be drawn on the relative efficacy and safety of guselkumab versus other relevant comparators.

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 guselkumab (Tremfya) 200 mg for induction, administered by IV infusion, followed by guselkumab 100 mg for maintenance, administered by SC injection, for the treatment of adults with moderately to severely active UC.

Disease Background

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

IBD is a group of diseases characterized by chronic recurrent, progressive inflammation of the GI tract.³ There are 2 main types of IBD: CD and UC. UC is a chronic disease characterized by inflammation and ulcers in the mucosal layer of the large intestine (colon), typically beginning at the rectum (anus), progressing upward and, in some cases, affecting the entire colon.^4-6 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.⁷ Patients with UC present with the following symptoms: blood in the stool with mucus, frequent diarrhea, loss of appetite, and tenesmus (strong urge to use the bathroom without necessarily having a bowel movement), in addition to abdominal pain, rectal bleeding, and weight loss.^8-10 Although UC principally affects the GI tract, extraintestinal manifestations may also occur, such as arthritis.¹¹ There is no notable difference in the incidence of UC among male and female patients.¹² UC generally develops in young adulthood¹³ and persists throughout life, marked by periods of spontaneous remission and relapse.¹⁴ UC has a worldwide annual incidence rate of 1.2 to 20.3 cases per 100,000 people and a prevalence of 7.6 to 246.0 cases per 100,000 people.⁸ The prevalence for UC in Canada in 2023 was estimated to be 414 per 100,000.¹⁵ It is estimated that 32% to 46% of the people in Canada with UC have moderate disease, and 13% to 14% have severe disease.¹⁶

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 increased mortality compared with the general population.¹⁷ About 30% to 60% of UC patients first present with isolated proctitis (involvement is limited to the rectum).^18,19 Patients with proctitis are prone to proximal extension, which is associated with more colon involved in active disease, higher colectomy rates, increased need for ADT, and higher hospitalization rates than patients who start with extensive colitis.^18,20,21 Among patients with isolated proctitis who are untreated for 1 year, the relapse rate is between 47% and 86%.²²

UC can be further classified in clinical practice based on severity: mild, moderate, or severe disease, depending on the specific index score used (Truelove and Witts severity index, Mayo score, or the Montreal classification).²³ While most patients have a mild to moderate disease course, about 10% to 15% experience an aggressive course of UC.¹³ Relapse is common, with the cumulative risk of relapse being 70% to 80% at 10 years.¹³ Achieving endoscopic healing earlier may be associated with a reduced risk of future colectomy.¹³ The chronic nature of UC has a considerable impact on patients’ HRQoL, including psychological, physical, sexual, and social domains of HRQoL due to the chronicity of symptoms such as urgency and frequency, and incontinence.^24,25 The medical and surgical treatments for UC (e.g., colectomies) and their potential accompanying complications can also negatively impact HRQoL and productivity.^26-30 Individuals with UC are at greater risk of comorbid anxiety, depression, and impaired social interactions.^24,25,31,32 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.^27,33-35 Furthermore, the disease can impact the patients’ caregivers and family, workplace, and community.¹⁷

Standards of Therapy

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

The clinical experts consulted by CDA-AMC noted that short- and long-term treatment priorities for adults with moderately to severely active UC are to induce and maintain clinical remission (i.e., improve symptoms) and mucosal healing, reduce the use of corticosteroids, minimize adverse events (AEs), and improve HRQoL. The current standard of care for first-line treatment is oral corticosteroids but, due to their adverse effects, they are used only for inducing remission.^36,37 To maintain remission, thiopurines (e.g., azathioprine and 6-mercaptopurine), 5-ASAs, anti-TNF therapy, or vedolizumab can be used.^36,37 If 5-ASAs, corticosteroids, or thiopurines are ineffective or not tolerated, ADTs are considered (e.g., TNF antagonists, Janus kinase inhibitors, interleukin [IL]-23 inhibitors). However, most Canadian drug plans require unsuccessful steroid tapering with azathioprine or 6-mercaptopurine before a patient with moderately to severely active UC can be eligible for a biologic. As such, ADTs are typically not used for first-line maintenance of steroid-induced remission.³⁷

For patients in whom 5-ASAs, corticosteroids, or thiopurines have not induced or maintained remission or are not tolerated, ADTs 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).^36,37 However, clinical practice has evolved since then, and the clinical experts consulted by CDA-AMC noted that early introduction of effective ADT is important for patient benefit, particularly for avoiding the adverse effects of recurrent or prolonged courses of steroids. The clinical experts and sponsor noted there are currently no Canadian guidelines to assist with the sequencing of ADTs; therefore, the choice of which ADT to prescribe is dependent on the patient’s disease characteristics, comorbidities, and preferences. Patients who experience treatment failure or loss of response or are intolerant to 1 advanced treatment would be offered a different drug, potentially in a different medication class with a different mechanism of action. If these therapies fail to keep a patient’s UC in complete remission, colectomy (removal of all or a part of the colon) may be required.

Drug Under Review

Key characteristics of guselkumab and other treatments available for moderately to severely active UC in adult patients are summarized in Table 3.

The reimbursement criteria requested for guselkumab is for the treatment of adult patients with moderately to severely active UC. In general, the reimbursement request aligns with the approved Health Canada indication, except that the indication is not limited to patients who have experienced an inadequate response or are unable to tolerate conventional therapy or ADT. Other Health Canada indications for guselkumab included plaque psoriasis and psoriatic arthritis; guselkumab received a CADTH recommendation for reimbursement with conditions for both indications.

The recommended induction dosage for UC is 200 mg of guselkumab IV administered by IV infusion over a period of at least 1 hour at week 0, week 4, and week 8. The recommended maintenance dosage for UC is 100 mg of guselkumab administered by SC injection at week 16 and every 8 weeks thereafter after completion of induction dosing. A dose of 200 mg administered by SC injection at week 12 and every 4 weeks thereafter may be considered for patients who do not show adequate therapeutic benefit to guselkumab, or according to clinical judgment.

Guselkumab is a human immunoglobulin G1 lambda monoclonal antibody that selectively binds to the p19 subunit of IL-23,³⁸ which is a cytokine implicated in IBD pathogenesis because it drives intestinal inflammation.³⁹ Guselkumab blocks the binding of extracellular IL-23 to the cell-surface IL-23 receptor, inhibiting IL-23–mediated intracellular signalling, activation, and production of inflammatory cytokines involved in IBD pathogenesis, such as IL-17A, IL-17F, and IL-22.⁴⁰

Table 3: Key Characteristics of Guselkumab 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; 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.

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

^aHealth Canada–approved indication.

Sources: Product monographs.^41-64

Perspectives of Patients, Clinicians, and Drug Programs

The full patient group submissions received are available in the consolidated patient group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

Two patient groups, Crohn’s and Colitis Canada and the Gastrointestinal Society provided input for guselkumab for the treatment of UC. Patient input for Crohn’s and Colitis Canada was gathered from an online survey conducted in 2022, including responses from 1,706 patients in Canada with CD or UC and their caregivers. A total of 354 patients from this survey identified as having moderate to severe UC. Patient input for the Gastrointestinal Society was based on responses to questionnaires conducted in 2024, 2023, 2022, 2020, 2018, and 2015, and 1 focus group conducted in 2022. A total of 514 respondents from Canada completed the 2024 survey about the unmet needs of individuals living with IBD, along with a follow-up survey focusing on opinions regarding biologics and biosimilars completed by 55 respondents. A total of 7 respondents (nationality not indicated) and 54 respondents with IBD from Canada completed the 2023 and 2022 surveys, respectively. For the 2020 survey, 145 respondents, most of whom had IBD (some had other inflammatory conditions), completed the survey on biosimilars, whereas 579 respondents completed the survey regarding the unmet needs of IBD. A total of 432 respondents with IBD from Canada completed the 2018 survey on the unmet needs in IBD, and 423 respondents from Canada with IBD, including CD and UC, completed the 2015 survey on biologics and biosimilars (then called subsequent-entry biologics).

When asked what UC-related complications patients were experiencing currently or had experienced within the past year, the most frequently reported complications cited by respondents in the Crohn’s and Colitis Canada input were mental health and stress (65%), followed by joint inflammation and arthritis (51%), anal fissures and hemorrhoids (40%), anemia (33%), and skin conditions and malnutrition and weight loss, both of which were reported by around 30% of respondents. Other complications reported by the respondents in this input included strictures, adhesions (scar tissue), bowel obstruction, eye inflammation, perianal or anal fistulas and abscesses, internal (or intra-abdominal) fistulas or abscesses, stricture, ankylosing spondylitis (arthritis of the spine), liver conditions, and cancer. On the other hand, diarrhea, bowel urgency, incontinence, abdominal pain, fever, rectal bleeding, and nausea were reported by the respondents in the Gastrointestinal Society input as the common symptoms of UC. Respondents from this input also reported a profound effect on an individual’s life — physically, emotionally, and socially, both at home and at school or in the workplace. Respondents also indicated that the severity of the disease could fluctuate, making it necessary to go through routine testing, reassessments, and medication changes. The Gastrointestinal Society input further added that UC is particularly difficult for children and young adults because it often affects a person’s sense of self. Patients from the Gastrointestinal Society input added that sustained remission or treatment response was more important than relieving any 1 symptom.

In the 2022 survey conducted by Crohn’s and Colitis Canada, most patients reported using a combination of medications to manage their disease, with systemic steroids (79%), sulfasalazine and 5-ASAs (76%), and biologics (57%) being most common among those with UC, followed by immunomodulators (45%), antibiotics (42%), and nonsystemic steroids (38%). In the 2020 and 2024 surveys conducted by the Gastrointestinal Society, 33% and 29% of respondents believed their IBD was not well controlled by their current medications. Among the surveyed patients in the Crohn’s and Colitis Canada input, more than half (56%) of the respondents believed that different treatment options could make them feel better. Both patient groups emphasized that patients affected by UC need access to medications that work and can mitigate symptoms. The Gastrointestinal Society input further elaborated the importance of having a variety of options, keeping in mind that patients experience different responses to various medications and, in some cases, stop experiencing a response to medications after using them for some time.

While the Gastrointestinal Society indicated that corticosteroids are helpful for reducing inflammation in moderate to severe cases, it also emphasized that these medications are appropriate for short-term treatment only because they are generally not well tolerated and can have potentially serious side effects. Half of the respondents in the Crohn’s and Colitis Canada input indicated that systemic steroids are or were a burden in the management of UC, particularly among those with moderate to severe forms of UC, and among women. According to patients in the Crohn’s and Colitis Canada input who indicated that managing medication use is important, having enough treatment options, understanding the side effects of treatments, and minimizing steroid use were the most important aspects in the management of UC.

No patients from either patient group had experience with the drug under review. However, the Gastrointestinal Society reported conducting several patient surveys on biologics and biosimilars across several disease areas. In 1 of the surveys conducted by this group, 63% of respondents reported symptom reduction while receiving a biologic and 23% reported confirmed remission. In the 2024 survey on IBD conducted by the Gastrointestinal Society, 30% of respondents indicated they had no preferred route of administration and 41% preferred a daily oral medication; monthly injections were less preferred.

Clinician Input

Input From the Clinical Experts Consulted by CDA-AMC

All CDA-AMC 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 2 clinical specialists with expertise in the diagnosis and management of moderately to severely active UC.

Unmet Needs

The clinical experts indicated that the treatment goals for patients with moderately to severely active UC is to induce and maintain clinical and endoscopic remission. The experts noted that first-line therapy typically includes oral mesalamine (a 5-ASA) plus corticosteroids, which are used for rapid achievement of clinical remission. Corticosteroids are not used in maintenance therapy and are avoided for use as a recurrent “rescue” medication, given the wide array of adverse effects common to their use. The experts noted that although mesalamine is effective for some patients, it is ineffective in those with more severe disease and, therefore, these patients require an alternative ADT to maintain remission. The experts noted that the challenge with currently available therapies for UC in Canada is that a portion of patients will not respond to ADT and, among the patients who experience a response initially, most experience a loss of response after a period of symptom relief. As such, in many patients, it is necessary to escalate the dose and try several types of therapy to maintain response and meet longer-term treatment goals. The clinical experts pointed out that multiple drug failures and ongoing progressive disease activity may lead to adverse consequences, including surgery to remove the entire colon. The experts noted there is also a gap in available oral therapies, given that most current therapies are administered intravenously or subcutaneously.

Place in Therapy

The clinical experts indicated that a clear sequence of medications that is optimal to treat moderate to severe UC is not yet established. In the clinical experts’ opinion, guselkumab should be available as a first-line treatment option, and failure of previous therapy should not be a criterion to access the drug. They noted that corticosteroids would commonly be used to induce response or remission before the initiation of guselkumab, but corticosteroids have recognized limitations and are not an option for long-term maintenance therapy.

Patient Population

The clinical experts agreed that the patients best suited for guselkumab would be those with moderately to severely active UC. The experts highlighted that patients would be identified based on clinical judgment and an examination that included a review of a patient’s history of symptoms, a biomarker evaluation, an endoscopic assessment, and a histopathological evaluation.

Assessing the Response Treatment

The clinical experts indicated that in clinical practice, a combination of clinical scoring systems (e.g., full Mayo and partial Mayo scores), endoscopic outcomes, histopathological evaluation, and patient-reported HRQoL scores is used to determine whether a patient is experiencing a response or disease progression on treatment. They also noted that biomarkers (most commonly fecal calprotectin) are used to monitor ongoing treatment response and maintenance therapy. The experts noted that patients starting a new ADT should have a clinical follow-up assessment within 14 to 16 weeks of initiating therapy. This could include biomarker evaluation in addition to the clinical assessment.

Discontinuing Treatment

The clinical experts indicated that treatment with guselkumab should be discontinued if patients are primary nonresponders, and if patients experience disease progression (e.g., ongoing symptoms or symptom escalation) while on maintenance therapy. The experts noted that disease progression while on guselkumab maintenance therapy would not necessarily mean the medication needs to be discontinued, and that further clinical assessment would be required to determine whether discontinuation is warranted. They also noted that anaphylactic reactions would necessitate discontinuation of the medication.

Prescribing Considerations

The clinical experts indicated that patients receiving guselkumab should be under the care of a gastroenterologist or general internist with experience in the treatment of IBD. They noted it would be reasonable for patients to receive the therapy in any clinical setting, including outpatient.

Clinician Group Input

No clinician group input was received by CDA-AMC for this review.

Drug Program Input

The drug programs provide input on each drug being reviewed through CDA-AMC Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. Their implementation questions and the corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 4.

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

ADT = advanced therapy; CDEC = Canadian Drug Expert Committee; PLA = product listing agreement; SC = subcutaneous; TNF = tumour necrosis factor; UC = ulcerative colitis.

Clinical Evidence

The objective of this CDA-AMC Clinical Review is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of guselkumab 200 mg for induction, administered by IV infusion, followed by 100 mg of guselkumab for maintenance, administered by SC injection, for the treatment of adults with moderately to severely active UC. The focus will be placed on comparing guselkumab with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of guselkumab is presented in 4 sections, with the CDA-AMC 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. The CDA-AMC 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 would typically include long-term extension studies; however, none were submitted by the sponsor. The third section includes indirect evidence from the sponsor. The fourth section would typically include additional studies to address important gaps in the systematic review evidence; however, none were submitted by the sponsor.

Included Studies

Clinical evidence from the following is included in the CDA-AMC review and appraised in this document:

• 2 pivotal trials identified in the systematic review

• 1 ITC.

Systematic Review

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

Description of Studies

Characteristics of the included studies are summarized in Table 5. The QUASAR trial consists of 3 separate studies conducted under a single protocol: a phase II induction dose-ranging study, a phase III induction study,¹ and a phase III maintenance study.² For the purpose of this review, the phase III induction (referred to herein as the induction study) and maintenance studies are summarized. The phase II dose-ranging study was not included in this review because some of the doses did not match the recommended dose for the approved indication, the sample size was substantially smaller than the phase III study sample size, and the outcomes between the studies overlapped. It should be noted that clinical responders from both the phase II and phase III induction studies were included in the maintenance study. The study designs of the induction and maintenance studies are depicted in Figure 1. The focus of the approved Health Canada indication and reimbursement request is generally aligned with the phase III induction and maintenance study populations, except that the indication is not limited to patients who have experienced an inadequate response or are unable to tolerate ADT or conventional therapy.

Induction

The QUASAR phase III induction study is a randomized, double-blind, parallel-group, multicentre trial that aimed to evaluate the efficacy and safety of guselkumab 200 mg IV as induction therapy versus matching placebo administered at weeks 0, 4, and 8 in adults with moderately to severely active UC.¹ Using a permuted block design, enrolled patients were randomly assigned via an interactive web response system in a 3:2 ratio (N = 736 patients from 240 sites) to receive guselkumab 200 mg IV (N = 421) or placebo IV (N = 280). There were 8 patients included from 4 Canadian sites. Randomization was stratified by ADT failure status (yes or no), region (Eastern Europe, Asia, or rest of world), and concomitant use of corticosteroids at baseline (yes or no). The trial included an 8-week screening phase and a treatment phase; patients could become eligible for the maintenance study if they had demonstrated a clinical response to guselkumab or placebo treatment at week 12 or week 24. At the follow-up phase, nonresponders at week 24 stopped treatment and had a safety follow-up 12 weeks after their last intervention dose. The date of the last observation recorded as part of the database lock was January 12, 2023.

Maintenance

The QUASAR phase III maintenance study is a randomized, double-blind, parallel-group, multicentre trial that aimed to evaluate the efficacy and safety of guselkumab SC injection maintenance regimens (100 mg or 200 mg) versus matching placebo in patients who experienced a clinical response with guselkumab IV induction treatment in either the phase II or phase III induction study.² Patients were randomized via an interactive web response system in a 1:1:1 ratio to guselkumab 200 mg (N = 190) every 4 weeks, guselkumab 100 mg (N = 188) every 8 weeks, or placebo (N = 190) every 4 weeks starting at week 0 and continuing through week 44. There were 6 patients included from 3 Canadian sites. Patients were allocated to an intervention group using permuted block randomization stratified by clinical remission status at maintenance baseline (yes or no), concomitant use of corticosteroids at maintenance baseline (yes or no), and induction treatment: guselkumab 400 mg IV, guselkumab 200 mg IV, and placebo IV or guselkumab 200 mg IV (placebo crossover). The date of the last observation recorded as part of the database lock for the maintenance study was September 19, 2023. Patients who completed the safety and efficacy evaluations (including the required endoscopy procedure) at week 44 and who, in the opinion of the investigator, might benefit from continued study intervention, entered the long-term extension of the maintenance study.

Table 5: Details of Studies Included in the Systematic Review

EQ VAS = EQ visual analogue scale; IBDQ = Inflammatory Bowel Disease Questionnaire; LTE = long-term extension; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; SC = subcutaneous; TNF = tumour necrosis factor; UC = ulcerative colitis.

^aAdvanced therapy is considered to be treatment with 1 or more TNF alpha antagonists or vedolizumab or tofacitinib at a dose approved for the treatment of UC.

Sources: QUASAR induction and maintenance Clinical Study Reports.^1,2 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Figure 1: Study Design of QUASAR Induction and Maintenance Trials

I = induction; LTE = long-term extension; q4w = every 4 weeks; q8w = every 8 weeks; R = randomization.

^†Placebo responders at week I-12 and guselkumab 24-week responders entered the maintenance study but did not undergo re-randomization.

*Induction study 2 will not begin until the phase III guselkumab induction dose is selected based on an interim analysis of induction study 1.

Sources: QUASAR induction and maintenance Clinical Study Reports.^1,2 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Populations

Inclusion and Exclusion Criteria

A detailed description of the key inclusion and exclusion criteria for the QUASAR induction and maintenance studies is in Table 5.

Induction Study

Eligible patients were adults aged 18 years or older with moderately to severely active UC who had demonstrated an inadequate response or inability to tolerate conventional therapy (i.e., 6-mercaptopurine, azathioprine, or corticosteroids) or ADT (i.e., TNF antagonists, vedolizumab, or tofacitinib). Patients were required to have an MMS of 4 to 9, a Mayo rectal bleeding score of 1 or more, and a Mayo endoscopy subscore of 2 or more. Patients were excluded if they were hospitalized for treatment of UC, were likely to require a colectomy within 12 weeks of baseline, had required any surgery within the 2 months before screening for active GI bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess requiring surgical drainage, or any other conditions possibly modifying the evaluation of benefit from the study intervention treatment.

Maintenance Study

Patients were eligible if they had demonstrated a clinical response to induction guselkumab IV or placebo at week 12 or 24. Patients who initiated or increased the dose of a UC-specific medication (or a restricted or prohibited medication) during the induction studies were prohibited from entering the maintenance study.

Interventions

Induction Study

Guselkumab was supplied as a 100 mg/mL sterile liquid in a single-dose prefilled syringe. Placebo was supplied as a 1 mL sterile liquid in a single-dose syringe assembled in the same way as for guselkumab. The study intervention was administered intravenously at the study site over a period of no less than 1 hour and not more than 2 hours (including the flush). From week 0 through week 8, patients were randomized to either guselkumab 200 mg IV at weeks 0, 4, and 8 (i.e., 3 IV doses) or matching placebo IV.

At week 12, all patients were evaluated for clinical response. Further study intervention administration was determined by the participant's clinical response status (using the Mayo endoscopy subscore assigned by the local endoscopist) at week 12 using the following procedure:

• Guselkumab and placebo clinical responders at week 12 entered the maintenance study.

• Patients initially randomized to placebo who were not in clinical response at week 12 crossed over to guselkumab and received 3 doses of guselkumab 200 mg IV at weeks 12, 16, and 20.

At week 24, patients who were not in clinical response at week 12 were re-evaluated for clinical response and entry into the maintenance study. This included patients initially randomized to placebo who were not in clinical response at week 12 who then crossed over to guselkumab induction 200 mg IV and achieved clinical response at week 24.

Maintenance Study

Guselkumab and placebo SC was supplied in the same manner as described in the induction study. Randomized patients received 1 of the 3 following interventions:

• Guselkumab 100 mg SC every 8 weeks starting at week 4 and continuing through week 44 (1 injection at each visit). To maintain the blind, patients received 1 placebo SC injection plus 1 injection of 100 mg guselkumab or 2 placebo SC injections at alternating visits.

• Guselkumab 200 mg SC every 4 weeks at week 0 and continuing through week 44 (2 injections of 100 mg at each visit).

• Placebo SC every 4 weeks starting at week 0 and continuing through week 44. To maintain the blind, patients received 2 placebo injections at each visit.

Patients who were randomized and met predefined criteria for loss of clinical response were eligible to receive a single blinded dose adjustment to guselkumab 200 mg SC every 4 weeks beginning at a scheduled visit between week 8 and week 32. In addition, guselkumab induction responders at week 24 and induction placebo responders at week 12 from both induction studies entered the maintenance study but were not randomized. Patients remained on their assigned study intervention through week 44.

Concomitant Therapies

Patients who were receiving oral 5-ASA compounds, oral corticosteroids, 6-mercaptopurine, azathioprine, or methotrexate for the treatment of UC at baseline (i.e., week 0) were required to maintain a stable dose through week 44, except for corticosteroids. Oral corticosteroids were to be maintained at baseline doses during induction, and all patients were required to taper oral corticosteroids at week 0 of the maintenance study, unless this was medically not feasible.

Outcomes

A list of efficacy end points assessed in this Clinical Review is provided in Table 6, followed by descriptions of the outcome measures. 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 experts consulted by CDA-AMC and the input received from the patient groups and public drug plans. Using the same considerations, the review team selected end points that were considered most relevant to inform the expert committee deliberations and finalized this list in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. A description of the efficacy outcome measures and their measurement properties that were used in both the induction and maintenance studies are presented in Table 7.

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

IBDQ = Inflammatory Bowel Disease Questionnaire.

^aStatistical testing was performed hierarchically based on a US-specific testing procedure.

Sources: QUASAR induction and maintenance Clinical Study Reports.^1,2 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Clinical Remission

The primary outcome of clinical remission for the induction study at week 12 and maintenance study at week 44 was defined as a Mayo score stool frequency subscore of 0 or 1 that had not increased from induction baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. The Mayo score instrument, which was administered by an investigator, is composed of 4 parts: rectal bleeding, stool frequency, physician assessment, and endoscopy appearance. Each part is rated from 0 to 3, giving a total score of 0 to 12, with a higher score indicative of more severe symptoms. The validity, reliability, responsiveness, and minimal important difference (MID) of the Mayo score is summarized in Table 7, although the findings are not specific to patients with UC.

Endoscopic Healing

The secondary outcome of endoscopic healing for the induction study at week 12 and maintenance study at week 44 was defined as a Mayo endoscopy subscore of 0 or 1 with no friability present on the endoscopy. The endoscopic findings were assessed by the investigator (i.e., local endoscopist) during the endoscopy procedure and by a central reader reviewing a video of the endoscopy.

Clinical Response

The secondary outcome of clinical response for the induction study at week 12 was defined as a decrease from induction baseline in the MMS of 30% or more and 2 points or more, with a decrease of 1 point or more from induction baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. The MMS is the Mayo score without the Physician’s Global Assessment subscore and was calculated as the sum of the stool frequency, rectal bleeding, and endoscopy subscores. The total score ranges from 0 to 9. An MMS of 5 to 9 and 7 to 9 indicate moderate and severe active disease, respectively. Maintenance of clinical response for the maintenance study was defined as clinical response at week 44 among patients in clinical response at maintenance baseline. The validity, reliability, responsiveness, and MID of the MMS are summarized in Table 7.

Corticosteroid-Free Clinical Remission

The secondary outcome of corticosteroid-free clinical remission for the maintenance study at week 44 was defined as clinical remission (as defined previously) without any use of corticosteroids for at least 8 weeks before assessment.

IBDQ-Defined Remission

The secondary outcome of IBDQ remission at week 12 in the induction study and week 44 in the maintenance study was used to assess disease-specific HRQoL, defined as a total IBDQ score of 170 or greater. The IBDQ consists of a 32-item list that is subdivided into 4 dimensions: systemic symptoms, bowel symptoms, emotional function, and social function. Total scores range from 32 to 224, with a higher score indicating better HRQoL. The IBDQ has been shown to have good internal consistency and test–retest reliability and responsiveness to change in IBD. Available studies have suggested that an improvement of 30 points from baseline or an improvement of at least 15 points versus placebo may constitute an MID.

Harms Outcomes

The assessment of safety was based on the proportion of patients experiencing 1 or more TEAEs, serious TEAEs, TEAEs leading to discontinuation, and deaths. TEAEs were coded using the Medical Dictionary for Regulatory Activities. Notable AEs identified by the sponsor and considered important by the clinical experts included malignancy and active tuberculosis or opportunistic infections.

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; SE = standard error; SIBDQ = Short Inflammatory Bowel Disease Questionnaire; UC = ulcerative colitis; WPAI = Work Productivity and Activity Impairment questionnaire; vs. = versus.

Statistical Analysis

The statistical analysis of efficacy outcomes in the induction and maintenance studies is summarized in Table 8.

Sample Size and Power Calculation

Induction Study

The sample size for the phase III induction study was based on achieving 90% power to detect a treatment difference in the primary efficacy evaluation of clinical remission at week 12 using a 2-sided chi-square test and 0.05 significance level. Assuming an 8% clinical remission in the placebo group and 20% in the guselkumab group (assumed rates were based on data from the CNTO1275UCO3001 ustekinumab UC induction study and the mirikizumab phase II UC study), enrolling 148 patients in the placebo group and 222 patients in the 200 mg guselkumab group (370 patients in total, with a 2:3 placebo to guselkumab randomization ratio) was sufficient to achieve the prespecified statistical power.

To provide a sufficient number of patients for the primary analysis population in the maintenance study, it was estimated that a total sample size of approximately 1,000 patients across the phase II induction study and the phase III induction study was required and that the sample size for the phase III induction study would be at least 560 patients in the primary analysis population.

Maintenance Study

Assuming a 25% clinical remission rate at week 44 for placebo and 45% for each of the guselkumab treatment groups (assumed rates were based on data from the CNTO1275UCO3001 ustekinumab UC maintenance study), 118 patients in each randomized group (354 patients in total) would provide 90% power to reach a (2-sided) significance level of 0.05 for the primary outcome of clinical remission. However, the targeted number in the primary analysis population was increased to 484 patients due to the need to power at least 90% for the major secondary outcomes included in this report. The actual number of patients in the primary analysis population of this study depended on the number of guselkumab clinical responders at induction weeks 12 and 24 from the phase II and phase III induction studies.

Statistical Testing and Multiple Testing Procedures

Induction Study

The proportion of patients in clinical remission at week 12 was summarized within the treatment group, along with the associated 95% CIs. The adjusted treatment difference between treatment groups, incorporating Cochran-Mantel-Haenszel (CMH) weights and the corresponding 95% CI were also calculated. Primary outcome testing was conducted using a 2-sided CMH test, stratified by ADT failure status (yes or no) and baseline concomitant corticosteroid use (yes or no). The comparison between guselkumab and placebo was controlled at a 2-sided significance level of 0.05. Categorical data analyses, including chi-square tests, CMH chi-square tests, and logistic regression, were employed as appropriate to compare the proportions of patients achieving the specified outcomes. For continuous response parameters measured at multiple postbaseline visits, a mixed model for repeated measures was used, while an analysis of variance or analysis of covariance was applied when only 1 postbaseline visit was involved. The statistical testing strategy of the major secondary outcomes was the same as that used for the primary outcome analysis.

The hypothesis testing strategy adjusted for multiple testing by employing a fixed-sequence testing procedure to control for multiplicity across the primary and major secondary outcomes at a 2-sided 0.05 significance level. This means that after testing the primary outcome (clinical remission), the major secondary outcomes (endoscopic healing and clinical response) were tested in a specific order at the same significance level. If any outcome in this sequence was not significant, all subsequent tests were also considered not significant, and their corresponding P values were treated as nominal. Notably, the order of testing outcomes differed between the global and US strategies due to regional preferences. For example, IBDQ remission at week 12 was excluded from the US-specific testing procedure based on feedback from the FDA. For this submission, the US-specific testing procedure was presented because it was used in the Health Canada submission.

Maintenance Study

The proportion of patients achieving the primary and each key secondary outcome was summarized by treatment group, along with the associated 95% CIs. The adjusted treatment difference between treatment groups, incorporating CMH weights, and the corresponding 95% CIs were also presented. For all statistical comparisons of the primary and key secondary outcomes, a 2-sided CMH test was used, stratified by clinical remission status at maintenance baseline (based on the final endoscopy score, yes or no) and induction dose treatment. Similar to the induction study, the US-specific multiple testing procedure was used, starting with guselkumab 200 mg for clinical remission at week 44, to control the overall type I error rate at the (2-sided) 0.05 level for the primary and major secondary outcomes, except for IBDQ remission. The order of testing was as follows: clinical remission, endoscopic healing, maintenance of clinical response, and corticosteroid-free clinical remission.

Data Imputation

In both studies, any missing data for the outcomes were treated using nonresponder imputation (e.g., not in clinical remission). The patients who had an ostomy or colectomy, a prohibited change in UC medication, or discontinued the study intervention due to a lack of efficacy, an AE of worsening UC, or other reasons, except for reasons related to COVID-19 (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine, were considered to have not experienced the desired outcomes.

Subgroup Analysis

The prespecified subgroups of interest for both studies included patients who were ADT-naive and those who had experienced ADT failure. A subgroup analysis for both studies was conducted using the rate difference and 95% CIs, adjusted with CMH weights, incorporating treatment group, ADT failure status, and concomitant corticosteroid use as baseline factors. Missing values were imputed as nonresponders.

Sensitivity Analyses

The sensitivity analyses performed for the primary and secondary outcomes are summarized in Table 8.

Analysis Populations

The analysis populations are summarized in Table 9. The efficacy and safety analyses were based on the FAS and safety analysis set (SAS), respectively, which were defined as all randomized patients with an MMS of 5 to 9 who received at least 1 (partial or complete) dose of the study intervention. For the maintenance study, the FAS and SAS included patients with an MMS of 5 to 9 who were randomized and treated in the maintenance study.

Table 8: Statistical Analysis of Efficacy Outcomes

CMH = Cochran-Mantel-Haenszel; IBDQ = Inflammatory Bowel Disease Questionnaire.

Sources: QUASAR induction and maintenance Clinical Study Reports.^1,2 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 9: Analysis Populations of Induction and Maintenance Studies

FAS = full analysis set; MMS = modified Mayo score; SAS = safety analysis set.

Sources: QUASAR induction and maintenance Clinical Study Reports.^1,2 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Patient disposition for the induction and maintenance studies is summarized in Table 10 and Table 11, respectively.

Induction Study

Of the 1,005 patients screened, 736 were randomized in 240 centres across 32 countries or territories. The main reasons for unsuccessful screening were not reported. Of the 736 randomized patients, 702 had a baseline MMS of 5 to 9 and 1 patient was randomized to placebo at week 0 but was not treated because of inadequate venous access for administration of the study intervention and protocol-specified laboratory assessments. The FAS, which is the primary efficacy analysis set, comprised 701 treated patients with a baseline MMS of 5 to 9. In total, 62 patients (8.8%) in the FAS discontinued treatment. Treatment discontinuation before week 12 occurred in 18 patients (4.3%) in the guselkumab group and 24 patients (8.6%) in the placebo group. The most common reasons for treatment discontinuation for both groups were similar and consisted of AEs (2.3%) and withdrawal by participant (2.4%). In total, 20 patients discontinued the study treatment after week 12, with the most common reason being AEs (3.4%) for both groups. A total of 398 patients (94.5%) in the guselkumab group and 244 patients (87.1%) in the placebo group completed study participation.

Through week 12, a similar proportion of patients in each group had major protocol deviations (10.0% in the guselkumab group and 9.3% in the placebo group), with the most common reasons in both groups being not satisfying the study entry criteria (total of 5.6%) and “other” (total of 3.9%).

Maintenance Study

The maintenance study enrolled 846 patients, 568 of whom comprised the FAS primary analysis population of patients who had an MMS of 5 to 9 at induction baseline and who were randomized and treated. In the randomized FAS, treatment discontinuation before week 40 occurred in 20 patients (10.6%) in the guselkumab 100 mg group, 22 patients (11.6%) in the guselkumab 200 mg group, and 26 patients (13.7%) in the placebo group. The most common reasons for treatment discontinuation were similar across groups and consisted of AEs (5.1%) and withdrawal by participant for reasons other than AEs (3.3%).

Through week 44, a similar proportion of patients in each group had major protocol deviations (8.5% in the guselkumab 100 mg group, 6.3% in the guselkumab 200 mg group, and 8.4% in the placebo group), with the most common reason being “other” (total of 6.3%) in all groups.

Table 10: Summary of Patient Disposition for the Induction Study

FAS = full analysis set; NR = not reported; SAS = safety analysis set.

Sources: QUASAR induction Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 11: Summary of Patient Disposition for the Maintenance Study

FAS = full analysis set; NA = not applicable; NR = not reported; SAS = safety analysis set; SC = subcutaneous.

^aTwo patients who were randomized to the guselkumab 100 mg SC group received only placebo at week 0 (these 2 patients discontinued the study intervention before their first scheduled guselkumab dose at week 4). They were therefore included in the placebo SC treatment group for the safety analyses.

Sources: QUASAR maintenance Clinical Study Report.² Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics for the induction and maintenance studies are outlined in Table 12 and Table 13, respectively, and are limited to those that were considered most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

Induction Study

The baseline characteristics were generally similar between treatment groups. Patients were predominantly white (72.5%) and male (56.9%). The median age was 39.0 years (range, 18 to 79 years), and the median weight was 70.6 kg. The majority of patients in the FAS were from Eastern Europe (42.2%), followed by rest of world (37.5%) and Asia (20.3%). The mean duration of disease was 7.5 years, and the mean baseline MMS was 6.9, with 64.5% of patients with severely active disease (i.e., MMS of 7 to 9) and 47.8% presenting with extensive disease. At baseline, 43.1% of patients were taking corticosteroids, 20.8% were taking immunomodulatory drugs, and 72.5% were taking oral 5-ASAs, with generally similar proportions of patients across the treatment groups. Among all patients, 93.2% experienced an inadequate response or intolerance to corticosteroids and/or 6-mercaptopurine or azathioprine or experienced corticosteroid dependence. Overall, 49.1% of patients had a history of experiencing ADT failure (i.e., anti–TNF alpha, vedolizumab, or tofacitinib) and 50.9% had a history of experiencing ADT nonfailure.

Maintenance Study

Baseline characteristics in the randomized FAS were generally similar between treatment groups. At induction baseline, the majority of patients were white (73.2%) and male (54.8%). The median age was 39.0 years (range, 18 to 79 years), and the median weight was 70.0 kg. The majority of these patients were from Eastern Europe (48.4%), followed by rest of world (32.6%) and Asia (19.0%). At induction baseline, the median UC disease duration was 5.4 years, the mean MMS was 6.9 (63.9% had a score indicating severe disease, i.e., an MMS of 7 to 9), and the proportion of patients with a Mayo endoscopy subscore of 3 (severe) was 66.4%. At induction baseline, 40% of patients were taking corticosteroids and 22.2% were taking immunomodulatory drugs (6-mercaptopurine, azathioprine, or methotrexate), 57.7% did not have a history of experiencing an inadequate response or intolerance to ADT (of these, 94.2% were naive to ADT), and 42.3% had experienced a prior inadequate response or intolerance to ADT (of these, 42.5% had experienced the failure of ≥ 2 ADT classes). At maintenance baseline, the mean MMS was 2.5, 34.2% of patients were in clinical remission, and 39.1% achieved endoscopic healing.

Table 12: Summary of Baseline Characteristics for the Induction Study — FAS Population

CRP = C-reactive protein; FAS = full analysis set; SD = standard deviation; UC = ulcerative colitis.

^aSome patients were missing data; as a result, the total N does not match.

Sources: QUASAR induction Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 13: Summary of Baseline Characteristics for the Maintenance Study — Randomized FAS Population

CRP = C-reactive protein; FAS = full analysis set; IBDQ = Inflammatory Bowel Disease Questionnaire; SC = subcutaneous; SD = standard deviation; UC = ulcerative colitis.

^aSome patients were missing data; as a result, the total N does not match. Please refer to the maintenance study Clinical Study Report for the exact N.

Sources: QUASAR maintenance Clinical Study Report.² Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Induction Study

In the FAS, all patients received at least 1 (partial or complete) dose of the study intervention. A total of 290 patients who were not in clinical response at week 12 received guselkumab between week 12 and week 24 as follows: the patients who received placebo IV crossed over to guselkumab 200 mg IV (165 patients), and the patients who received guselkumab 200 mg IV crossed over to guselkumab 200 mg SC (125 patients).

Maintenance Study

Patients in the randomized SAS received the study intervention (up to the dose adjustment) as follows:

• Guselkumab 100 mg SC every 8 weeks: 186 patients received guselkumab 100 mg, with a median cumulative dose of 500.0 mg

• Guselkumab 200 mg SC every 4 weeks: 190 patients received guselkumab 200 mg, with a median cumulative dose of 2,200.0 mg

• Placebo SC: 192 patients

Concomitant Medications

Induction Study

At baseline, 612 patients (87.3%) in the FAS were receiving 1 or more concomitant medications for UC with similar proportions of patients across both treatment groups. At baseline, a total of 302 patients (43.1%) were receiving oral corticosteroids, 146 patients (20.8%) were receiving immunomodulatory drugs (i.e., azathioprine, 6-mercaptopurine, or methotrexate), and 508 patients (72.5%) were receiving oral 5-ASAs, with generally similar proportions of patients in both guselkumab treatment groups. Concomitant UC medications were to be maintained at a stable dose throughout the study.

Maintenance Study

For patients who were receiving oral corticosteroids on entry into the maintenance study, the investigator was to begin tapering the daily dose of corticosteroids at week 0. Other UC-specific therapies (i.e., oral 5-ASA compounds, 6-mercaptopurine, azathioprine, or methotrexate) were to be maintained at stable doses through week 44 (without initiation or increase in dose) unless investigator judgment required that the therapy be discontinued or the dose reduced because of toxicity or medical necessity. Tapering of the daily dose of corticosteroids was allowed to be paused for patients who met clinical flare criteria.

Efficacy

A summary of the key efficacy results for both studies is in Table 14. For the induction study, the primary analysis of efficacy outcomes was conducted in the FAS, which included patients who received at least 1 (partial or complete) dose of the study intervention who had a baseline MMS of 5 to 9. For the maintenance study, the primary analysis of the efficacy outcomes was performed in the randomized FAS among treated patients who had an MMS of 5 to 9 at induction baseline.

Clinical Remission (Primary Outcome)

Induction Study

A greater proportion of patients in the guselkumab group (22.6%) compared with the placebo group (7.9%) experienced clinical remission at week 12, with an estimated adjusted between-group difference of 14.9% (95% CI, 9.9 to 19.9; P value < 0.001).

Subgroup Analyses

The results for clinical remission were consistent across the prespecified ADT-related subgroups of interest (i.e., patients who were ADT-naive versus those who had experienced ADT failure) in favour of guselkumab compared with placebo, with an adjusted between-group difference of 20.0% (95% CI, 11.6 to 28.3) and 8.8% (95% CI, 3.4 to 14.3), respectively.

Maintenance Study

A greater proportion of patients in the guselkumab 100 mg (45.2%) and guselkumab 200 mg (50.0%) groups compared with the placebo group (18.9%) experienced clinical remission at week 44, with an estimated adjusted between-group difference of 25.2% (95% CI, 16.4 to 33.9; P value < 0.001) and 29.5% (95% CI, 20.9 to 38.1; P value < 0.001), respectively.

Subgroup Analyses

The results for clinical remission were consistent across the 2 prespecified ADT-related subgroups of interest (i.e., patients who were ADT-naive versus those who had experienced ADT failure) in favour of guselkumab 100 mg and 200 mg compared with placebo, with an adjusted between-group difference of 24.3% (95% CI, 12.0 to 36.5) and 28.8% (16.5% to 41.1), respectively.

Endoscopic Healing

Induction Study

A greater proportion of patients in the guselkumab group (26.8%) compared with the placebo group (11.1%) had endoscopic healing at week 12, with an estimated adjusted between-group difference of 16.0% (95% CI, 10.5 to 21.4; P value < 0.001).

Maintenance Study

A greater proportion of patients in the guselkumab 100 mg (49.5%) and guselkumab 200 mg (51.6%) groups compared with the placebo group (18.9%) had endoscopic healing at week 44 of the maintenance study, with an estimated adjusted between-group difference of 29.5% (95% CI, 20.7 to 38.3; P value < 0.001) and 31.1% (95% CI, 22.5 to 39.8; P value < 0.001), respectively.

Clinical Response

Induction Study

Overall, 77.2% of patients (n = 325) achieved clinical response at week 12 or week 24; among patients who were not in clinical response at week 12 to IV guselkumab and received SC guselkumab treatment (n = 125), 55.2% (n = 69) achieved clinical response at week 24. A greater proportion of patients in the guselkumab group (61.5%) compared with the placebo group (27.9%) experienced clinical response at week 12, with an estimated adjusted between-group difference of 33.8% (95% CI, 26.9 to 40.7; P value < 0.001).

Maintenance Study

A greater proportion of patients in the guselkumab 100 mg (77.7%) and guselkumab 200 mg (74.7%) groups compared with the placebo group (43.2%) maintained clinical response at week 44, with an estimated adjusted between-group difference of 33.6% (95% CI, 24.5 to 42.7; P value < 0.001) and 30.7% (95% CI, 21.5 to 40.0; P value < 0.001), respectively.

Corticosteroid-Free Clinical Remission

Maintenance Study

A greater proportion of patients in the guselkumab 100 mg (45.2%) and guselkumab 200 mg (48.9%) groups compared with the placebo group (18.4%) achieved clinical remission and were corticosteroid-free at week 44, with an estimated adjusted between-group difference of 25.7% (95% CI, 17.0 to 34.5; P value < 0.001) and 29.0% (95% CI, 20.5 to 37.6; P value < 0.001), respectively.

HRQoL Measured by IBDQ Remission

Induction Study

A greater proportion of patients in the guselkumab group (51.3%) compared with the placebo group (29.6%) achieved IBDQ remission at week 12, with an estimated adjusted between-group difference of 21.9% (95% CI, 14.9 to 29.0; P value < 0.001).

Maintenance Study

A greater proportion of patients in the guselkumab 100 mg (64.4%) and guselkumab 200 mg (64.2%) groups compared with the placebo group (37.4%) achieved IBDQ remission at week 44 of the maintenance study, with an estimated adjusted between-group difference of 26.3% (95% CI, 16.8 to 35.7; P value < 0.001) and 25.9% (95% CI, 16.5 to 35.4; P value < 0.001), respectively.

Subgroup Analyses of Key Secondary Outcomes

For both studies, the results for endoscopic healing, clinical response, corticosteroid-free clinical remission (maintenance only), and IBDQ remission were consistent across the 2 prespecified ADT-related subgroups of interest (i.e., patients who were ADT-naive versus those who had experienced ADT failure) and were in favour of guselkumab compared with placebo (data not shown).

Sensitivity Analyses

For both studies, the results of sensitivity analyses for clinical remission, endoscopic healing, clinical response, corticosteroid-free clinical remission (maintenance only), and IBDQ remission were consistent with the primary analysis results at week 12 of the induction study and week 44 of the maintenance study, respectively.

Table 14: Summary of Key Efficacy Results for the Induction and Maintenance Studies — FAS Population

ADT = advanced therapy; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; FAS = full analysis set; IBDQ = Inflammatory Bowel Disease Questionnaire; SC = subcutaneous.

Note: Includes only patients with a modified Mayo score of 5 to 9 at induction baseline.

^aThe 95% CIs for the proportion of patients meeting the end point in each treatment group were based on the normal approximation confidence limits.

^bThe adjusted treatment difference and CIs were based on the Wald statistic with CMH weight.

^cFor the induction study, the P values were based on the CMH chi-square test, stratified by ADT failure status (yes or no) and concomitant use of corticosteroids at baseline (yes or no). For the maintenance study, the P values were based on a CMH chi-square test, stratified by clinical remission status at maintenance baseline (yes or no) and induction treatment (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV).

^dIBDQ remission was not adjusted for multiplicity.

Sources: QUASAR induction and maintenance Clinical Study Reports.^1,2 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

A summary of harms reported in the SASs in the induction and maintenance studies in active tuberculosis was reported in both studies in Table 15 and Table 16, respectively.

Adverse Events

In the induction study, 49.4% and 49.3% of patients reported at least 1 TEAE in the guselkumab and placebo groups, respectively. Over the 12-week treatment period, the most frequently reported TEAEs in the guselkumab and placebo groups were anemia (5.0% and 6.8%, respectively), COVID-19 (5.0% and 4.3%), headache (3.1% and 2.9%), and UC (2.4% and 8.2%). Of these TEAEs, a numerically higher proportion of UC was reported in patients receiving placebo compared with those receiving guselkumab.

In the maintenance study, 64.5%, 70.0%, and 68.2% of patients reported at least 1 TEAE in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups, respectively. Over the 44-week treatment period, the most frequently reported TEAEs in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups were colitis ulcerative (9.1%, 13.2%, and 29.7%, respectively) and COVID-19 (12.9%, 9.5%, and 14.1%). Of these TEAEs, a numerically higher proportion of colitis ulcerative was reported in patients receiving placebo compared with those receiving guselkumab.

Serious Adverse Events

In the induction study, 2.9% and 7.1% of patients reported at least 1 serious TEAE in the guselkumab and placebo groups, respectively.

In the maintenance study, 2.7%, 6.3%, and 0.5% of patients reported at least 1 serious TEAE in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups, respectively.

Withdrawals Due to Adverse Events

In the induction study, 1.7% and 3.9% of patients reported at least 1 TEAE leading to discontinuation of treatment in the guselkumab and placebo groups, respectively.

In the maintenance study, 3.8%, 2.6%, and 6.8% of patients reported at least 1 TEAE leading to discontinuation of treatment in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups, respectively.

Mortality

In the induction study, 1 and 2 deaths were reported in the guselkumab and placebo groups, respectively. There were no deaths reported in the maintenance study.

Notable Harms

In the induction study, the incidence of notable TEAEs, which included infections and serious infections, were similar between groups. Infections were reported in approximately 15% of patients and serious infections were reported in less than 1% of patients in both groups.

Table 15: Summary of Harms Results for the Induction Study — SAS Population

AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; SAS = safety analysis set; TEAE = treatment-emergent adverse event.

^aIncludes data up to week 12 for patients who received treatment at week 12, and all data through the final safety visit for patients who did not receive treatment at week 12.

^bInfections were defined as any AE that was coded to the MedDRA “infections and infestations” system organ class.

Sources: QUASAR induction Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

In the maintenance study, the incidence of notable infections and serious infections were also similar between groups. Infections were reported in approximately 32% of patients in all groups, and serious infections were reported in approximately 1% of patients in the guselkumab groups and 0 patients in the placebo group. No cases of active tuberculosis were reported in either study.

Table 16: Summary of Harms Results for the Maintenance Study — Randomized SAS Population

AE = adverse event; SAS = safety analysis set; SC = subcutaneous; TEAE = treatment-emergent adverse event.

Note: Includes only patients with a modified Mayo score of 5 to 9 at induction baseline.

^aInfections were defined as any AE coded to the Medical Dictionary for Regulatory Activities “infections and infestations” system organ class.

Sources: QUASAR maintenance Clinical Study Report.² Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Both the induction and maintenance studies were randomized, double-blind, placebo-controlled, parallel-group trials. Randomization and allocation concealment for both studies were performed using appropriate methodology via an interactive web response system. Randomization stratification was prespecified and was based on relevant prognostic factors, i.e., ADT failure status, region, and concomitant use of corticosteroids at baseline for the induction study and clinical remission status at maintenance baseline, concomitant use of corticosteroids at maintenance baseline, and induction treatment for the maintenance study. Overall, the baseline demographic and disease characteristics appeared to be reasonably balanced between treatment groups in both studies.

For the induction study, patients were eligible and enrolled if they had a baseline MMS of 4 to 9, and those with a baseline MMS of 4 were capped at 5% of the trial population or less. However, according to the sponsor, the statistical analysis plan was amended per “health authority request” (on April 26, 2022, after patient enrolment) for the primary efficacy and safety analyses to include randomized and treated patients with a baseline MMS of 5 to 9. As a result, a total of 34 patients with a baseline MMS of 4 were excluded from the FAS primary efficacy and safety analyses, which could have compromised randomization. In general, the CDA-AMC review team and the clinical experts consulted by CDA-AMC did not consider this exclusion to have had an important impact on study results because the patient characteristics appeared to be balanced between the treatment groups, and the findings of the supplementary analyses that included those with an MMS of 4 were consistent with the primary analyses.

In both studies, the double-blind approach of masking patients and investigators (including the outcome assessors) to treatment allocation from the time of random assignment until the time of unblinding, per the study protocols, was appropriate. The study drugs were identical in physical appearance and packaging. Some efficacy outcomes (clinical remission and clinical response) were composite outcomes that included Mayo subscores of stool frequency and rectal bleeding, which were reported by patients. The HRQoL outcome assessed with 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.

Both studies used placebo as the comparator instead of an ADT for UC that is relevant to clinical practice in Canada. The clinical expert consulted by CDA-AMC noted 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 the comparative effectiveness that is summarized in the ITC section of the current report.

In the induction study, most patients received 1 or more concomitant medications for UC, including oral corticosteroids, immunomodulatory drugs, and oral 5-ASAs. The use of these concomitant drugs was generally similar between groups and, according to the clinical experts, unlikely to have confounded the study results.

Overall, the statistical methods used in both studies were appropriate. The studies were powered based on their primary and key secondary outcomes between the treatment groups. The subgroup analyses were 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 IBDQ remission and the subgroup analyses. The sponsor noted that, based on feedback from the FDA, IBDQ remission was not included in the US-specific hierarchical testing procedure.

Rates of study discontinuation were generally low in both studies and similar between groups although, in the induction study, the rate in the placebo group (12.9%) was higher than in the guselkumab group (5.5%), mostly attributed to withdrawal by patients. Nonresponder imputation was used for missing data in the primary analysis, and preplanned sensitivity analyses were done under different assumptions. Nonresponder imputation is a method in which missing data are believed to occur randomly and are unrelated to observed or unobserved variables. However, this assumption is often unrealistic and, if violated, the imputed values may be biased, especially when differences between groups are pronounced. However, the between-group differences did not appear pronounced in these trials and appropriate methods (e.g., tipping point and multiple imputation) for the sensitivity analyses were used, which confirmed that the results of the studies remained robust to the differential discontinuations between groups.

External Validity

In general, the population requested for reimbursement aligns with the approved Health Canada indication, except that the indication is not limited to patients who have experienced an inadequate response or are unable to tolerate ADT or conventional therapy. The clinical experts did not consider the broader indication to affect the generalizability of the findings from the induction and maintenance studies. The dosing and administration of guselkumab were consistent with the approved product monograph.

Most patients enrolled in both studies (41% to 47%) were from Eastern Europe, with the remainder distributed across Asia (21%) and rest of world (32% to 38% across Western Europe, North America, Latin America, Australia, Israel, and New Zealand). There were 8 and 6 patients from Canada included in the induction and maintenance studies, respectively. Also, there was a relatively high rate of unsuccessful screenings in the induction study (269 out of 1,005 patients were screened out), mainly due to patients not meeting eligibility criteria. The clinical experts did not regard these factors as influencing the generalizability of the studies’ results.

According to the clinical experts, the patient eligibility criteria and baseline characteristics of both studies were generalizable to adults with moderately to severely active UC in the clinical setting in Canada.

The studies included outcomes that were important to patients and clinicians, including clinical remission, clinical response, corticosteroid-free clinical remission, and HRQoL.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform the CDA-AMC expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^36,82

• 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 RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer 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.

For the GRADE assessments, the induction and maintenance studies were assessed individually because they had different treatment regimens and durations and different time points for assessing outcomes.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for guselkumab versus placebo.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Evidence

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

Objectives for the Summary of Indirect Evidence

The aim of this section is to summarize and critically appraise 1 sponsor-submitted NMA that was used to inform the pharmacoeconomic model and to fill gaps in the comparative evidence for guselkumab versus other treatments of interest for moderately to severely active UC.

Description of Indirect Comparison

The systematic literature search and study selection criteria for the NMA are summarized in Table 17.

Indirect Treatment Comparison Design

Objectives

The objective of the sponsor-submitted NMA was to compare the treatment effects of guselkumab versus other relevant comparators for the treatment of adults with moderately to severely active UC in induction and maintenance. In this setting, maintenance outcomes evaluated response at 1 year in all enrolled patients (i.e., not the response in the subpopulation of induction responders). The protocol of the systematic review and NMA was a priori registered in PROSPERO (CRD42023466248).

Table 17: Study Selection Criteria and Methods for NMA Submitted by the Sponsor

ADT = advanced therapy; EBM = Evidence-Based Medicine; IL = interleukin; JAK = Janus kinase; NICE = National Institute for Health and Care Excellence; NMA = network meta-analysis; PROMIS-29 = 29-item Patient-Reported Outcomes Measurement Information System questionnaire; RCT = randomized controlled trial; TNF = tumour necrosis factor.

^aClinical remission is measured as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability present on the endoscopy, where the stool frequency subscore has not increased from induction baseline.

^bClinical response is measured as a decrease from induction baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a ≥ 1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. The modified Mayo score is a 3-component (stool frequency, rectal bleeding, and endoscopy subscores) Mayo score without the Physician’s Global Assessment.

Sources: NMA technical report.⁸⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Study Selection Methods

A systematic literature search was conducted on July 27, 2023, using the criteria described in Table 17. The review included trials investigating treatments in adults with moderately to severely active UC treated with biologics, Janus kinase inhibitors, or sphingosine 1-phosphate receptor modulators. The following efficacy outcomes of interest for this CDA-AMC review that were reported were clinical remission and clinical response assessed at the induction and maintenance treatment periods. The identified clinical trials were assessed for eligibility against predefined inclusion and exclusion criteria. Two reviewers independently screened titles and abstracts and relevant full-text citations for inclusion. Discrepancies were resolved through consensus or by a third reviewer. Data extraction and a quality assessment of the included studies were performed by 1 reviewer and validated by a second reviewer, and discrepancies were resolved through consensus or by a third reviewer. The assessment of the risk of bias of the included studies was performed using the National Institute for Health and Care Excellence Single Technology Appraisal Evidence Submission checklist for assessing the risk of bias in RCTs.

ITC Analysis Methods

Details of the NMA analysis methods are in Table 18. An NMA feasibility assessment was undertaken to ascertain the extent of clinical heterogeneity across the trials identified in the systematic literature review. Trial design characteristics, patient eligibility criteria, baseline patient characteristics, outcome characteristics (i.e., definitions and methods of reporting outcomes), and placebo response were considered sources of clinical heterogeneity and explored in the feasibility assessment. Based on the feasibility assessment, an NMA was used for the outcomes of clinical remission and clinical response for induction and maintenance (1-year analysis).

Studies were included in the NMA if they reported outcomes of interest for patients receiving doses approved in Europe, the US, Canada, and Japan. Only studies with a minimum follow-up duration of 38 weeks were included in the maintenance analysis. NMA outcomes included clinical remission and clinical response, assessed at the induction and maintenance treatment periods. For the induction analyses, the trial’s primary time point was used. For the maintenance analyses, the time point closest to 52 weeks (and later than 24 weeks) was used. The goal of the NMA was to inform the comparative effectiveness of guselkumab across a broad range of available comparators; however, given that some comparators were not relevant to Canadian public payers (e.g., risankizumab, filgotinib) they have been excluded from the Clinical Review.

A Bayesian NMA was conducted as the primary analysis of outcomes. Clinical remission and clinical response were analyzed together as an ordinal outcome using an inverse logit multivariate regression model for ordered categorical data. Within the ordinal model, it was assumed that all patients achieving remission also achieved response; thus, the response was redefined to be response without remission. In the induction setting, ordinal ORs were estimated from a random-effects model that adjusted for a baseline response rate estimated from the QUASAR placebo group. The 1-year maintenance analyses were based on an unadjusted random-effects model. In both cases, informative prior distributions were used based on recommendations in Turner et al.^85,86 All effect estimates were accompanied with 95% CrIs.

Fixed-effect NMAs were also conducted for maintenance time points but are not included in the report. All analyses were performed using 4 unique sets of starting values and were based on at least 20,000 iterations with a burn-in of 20,000. Convergence was monitored quantitatively using 4 chains and the latest implementation Gelman-Rubin diagnostic (Rhat) to capture nonconvergence from stationary but nonoverlapping chains, overlapping nonstationary chains, chains with heavy tails, and chains with different variances. Samples were considered to have converged if the Rhat was 1.05 or less. This was assessed for all parameters used in each model. Effective sample size and Monte Carlo standard errors were also assessed to ensure sufficient postconvergence samples were taken to support inference. If the rank-normalized effective sample size was greater than 400 (i.e., 100 per chain) then additional samples were taken to ensure the Monte Carlo standard error was small enough to allow for stable estimates to at least 1 decimal place.

Table 18: NMA Analysis Methods

ADT = advanced therapy; NMA = network meta-analysis; UC = ulcerative colitis.

Sources: NMA technical report.⁸⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Subgroup NMAs (induction and 1-year analyses) were conducted for 2 distinct patient populations: ADT failure and ADT nonfailure. For the 1-year NMAs, trial data were normalized to mimic a type 1 treat-through trial design as best as possible. This normalization approach is termed the 1-year “with delayed responders” analysis. Analyses applying imputation methods that do not account for delayed responders were also conducted, and these analyses were used to inform the economic model.

Results of the NMA

Summary of Included Studies

The search identified ████ unique RCTs, of which ████ trials were excluded from the NMA feasibility assessment; ████ due to unapproved treatment regimens and ███ █████ because it recruited a patient subgroup not of interest (i.e., | █████ including Japanese patients from a broader etrasimod trial). A total of ██ trials were included in the NMA, of which ████ trials were phase III, ███ trials were phase II, and ███ trials were phase IIb or III. All trials were conducted in multicentre settings. ███ █████ did not explicitly report phase; however, its design and objectives aligned with those of a phase III trial. The following therapies were included in the NMA: adalimumab,^87-90 infliximab,^91-93 tofacitinib,^94-96 and upadacitinib^97-99 were each investigated by ███ trials; mirikizumab^100,101 and vedolizumab^88,102,103 were investigated by ███ trials each; etrasimod,^104-106 ozanimod,^100,101 ustekinumab,¹⁰⁷ and guselkumab,¹⁰⁸ were each examined by ███ trials.

Assessment of homogeneity is summarized in Table 19, and a summary of the included RCTs is in Table 20. ████████ ██████^{████████████████████████████████} had evidence available for both induction and maintenance trial periods, while ████████^{██████████████████████████████} and █████ ██████^{████████████████████████████████████████} had data for only induction and only maintenance periods, respectively. All trials included in the NMA were double-blind, comparative, randomized trials. Only ███ trials ^{██████} were head-to-head comparisons of 2 active therapies, ███ █████^███ assessed a biologic and immunosuppressant combination therapy regimen against biologic monotherapy, and the remaining trials utilized a placebo comparator. A total of ██████ trials employed responder re-randomization, ███ trials ^{█████████████████████████} were treat-through design, ████ trials ^{██████████████} were induction only, and ███ █████^███ was response conditional (i.e., patients continued active therapy if they experienced a response to treatment at assessment).

A summary of the baseline patient characteristics across the trials included in the NMA is in Table 21. The QUASAR trial program included patients aged 18 years and older with a baseline MMS score of 5 to 9, a rectal bleeding subscore of at least 1, and a Mayo endoscopic subscore of at least 2. Patients in the QUASAR trial must also have experienced the failure of a biologic, advanced, or conventional therapy before inclusion and have at least 20 cm of colon affected by the disease process. There was no prespecified minimum disease duration for the QUASAR trial. Additionally, endoscopy and histological confirmation was performed as part of trial enrolment for QUASAR trial eligibility. Overall, both age requirements and endoscopic and histological confirmation were relatively similar between the comparator studies and the QUASAR trial. Disease duration, baseline Mayo score, prior failure of biologic, advanced, or conventional therapies, and extent of disease varied across comparator trials, as follows:

• The QUASAR trial and ██████ other studies ████████████ excluded patients who had been previously exposed to a biologic therapy targeting IL-12 and/or IL-23.

• A majority of trials (including QUASAR) employed the same definition of clinical remission predicated on the total Mayo score, while █████ trials █████████ used the MMS, ███ trials ██████ used the adapted Mayo score, ███ █████ ████ used the partial Mayo score ███^███ and 3-component Mayo score. ██ Specific aspects of the definition used for clinical remission were assessed as well, including requirements for the endoscopic subscore, total Mayo score, stool subscore, rectal bleeding subscore, and an aggregate requirement for all subscores. A total of █████ trials had criteria identical to the QUASAR trial, while minor variations were noted in the remaining █████ trials. ^{█████████████████████████████████████████████████████}

• A total of █████ trials used the same clinical response definition as the QUASAR trial. ^{███████████████████████████████████████████████████████}. Trials were additionally evaluated based on specific aspects of the clinical response definition, including the type of Mayo scoring system used, the overall Mayo score requirement, and the rectal bleeding subscore requirement. None of the trials reported an absolute Mayo score or endoscopic subscore requirement.

• Most trials reported induction periods ranging from 6 to 14 weeks, with maintenance periods that typically measured outcomes around 52 weeks but had a large amount of variance in timing.

Table 19: Assessment of Homogeneity for the NMA

IL = interleukin; NMA = network meta-analysis.

Sources: NMA technical report.⁸⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 20: Summary of Study Characteristics Included in the NMA

b.i.d. = twice a day; NMA = network meta-analysis; NR = not reported; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.d. = once a day; RR = responder re-randomization; SS = substudy; TT = treat through.

Sources: NMA technical report.⁸⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 21: Redacted

Results

The results for random-effects models for the relevant comparators are summarized for clinical remission and response. In the induction setting, the model was adjusted for baseline risk but not for the maintenance phase (1-year analysis) because of a lack of multistudy connections. Inconsistency analyses indicated concordance between direct and indirect evidence across the conducted NMAs. In general, the authors noted that the risk-of-bias assessment of the included trials was reported to be of good quality. However, the clinical experts noted heterogeneity in the inclusion and exclusion criteria and outcomes definitions and timing.

Induction Analysis

Network diagrams for studies reporting clinical response and clinical remission for the induction analysis in the ADT nonfailure and failure populations are presented in Figure 2 and Figure 3, respectively. For the population of patients who had not experienced ADT failure, the network consisted of ████ treatment nodes informed by ████ RCTs. Most connections between treatment nodes were informed by a single trial; however, some connections were informed by up to ███ trials. For the ADT failure population, the network consisted of ████ treatment nodes informed by ████ RCTs, and most connections between treatment nodes were informed by a single trial.

Clinical remission: In the ADT nonfailure population, no comparators were statistically significantly more effective than guselkumab 200 mg (i.e., 95% CrIs crossed the null) or vice versa (Figure 4). In the ADT failure population, the results favoured upadacitinib versus guselkumab 200 mg (Figure 5).

Clinical response: In the ADT nonfailure population, no comparators were statistically significantly more effective than guselkumab 200 mg, and the results favoured guselkumab versus golimumab and adalimumab (Figure 6). In the ADT failure population, no comparators were statistically significantly more effective than guselkumab, and the results favoured guselkumab versus adalimumab (Figure 7).

Maintenance Analysis

Network diagrams for studies reporting clinical response and clinical remission for the maintenance analysis in the ADT nonfailure and failure populations are presented in Figure 8 and Figure 9, respectively. For the ADT nonfailure population, the network consisted of ████ treatment nodes informed by ████ trials, and most connections between treatment nodes were informed by single trials. For the ADT failure population, the network consisted of ████ treatment nodes, and all connections between treatment nodes were informed by single trials.

Clinical remission: In the ADT nonfailure population, no comparators were statistically significantly more efficacious than guselkumab 100 mg or 200 mg (i.e., 95% CrIs crossed the null), and the results favoured guselkumab 200 mg versus adalimumab, and golimumab (Figure 10). In the ADT failure population, no comparators were statistically significantly more efficacious than guselkumab 100 mg or 200 mg or vice versa (Figure 11).

Clinical response: In the ADT nonfailure population, no comparators were statistically significantly more efficacious than guselkumab 100 mg or 200 mg (i.e., 95% CrIs crossed the null), and the results favoured both doses of guselkumab versus adalimumab (Figure 12). In the ADT failure population, no comparators were statistically significantly more efficacious than guselkumab 100 mg or 200 mg or vice versa (Figure 13).

Sensitivity analyses: The results of the sensitivity analyses for clinical remission and clinical response in the maintenance phase, which did not account for delayed responders, were consistent with the primary analyses (data not shown).

Figure 2: Redacted

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Figure 12: Redacted

Figure 13: Redacted

Critical Appraisal of NMA

The methods used to conduct the systematic literature review and NMA were prespecified with an a priori protocol and used appropriate criteria to search databases, select studies, extract data, and assess the risk of bias of the included studies. Selection bias is expected to be low, given the comprehensiveness of the searches and methods for study selection.

The NMA included relevant outcomes identified by the CDA-AMC team (clinical remission and clinical response); however, other clinically and patient-relevant outcomes such as endoscopic healing, corticosteroid-free clinical remission, HRQoL, and harms were not included in the comparisons.

The majority of comparators within the evidence network were informed by a single study, resulting in a star-shaped network and limiting certainty in the assumptions of the analysis. The authors of the sponsor’s NMA report noted that the results of the inconsistency analysis indicated broad concordance between the direct and indirect evidence for both clinical remission and clinical response. Because most nodes were informed by only 1 or 2 trials and, in several trials, patients were re-randomized, comparisons were underpowered, which contributed to wide CrIs in the analyses. In addition, infliximab and golimumab were not compared with guselkumab in the analysis of the population of patients who have experienced ADT failure due to a lack of data, which represents a gap in the available indirect evidence, given the shared place in therapy for UC.

Substantial heterogeneity was noted across the studies, and while the meta-regression random-effects model accounts for some sources of heterogeneity, there is a risk of the exchangeability assumption being violated. Specifically, potential effect modifiers across the included studies that could not be controlled for included trial design characteristics, patient eligibility criteria, baseline patient characteristics, and outcome characteristics (i.e., definitions and methods of reporting outcomes). Variations in the placebo effect estimates across studies support these concerns about heterogeneity as well as concerns about possible violations of the assumptions of transitivity for the NMA.

In addition, beyond the induction phase, the authors noted that although placebo is considered to be a common comparator across the majority of the included trials, placebo arms across re-randomized trials may not be equivalent due to variation in the treatments received during the preceding induction phase. In particular, the carryover effects observed due to previous treatments are likely to vary based on treatment mechanism, potentially constituting a substantial source of cross-trial heterogeneity, which is evidenced in part by variations in baseline risk across the included trials. Variations in the timing of the measured Mayo scores that informed the response and remission outcomes also introduce biases that could not be appropriately accounted for by the NMA methods. In general, the magnitude and direction of potential bias due to the heterogeneity of the outcome estimates cannot be predicted. The risk-of-bias assessment at the outcome level and its potential impact on the NMA effect estimates was not explicitly assessed or discussed, and no sensitivity analyses were conducted to examine the influence of studies with a high risk of bias on relative treatment effects, although the authors of the NMA stated that, in general, the trials were found to be of good quality.

Efforts were made in the NMA analysis to reduce heterogeneity by stratifying the patient population into ADT failure and ADT nonfailure subgroups. While this approach provides a more accurate estimate of efficacy within those populations, it does not provide an overall estimate of efficacy across the entire indicated population. Consequently, neither subgroup estimate of efficacy is representative of overall efficacy in the Canadian context.

The specified model, while referred to as an ordinal regression, is a multinomial regression that removes correlations between the outcomes of response and remission and estimates an OR for each outcome individually against no response or remission. Furthermore, the model restructures the data such that the response outcome used a definition that is different from the one used in the clinical trial setting, where it is defined as response without remission. This redefinition introduces a core issue in that the response outcome is defined conditionally on a separate outcome that can occur at a future date; thus, whether an improvement in response rate due to treatment is a benefit or a harm becomes unclear. Ultimately, the interpretation of the ordinal OR when the model assumptions are violated can create a misleading impression of how the outcomes and treatment are related.¹³⁶ Due to the limitations in the NMA, the relative treatment effects of guselkumab versus other relevant comparators is uncertain and there is no conclusive evidence of a preferred treatment, based on the reported results.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the pivotal phase III evidence were submitted by the sponsor.

Discussion

Summary of Available Evidence

Two pivotal phase III, randomized, double-blind trials and 1 ITC submitted by the sponsor have been summarized in this report.

The QUASAR induction (N = 701) and maintenance (N = 568) studies met the inclusion criteria for the systematic review conducted by the sponsor. The objective of the induction study was to assess the efficacy and safety of guselkumab 200 mg IV as induction therapy versus matching placebo administered at weeks 0, 4, and 8 in adults with moderately to severely active UC. The study enrolled patients who had experienced an inadequate response or failure to tolerate conventional therapy (i.e., 6-mercaptopurine, azathioprine, or corticosteroids) or ADT (i.e., TNF antagonists, vedolizumab, or tofacitinib). Patients were required to have an MMS of 4 to 9, a Mayo rectal bleeding score of 1 or more, and a Mayo endoscopy subscore of 2 or more. Patients were eligible for the maintenance study if they had demonstrated a clinical response to guselkumab or placebo treatment at weeks 12 or 24. The objective of the maintenance study was to assess the efficacy and safety of guselkumab SC injection maintenance regimens (100 mg or 200 mg) versus matching placebo in patients who achieved clinical response with guselkumab IV induction. Patients received guselkumab 200 mg every 4 weeks, guselkumab 100 mg every 8 weeks, or placebo every 4 weeks starting at week 0 through week 44. In general, the approved Health Canada indication and reimbursement request aligned with both study populations, except that the indication is not limited to patients who have experienced an inadequate response or are unable to tolerate ADT or conventional therapy. The outcomes most relevant to the CDA-AMC review included the primary outcome of clinical remission and secondary outcomes of endoscopic healing, clinical response and maintenance of clinical response, corticosteroid-free clinical remission (maintenance only), and HRQoL measured via IBDQ remission. For both studies, key baseline characteristics were generally balanced between treatment groups. Patients in the induction study were predominantly white (72.5%) and male (56.9%). The median age was 39.0 years (range, 18 to 79 years), and the majority of patients were from Eastern Europe (42.2%) followed by rest of world (37.5%) and Asia (20.3%). The mean duration of disease was 7.5 years, and the mean baseline MMS was 6.9, with 64.5% of patients presenting with severely active disease (i.e., an MMS of 7 to 9) and 47.8% with extensive disease. At baseline, 43.1% of patients were taking corticosteroids, 20.8% were taking immunomodulatory drugs, and 72.5% were taking oral 5-ASAs, with generally similar proportions of patients across the treatment groups. Among all patients, 93.2% experienced an inadequate response or intolerance to corticosteroids and/or 6-mercaptopurine or azathioprine or experienced corticosteroid dependence, 49.1% had a history of experiencing ADT failure (i.e., anti–TNF alpha, vedolizumab, or tofacitinib), and 50.9% had a history of nonfailure of ADT. At induction baseline for the patients in the maintenance study, 40% were taking corticosteroids and 22.2% were taking immunomodulatory drugs (6-mercaptopurine, azathioprine, or methotrexate), 57.7% did not have a history of experiencing an inadequate response or intolerance to ADT (of these, 94.2% were naive to ADT), and 42.3% had experienced a prior inadequate response or intolerance to ADT. At maintenance baseline, the mean MMS was 2.5, 34.2% of patients were in clinical remission, and 39.1% achieved endoscopic healing. For both studies, the primary analysis of efficacy and safety outcomes were conducted in the FAS, which included patients who received at least 1 (partial or complete) dose of the study intervention who had a baseline MMS of 5 to 9.

In the absence of direct comparative evidence of guselkumab versus relevant comparators of interest, the sponsor conducted an NMA. The NMA assessed the induction and maintenance treatment effects of guselkumab versus adalimumab, infliximab, tofacitinib, upadacitinib, mirikizumab, vedolizumab, etrasimod, ozanimod, and ustekinumab for the treatment of adults with moderately to severely active UC. Some comparators were not relevant to Canadian public payers (e.g., risankizumab, filgotinib) and have therefore been excluded from the Clinical Review. Outcomes of interest included clinical remission and clinical response. Bayesian NMAs were conducted using ordinal regression models to estimate ORs and 95% CrIs. Random-effects NMA results for both induction and maintenance therapies were summarized based on 2 distinct patient populations, ADT failure and ADT nonfailure.

Interpretation of Results

The evidence from the QUASAR induction and maintenance studies addressed treatment outcomes noted to be important by both patients and clinicians. The patient group inputs indicated that clinical remission, clinical response, corticosteroid-free clinical remission, and HRQoL are important to them. Similarly, the clinical experts consulted by the review team indicated that the unmet needs of patients with moderately to severely active UC would be new treatments that induce and maintain clinical and endoscopic remission.

Efficacy

Both the induction and maintenance studies supported a clinically meaningful improvement of guselkumab over placebo for clinical remission, endoscopic healing, clinical response, corticosteroid-free clinical remission (maintenance therapy only), and IBDQ remission at 12 weeks (induction therapy) and 44 weeks (maintenance therapy) (100 mg and 200 mg dosages) in adults with moderately to severely active UC. For clinical remission at 12 and 44 weeks, the estimated between-group difference was 14.9% (95% CI, 9.9 to 19.9) and 25.2% (95% CI, 16.4 to 33.9) for the 100 mg dose, and 29.5% (95% CI, 20.9 to 38.1) for the 200 mg dose, respectively. For the GRADE assessment, the clinical experts consulted by CDA-AMC suggested a clinically important threshold of 7.5% and 10% for the between-group absolute risk difference at 12 and 44 weeks, respectively. Based on these thresholds, there was a high certainty of evidence for a clinically important increase in clinical remission at both time points. For endoscopic healing at 12 and 44 weeks, the estimated between-group difference was 16.0% (95% CI, 10.5 to 21.4) and 29.5% (95% CI, 20.7 to 38.3) for the 100 mg dose and 31.1% (95% CI, 22.5 to 39.8) for the 200 mg dose, respectively. The clinical experts suggested a clinically important threshold of 10% for the between-group absolute risk difference at 44 weeks but could not determine a threshold at 12 weeks; therefore, the target-of-certainty appraisal was any effect (i.e., crossed the null). Based on the 10% threshold, there was a high certainty of evidence for a clinically important increase in endoscopic healing at 44 weeks. For clinical response at 12 weeks and maintenance of clinical response at 44 weeks, the estimated between-group difference was 33.8% (95% CI, 26.9 to 40.7) and 33.6% (95% CI, 24.5 to 42.7) for the 100 mg dose and 30.7% (95% CI, 21.5 to 40.0) for the 200 mg dose, respectively. Using the same thresholds as those used for clinical remission, as suggested by the clinical experts, there was a high certainty of evidence for a clinically important increase in clinical response at 12 weeks and in maintenance of clinical response at 44 weeks. For corticosteroid-free clinical remission at 44 weeks, the estimated between-group difference was 25.7% (95% CI, 17.0 to 34.5) for the 100 mg dose and 29.0% (95% CI, 20.5 to 37.6) for the 200 mg dose. For the GRADE assessment, the clinical experts suggested a clinically important threshold of 15% in the between-group absolute risk difference at 44 weeks. Based on this threshold, there was a high certainty of evidence for a clinically important increase in corticosteroid-free clinical remission at 44 weeks. For IBDQ remission at 12 and 44 weeks, the estimated between-group difference was 21.9% (95% CI, 14.9 to 29.0) and 26.3% (95% CI, 16.8 to 35.7) for the 100 mg dose and 25.9% (95% CI, 16.5 to 35.4) for the 200 mg dose. Using the same thresholds as those used for clinical remission, as suggested by the clinical experts, there was a high certainty of evidence for a clinically important increase in IBDQ remission at both time points. The results for all primary and secondary outcomes listed were consistent across the prespecified subgroups of interest (i.e., ADT-naive and ADT failure), in favour of guselkumab.

Based on the sponsor-submitted NMA, the results for clinical remission at induction in the ADT nonfailure population did not favour any particular treatment (i.e., 95% CrIs crossed the null), and the results for the ADT failure population favoured only upadacitinib versus guselkumab 200 mg. For clinical remission at maintenance in the ADT nonfailure population, the results favoured guselkumab 200 mg versus adalimumab and golimumab, and the results for the ADT failure population did not favour any treatments. The results for clinical response at induction in the ADT nonfailure population favoured guselkumab 200 mg versus golimumab and adalimumab, and the results for the ADT failure population favoured guselkumab versus adalimumab. For clinical response at maintenance in the ADT nonfailure population, the results favoured guselkumab 100 mg and 200 mg versus adalimumab, and the results for the ADT failure population did not favour any treatments. However, there were several notable sources of heterogeneity for potential effect modifiers across the included studies that create uncertainty in the NMA results. These included trial design characteristics, patient eligibility criteria, baseline patient characteristics, and definitions and methods of reporting outcomes. In addition, beyond the induction phase, the authors noted that although placebo is a common comparator across the majority of the included trials, placebo groups across re-randomized studies may not be equivalent due to variation in the treatments received during the preceding induction phase. The magnitude and direction of potential bias due to heterogeneity on outcome estimates cannot be predicted. Additionally, the interpretation of the ordinal OR when the model assumptions are violated can create a misleading impression of how the outcomes and treatments are related. It should also be noted that the NMA results were based on the ADT failure and ADT nonfailure subgroups and not on the overall population, which is the focus of the approved Health Canada indication. Due to these limitations in the NMA, no definitive conclusions could be drawn on the relative treatment effects of guselkumab induction and maintenance therapies versus other relevant comparators for the treatment of moderately to severely active UC.

Harms

In both the induction and maintenance studies, most patients reported at least 1 TEAE. During the 12-week induction treatment period, the most frequently reported TEAEs in the guselkumab and placebo groups were anemia, COVID-19, headache, and UC. Of these TEAEs, a numerically higher proportion of UC was reported in patients taking placebo. Over the 44-week maintenance treatment period, the most frequently reported TEAEs in the guselkumab 100 mg, guselkumab 200 mg, and placebo groups were UC and COVID-19, with a numerically higher proportion of UC being reported in patients taking placebo. In both studies, serious TEAEs, TEAEs leading to discontinuation of treatment, and death were infrequent and similar across the treatment groups; no deaths were reported in the maintenance study. In both studies, the incidence of notable harms, which included infections and serious infections, was similar between groups, and serious infections were infrequent. No cases of active tuberculosis were reported in either study. The clinical experts indicated that the incidence of these TEAEs is expected with guselkumab and would be manageable for many patients.

The sponsor-submitted NMA did not include harms; therefore, no conclusions could be drawn on the relative safety of guselkumab versus other relevant comparators.

Conclusions

Evidence from 2 phase III double-blind RCTs (QUASAR induction and maintenance studies) reported on outcomes that were important to both patients and clinicians. The studies showed a high certainty of evidence that treatment with guselkumab results in a clinically meaningful increase in clinical remission, endoscopic healing, clinical response and maintenance of clinical response, corticosteroid-free clinical remission (maintenance only), and HRQoL via IBDQ remission at 12 weeks (induction therapy) and 44 weeks (maintenance therapy), compared with placebo in adults with moderately to severely active. Although the approved Health Canada indication is broader than the patient populations enrolled in the studies (i.e., patients who had experienced an inadequate response or were unable to tolerate ADT or conventional therapy), the clinical experts consulted by CDA-AMC did not consider the indication to affect the generalizability of the findings. No new safety signals were identified, and the safety of guselkumab was consistent with the drug’s known safety profile. Due to the limitations of the ITC, mostly attributed to the heterogeneity across studies, no conclusions can be drawn on the relative efficacy and safety of guselkumab versus other relevant comparators.

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104.Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al. Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology. 2020;158(3):550-561. doi: 10.1053/j.gastro.2019.10.035 PubMed

105.Feagan B, Peyrin-Biroulet L, Sandborn W, et al. MP289 Etrasimod 2mg Once daily as treatment for Biologic/Janus Kinase Inhibitor-Naive and -Experienced Patients with Moderately to Severely Active Ulcerative Colitis: Subgroup Analysis from the Phase 3 Elevate UC 52 and Elevate UC 12 Trials. United European Gastroenterol J. 2022;10(S8):388-390. doi: 10.1002/ueg2.1229

106.Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401(10383):1159-1171. doi: 10.1016/S0140-6736(23)00061-2 PubMed

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110.David T. Rubin JRA, Bruce E. Sands, Kuan-Hsiang Huang, Mary Kavalam, Matthew Germinaro, Rebecca WIlson, Hongyan Zhang, Emese Mihaly, Tadakazu Hisamatsu, Axel Dignass, Julian Panes. The Effect of Guselkumab Induction Therapy in patients with Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Results at Week 12 by prior Inadequate Reponse or Intolerance to Advanced Therapy. 2022.

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112.Feagan BG, Rubin DT, Danese S, et al. Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol. 2017;15(2):229-239 e5. doi: 10.1016/j.cgh.2016.08.044 PubMed

113.Schreiber S, Feagan B, Peyrin-Biroulet L, et al. OP07 Exploring disease control by combining clinical, biological, and health-related quality of life remission with endoscopic improvements among Ulcerative Colitis patients treated with filgotinib: A post-hoc analysis from the SELECTION trial. J Crohns Colitis. 2022;16(Supplement_1):i007-i008. doi: 10.1093/ecco-jcc/jjab232.006

114.Dotan I, Feagan BG, Taliadouros V, et al. Efficacy of Filgotinib in Patients with Ulcerative Colitis by Line of Therapy in the Phase 2b/3 SELECTION Trial. J Crohns Colitis. 2023;17(8):1207-1216. doi: 10.1093/ecco-jcc/jjad039 PubMed

115.Feagan BG, Danese S, Loftus EV, Jr., et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021;397(10292):2372-2384. doi: 10.1016/S0140-6736(21)00666-8 PubMed

116.Siegmund B, Axelrad J, Pondel M, et al. DOP43 Rapidity of ozanimod-induced symptomatic response and remission in patients with moderately to severely active Ulcerative Colitis: Results from the induction period of True North. J Crohns Colitis. 2022;16(Supplement_1):i092-i093. doi: 10.1093/ecco-jcc/jjab232.082

117.Sands BE, Jain A, Ahmad HA, et al. P376 Efficacy of ozanimod in vedolizumab-exposed patients with ulcerative colitis: a phase 3 True North post hoc analysis. J Crohns Colitis. 2023;17(Supplement_1):i507-i508. doi: 10.1093/ecco-jcc/jjac190.0506

118.Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142(2):257-65 e1-3. doi: 10.1053/j.gastro.2011.10.032

119.Feagan BG, Peyrin-Biroulet L, Sandborn WJ, et al. S734 Etrasimod 2mg Once Daily as Treatment for Patients With Moderately to Severely Active Ulcerative Colitis: Topline and Subgroup Analysis From ELEVATE UC 52 and ELEVATE UC 12. Am J Gastroenterol. 2022;117(10S):e516-e517. doi: 10.14309/01.ajg.0000859576.23012.a3

120.Sandborn WJ, Vermiere S, Peyrin-Biroulet L, et al. OP086 Etrasimod 2MG Once Daily as Treatment for Moderately to Severely Ulcerative Colitis: Reults from the Phase 3 ELVEATE UC 52 and ELEVATE UC 12 Trials. United European Gastroenterol J. 2022;10(S8):67-69. doi: 10.1002/ueg2.12293

121.Risankizumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Efficacy and Safety in the Randomized Phase 3 INSPIRE Study. Gastroenterol Hepatol (N Y). 2023;19(12 Suppl 9):9-10. PubMed

122.Panaccione R, Louis E, Colombel JF, et al. P593 Efficacy of Risankizumab in Patients With Moderately to Severely Active Ulcerative Colitis by Prior Advanced Therapy Failure and Mechanism of Action: Post Hoc Analysis of the INSPIRE and COMMAND Phase 3 Studies. J Crohns Colitis. 2024;18(Supplement_1):i1146-i1148. doi: 10.1093/ecco-jcc/jjad212.0723

123.Navabi S, D’Haens G, Samaan KH, et al. P469 Effect of mirikizumab on clinical and endoscopic outcomes based on prior advanced therapy failure in patients with moderately to severely active ulcerative colitis. J Crohns Colitis. 2023;17(Supplement_1):i598-i598. doi: 10.1093/ecco-jcc/jjac190.0599

124.D'Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023;388(26):2444-2455. doi: 10.1056/NEJMoa2207940 PubMed

125.Sandborn WJ, Sands BE, Vermeire S, et al. Modified Mayo score versus Mayo score for evaluation of treatment efficacy in patients with ulcerative colitis: data from the tofacitinib OCTAVE program. Therap Adv Gastroenterol. 2022;15:17562848221136331. doi: 10.1177/17562848221136331 PubMed

126.Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):85-95; quiz e14-5. doi: 10.1053/j.gastro.2013.05.048 PubMed

127.Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(2):392-400 e3. doi: 10.1053/j.gastro.2013.10.052 PubMed

128.Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60(6):780-7. doi: 10.1136/gut.2010.221127 PubMed

129.Feagan BG, Sands BE, Sandborn WJ, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023;8(4):307-320. doi: 10.1016/S2468-1253(22)00427-7 PubMed

130.Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis. Gastroenterology. 2020;158(3):537-549 e10. doi: 10.1053/j.gastro.2019.08.043 PubMed

131.Louis E, Panaccione R, Parkes G, et al. OP06 Risankizumab Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Efficacy and Safety in the Randomised Phase 3 COMMAND Study. J Crohns Colitis. 2024;18(Supplement_1):i10-i12. doi: 10.1093/ecco-jcc/jjad212.0006

132.Hibi T, Imai Y, Senoo A, Ohta K, Ukyo Y. Efficacy and safety of golimumab 52-week maintenance therapy in Japanese patients with moderate to severely active ulcerative colitis: a phase 3, double-blind, randomized, placebo-controlled study-(PURSUIT-J study). J Gastroenterol. 2017;52(10):1101-1111. doi: 10.1007/s00535-017-1326-1 PubMed

133.Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):96-109 e1. doi: 10.1053/j.gastro.2013.06.010 PubMed

134.Hoffmann-La Roche. NCT02163759: A Study Comparing the Efficacy and Safety of Etrolizumab With Adalimumab and Placebo in Participants with Moderate to Severe Ulcerative Colitis (UC) in Participants Naive to Tumor Necrosis Factor (TNF) Inhibitors (HIBISCUS I). 2021. Accessed October 21, 2025. https://clinicaltrials.gov/study/NCT02163759

135.Sandborn WJ, D'Haens GR, Reinisch W, et al. Guselkumab for the Treatment of Crohn's Disease: Induction Results From the Phase 2 GALAXI-1 Study. Gastroenterology. 2022;162(6):1650-1664 e8. doi: 10.1053/j.gastro.2022.01.047 PubMed

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Pharmacoeconomic Review

Abbreviations

Executive Summary

The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.

Table 1: Submitted for Review

cDMARD = conventional disease-modifying antirheumatic drug; NOC = Notice of Compliance.

Table 2: Summary of Economic Evaluation

ADT = advanced therapy; BIA = budget impact analysis; CDA-AMC = Canada’s Drug Agency; ICER = incremental cost-effectiveness ratio; LY = life-year; NMA = network meta-analysis; QALY= quality-adjusted life-year; SC = subcutaneous; TNF = tumour necrosis factor; UC = ulcerative colitis.

^aConventional therapy is assumed to comprise azathioprine, 6-mercaptopurine, methotrexate, 5-aminosalicylate, prednisone, and budesonide.

^bADT is assumed to comprise anti-TNFs (adalimumab, infliximab, and golimumab), vedolizumab, and tofacitinib.

^cNot included as a comparator in the ADT-experienced subgroup due to a lack of clinical data.

Conclusions

The CDA-AMC Clinical Review found that, compared with placebo, treatment with guselkumab results in a clinically meaningful increase in clinical remission, endoscopic healing, clinical response and maintenance of clinical response, corticosteroid-free clinical remission (maintenance therapy only), and health-related quality of life at 12 weeks of induction therapy and 44 weeks of maintenance therapy in adults with moderately to severely active ulcerative colitis (UC). Although the proposed health Canada indication is for a broader patient population than the populations enrolled in the studies (i.e., patients who have experienced an inadequate response or were unable to tolerate conventional therapy or advanced therapy [ADT]), the clinical experts consulted by CDA-AMC did not consider the proposed indication to affect the generalizability of the findings. No new safety signals were identified and the safety of guselkumab was consistent with the known safety profile the drug. Due to limitations of the indirect treatment comparison, mostly attributed to heterogeneity across studies, no conclusions can be drawn on the relative efficacy and safety of guselkumab versus other relevant comparators.

In the sponsor’s base case, guselkumab was dominated by comparators. In the ADT-naive population, guselkumab was dominated by ustekinumab and upadacitinib (greater costs: $12,641 to $27,749; fewer quality-adjusted life-years [QALYs]: 0.09 to 0.10); in the ADT-experienced population, guselkumab was dominated by ustekinumab, etrasimod, and ozanimod (greater costs: $586 to $23,076; fewer QALYs: 0.09 to 0.19). According to the CDA-AMC Clinical Review, the comparative efficacy of guselkumab versus other ADTs is uncertain. Given that no conclusions can be drawn on the relative efficacy and safety of guselkumab versus other relevant comparators, there is insufficient evidence to suggest that total treatment costs for guselkumab should be higher than other currently available biologics used in the treatment of moderately to severely active UC.

Input Relevant to the Economic Review

This section is a summary of the feedback received from patient groups and drug plans that participate in the CDA-AMC review process.

Patient group input was received from the Gastrointestinal Society and Crohn’s and Colitis Canada. Information from the Gastrointestinal Society was collected from respondents who have experience with inflammatory bowel disease through surveys, interviews, a focus group, conversations, a patient round table, and social media. Information from Crohn’s and Colitis Canada was collected from caregivers and patients in Canada who have experience with Crohn disease and UC. Input specific to UC noted that most patients reported having used a combination of medications to manage their UC that included systemic steroids, sulfasalazine and 5-aminosalicylates, biologics, immunomodulators, antibiotics, and nonsystemic steroids. Immunomodulators were more commonly used in patients with severe disease. The input noted that the majority of patients with moderate to severe UC continue to experience symptoms with current treatment options and that quality of life could be greatly improved if patients were to experience remission. No patients had experience with guselkumab.

No clinician group input was received for this review.

The drug plan input identified ustekinumab, mirikizumab, golimumab, vedolizumab, upadacitinib, adalimumab, infliximab, tofacitinib, ozanimod, and etrasimod as relevant comparators. However, the plans noted that not all relevant comparators are currently reimbursed, and funding varies by jurisdiction. It was noted that guselkumab will need to be administered by a trained health care professional in a hospital setting or infusion clinic in the induction phase and training will be required for patients or caregivers administering guselkumab in the maintenance phase. The drug plans noted there are several biologics, including biosimilars, currently reimbursed for UC; as such, it is difficult to estimate how much of the market will be displaced by guselkumab.

Several of these concerns were addressed in the sponsor’s model:

• The impact of disease and treatment on patient’s health-related quality of life was captured with utility values.

• The costs of administration during the induction period for guselkumab were included in the sponsor’s model.

Because golimumab and infliximab were not included as comparators in the sponsor’s pharmacoeconomic base case in the ADT-experienced population, and because training costs for subcutaneous administration for guselkumab in the maintenance phase were also not included in the sponsor’s base case, the comparative clinical efficacy of guselkumab versus comparators is uncertain; CDA-AMC was unable to address this concern.

Economic Review

Economic Evaluation

Summary of Sponsor’s Economic Evaluation

Overview

The sponsor submitted a cost-utility analysis (CUA) assessing guselkumab compared with adalimumab, conventional therapy (i.e., 6-mercaptopurine, azathioprine, or corticosteroids), etrasimod, golimumab, infliximab, mirikizumab, ozanimod, tofacitinib, upadacitinib, ustekinumab, and vedolizumab for adult patients with moderately to severely active UC who have experienced an inadequate response or failure to tolerate conventional therapy (ADT-naive subgroup) or ADT (i.e., tumour necrosis factor antagonists, vedolizumab, or tofacitinib) (ADT-experienced subgroup).¹ The modelled population was aligned with the population enrolled in the QUASAR trial.² However, the modelled population is narrower than the proposed Health Canada indication and reimbursement request, which do not restrict the use of guselkumab to those who have experienced an inadequate response or failure to tolerate conventional therapy or ADT.³

Guselkumab is available as a 100 mg/mL solution for injection in either a prefilled syringe or patient-controlled injector, as a 200 mg/2 mL solution for injection in a prefilled syringe or prefilled pen, and as a 200 mg/20 mL vial for IV infusion at a submitted price of $3,059.74.¹ The recommended dosage, per the proposed product monograph, is 200 mg by IV in week 0, week 4, and week 8 followed by 100 mg by subcutaneous injection at week 16 and 100 mg every 8 weeks thereafter.³ The product monograph notes that a dose of 200 mg administered by subcutaneous injection at week 12 and 200 mg administered every 4 weeks thereafter may be considered for patients who do not show adequate therapeutic benefit to guselkumab or according to clinical judgment.³ Assuming 49.7% of patients received the lower maintenance dose (i.e., 100 mg every 8 weeks) and assuming wastage of unused product (i.e., no vial sharing), the sponsor estimated drug acquisition costs for guselkumab to be $32,252 in year 1 and $29,995 annually thereafter. Comparator costs ranged from $1,617 (for conventional therapy) to $37,060 (for vedolizumab) in year 1 and $1,370 (for conventional therapy) to $32,616 (for vedolizumab) annually in the maintenance period.

The clinical outcomes modelled were clinical response and clinical remission. The model simulated life-years, QALYs, and costs for each treatment over a lifetime time horizon (58 years), discounted at a rate of 1.5% per annum. The analysis was undertaken from the perspective of the Canadian public health care payer.

Model Structure

The sponsor’s analysis included a short-term induction phase and a longer-term maintenance phase (Appendix 2, Figure 1 and Figure 2), with the same model structure for both the ADT-naive subgroup and ADT‑experienced subgroup. Patients entered the induction phase and received guselkumab or a comparator. The length of induction differed across treatments (range, 8 to 12 weeks). At the end of the induction period, patients could experience either a response or remission and receive the same treatment during maintenance therapy, not experience a response to therapy and transition to another ADT, or transition to the death health state.

Following the induction phase, patients who had experienced remission or a response entered the maintenance phase in the corresponding health state and remained on their initial treatment. Each cycle (2‑week cycle length), a proportion of patients in these states was assumed to be at risk of experiencing a loss of response. The sponsor assumed that patients who do not experience a response to initial treatment or who experience the loss of the initial response will try up to 2 lines of subsequent therapy, with a portion of patients transitioning to conventional therapy each cycle. Patients who transition to conventional therapy may transition to the first surgical health state, after which they could experience surgical remission or complications. Patients who experienced surgical complications could receive a second surgery, after which they were assumed to not experience any further complications. All patients who undergo surgery were assumed to remain in the postsurgery health states for the remainder of the model’s time horizon. Patients could transition to death from any health state.

Model Inputs

Baseline patient characteristics in the model were aligned with those of the QUASAR induction trial (ADT‑naive subgroup: aged 39.6 years, weight of 71.4 kg, 57.1% male; ADT-experienced subgroup: aged 42.2 years, weight of 72.2 kg, 58.1% male).² Patient weight was used to calculate treatment costs for therapies with weight-based dosing.

Transition probabilities between health states were derived from the sponsor-submitted network meta-analyses (NMAs).⁴ A constant risk of loss of response was assumed throughout the maintenance period to extrapolate beyond the trial period. The probabilities of undergoing surgery and postsurgery complications were derived from the literature.^5,6 The rate of serious infections was obtained from the QUASAR trial for guselkumab and conventional therapy and from published sources for all other ADTs.^7-16 Discontinuation of ADT was assumed to occur only due to a loss of response; it was assumed no patients discontinued ADT during the induction period.

The sponsor incorporated age- and sex-specific mortality risk in the model,¹⁷ as well as an increased risk of mortality for patients in the surgery health states compared with the general population in Canada (standardized mortality ratio = 1.3).¹⁸

Health state utility values were sourced from published literature and a utility decrement was included for serious infections.^19-21

The costs considered in the submitted economic model included those associated with drug acquisition and administration, health care resource use, surgery, and serious infections (i.e., adverse events). Drug acquisition costs, including for guselkumab, were obtained from the 2024 McKesson Price list,²² and the recommended dosages were based on the Health Canada–approved monograph for each treatment. For treatments in which both a low dose and a high dose for maintenance are specified in the product monograph (i.e., guselkumab, adalimumab, infliximab, golimumab, vedolizumab, ustekinumab, tofacitinib, and upadacitinib), the proportion of patients receiving a low dose versus a high dose was based on the clinical expert input elicited by the sponsor and, for golimumab and upadacitinib, on the CADTH review of upadacitinib for rheumatoid arthritis.²³ Administration costs for IV treatments were sourced from Tam et al.²⁴ Infusion times for guselkumab were sourced from the QUASAR trial; comparator infusion times were sourced from their respective product monographs.^10,11,25,26 For simplicity, the cost of concomitant therapies (e.g., immunomodulators) was not considered. Health care resource use frequencies were sourced primarily from the UK;^27-29 costs were obtained from various sources.^30-32 The costs of serious infections were derived from a previous CADTH submission and published literature.^23,33

Summary of Sponsor’s Economic Evaluation Results

The base-case analyses were run probabilistically (3,000 iterations); the sensitivity analyses were conducted deterministically. The deterministic and probabilistic results were similar. The probabilistic findings are presented subsequently.

Base-Case Results

The submitted analysis was based on publicly available prices of the comparator treatments. Results from the base case of the submitted economic evaluation are presented in Table 3 and Table 4. Additional results from the sponsor’s submitted economic evaluation base case are presented in Appendix 2.

In the sponsor’s submitted base case for the ADT-naive subgroup, the expected total costs and QALYs over a lifetime horizon for guselkumab were $301,857 and 14.44, respectively (Table 3). In the sponsor’s submitted base case for the ADT‑experienced subgroup, the expected total costs and QALYs over a lifetime horizon for guselkumab were $282,610 and 13.62, respectively (Table 4). In both subgroups, guselkumab was dominated (i.e., guselkumab is more costly and less effective than at least 1 comparator). In the ADT‑naive subgroup, guselkumab was dominated by ustekinumab biosimilar and upadacitinib (greater costs: $27,749 and $12,641, respectively; fewer QALYs: 0.10 and 0.09, respectively). In the ADT‑experienced subgroup, guselkumab was dominated by ustekinumab biosimilar, etrasimod, and ozanimod (greater costs: $20,506, $23,076, and $586, respectively; fewer QALYs: 0.09, 0.17, and 0.19, respectively). In both subgroups, guselkumab had a 0% probability of being cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained. Results were driven largely by drug acquisition costs and QALYs gained in the “remission” health state (refer to Table 6 and Table 7 for disaggregated results for the ADT‑naive and ADT‑experienced subgroups, respectively).

Table 3: Summary of the Sponsor’s Economic Evaluation Results, ADT-Naive Subgroup

ADT = advanced therapy; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Source: Sponsor’s pharmacoeconomic submission.¹

Table 4: Summary of the Sponsor’s Economic Evaluation Results, ADT-Experienced Subgroup

ADT = advanced therapy; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Source: Sponsor’s pharmacoeconomic submission.¹

Sensitivity and Scenario Analysis Results

The sponsor conducted deterministic scenario analyses encompassing considerations such as alternative time horizons, discount rates, utility values, comparators in the ADT-experienced population, induction and maintenance response rates, the inclusion of a delayed response period, the exclusion of subsequent therapies, and the exclusion of adverse events. The results of the sponsor’s scenario analyses in both subgroups showed that guselkumab remained dominated (i.e., guselkumab is more costly and less effective than at least 1 comparator).

The sponsor conducted scenario analyses from a societal perspective for both the ADT-naive and ADT‑experienced subgroups. These analyses included additional costs associated with loss of productivity. Similar to the sponsor’s base-case analysis using a health care payer perspective, guselkumab was dominated in both the ADT‑naive and ADT‑experienced subgroups.

CDA-AMC Appraisal of the Sponsor’s Economic Evaluation

CDA-AMC identified several key limitations to the sponsor’s analysis that have notable implications on the economic analysis:

• The comparative clinical efficacy and safety of guselkumab compared with other biologics is uncertain: There was no direct head-to-head evidence comparing guselkumab with other biologics used to treat UC in Canada. To inform the comparative efficacy estimate in the pharmacoeconomic analysis, the sponsor conducted NMAs that assessed the short-term comparative efficacy of guselkumab versus biologics in ADT-naive and ADT-experienced populations separately. According to the CDA-AMC Clinical Review, guselkumab was not statistically significantly better than any active comparators for: clinical remission in the induction analysis of the ADT nonfailure and ADT failure populations, clinical remission in the maintenance analysis of the ADT failure population, and clinical response in the maintenance analysis of the ADT failure population. As well, for clinical remission in the induction analysis of the ADT failure population, upadacitinib was favoured over guselkumab. For clinical remission in the maintenance analysis of the ADT nonfailure population, clinical response in the induction analysis of the ADT nonfailure and ADT failure populations, and clinical response in the maintenance analysis of the ADT nonfailure population, guselkumab was favoured over some comparators. Therefore, the NMA results indicate that guselkumab may be no different than, superior to, or inferior to some comparators, depending on the population and the outcome examined. Uncertainty regarding incremental benefit is demonstrated in the scatterplot results for guselkumab versus comparators (Appendix 2, Figure 3 and Figure 4), which highlight that, for most comparisons, guselkumab could lead to incremental benefit or harm. However, this conclusion is limited because, according to the CDA-AMC Clinical Review, no definitive conclusions could be drawn on the relative treatment effects of guselkumab versus other relevant comparators for the treatment of moderately to severely active UC. This was due to notable sources of heterogeneity for potential effect modifiers across the included studies (including trial design characteristics, patient eligibility criteria, baseline patient characteristics, and the definitions and methods for reporting outcomes). Additionally, the comparative safety of guselkumab relative to other ADTs is unknown because safety was not assessed in the sponsor’s NMAs.

  • Given the lack of direct evidence and limitations with the sponsor’s NMAs, the comparative efficacy and cost-effectiveness of guselkumab relative to other therapies currently reimbursed for adult patients with moderately to severely active UC who have experienced an inadequate response or failure to tolerate conventional therapy or ADT is highly uncertain. As such, it is uncertain whether guselkumab provides a net benefit relative to other therapies that are currently funded. CDA-AMC was unable to address this limitation in reanalyses.

• Comparators were not aligned between the pharmacoeconomic analysis and the budget impact analysis (BIA): In the sponsor’s pharmacoeconomic analysis, conventional therapy was included as a comparator for guselkumab. According to the clinical expert feedback received for this review, given the number of existing biologic treatments available for UC, the proportion of patients who would receive conventional therapy as opposed to an advanced treatment is expected to be low. As such, the relevancy of conventional therapy as a comparator is highly uncertain. The uncertainty in the relevance of conventional therapy as a comparator is further highlighted in the sponsor’s BIA, which did not include conventional therapy as a comparator. As such, the BIA implies that the entry of guselkumab will not impact the proportion of patients receiving conventional therapy, meaning that conventional therapy will not be displaced by guselkumab.

  Additionally, infliximab and golimumab were not included as comparators in the pharmacoeconomic analysis for the ADT-experienced population due to a lack of clinical data in this population.¹ In the sponsor’s BIA, infliximab has a market share of 15%, 13%, and 11% in years 1, 2, and 3, respectively, indicating that it is available and being used in the ADT-experienced population. Infliximab’s relevance as a comparator in the ADT-experienced population was confirmed by the clinical expert feedback received by CDA-AMC for this review. While golimumab’s market share in the BIA was small, it was identified by the clinical experts and in the drug plan input as being a relevant comparator in the ADT-experienced population.

  • In a scenario where conventional therapy is not a comparator, guselkumab would continue to be dominated by ustekinumab and upadacitinib in an ADT-naive population, and by ustekinumab, etrasimod, and ozanimod in an ADT-experienced population. Therefore, although the relevance of conventional therapy as a comparator is uncertain, excluding such therapy is not expected to change the overall conclusions regarding the cost-effectiveness of guselkumab.

  • In the absence of evidence, the relative effectiveness of guselkumab versus infliximab and golimumab is unknown. Based on the sponsor’s submitted price for guselkumab and the public list prices for comparators, drug acquisition costs for guselkumab are expected to be higher than for infliximab and golimumab (Table 5). Therefore, the inclusion of infliximab and golimumab in the ADT-experienced analysis is unlikely to change the overall conclusions regarding the cost-effectiveness of guselkumab (i.e., guselkumab is expected to remain dominated by ustekinumab, etrasimod, and ozanimod).

• The proportion of patients receiving high versus low dosing for guselkumab and comparators is uncertain: In the sponsor’s pharmacoeconomic analysis for guselkumab and comparators, the sponsor assumed that a proportion of patients would receive the low or high dose of a given treatment, which was meant to reflect dose escalations and de-escalations. The proportion of people receiving guselkumab 100 mg every 8 weeks versus 200 mg every 4 weeks was informed by the QUASAR trial and the opinion of the sponsor’s clinical expert.^1,2 The distribution of patients across the low and high doses for comparator regimens was based on the opinion of the sponsor’s clinical expert and a previous CADTH review.^1,23 This approach is uncertain for several reasons.

• Firstly, the proportion of patients on the high-dose treatment differed between the pharmacoeconomic analysis and the BIA for guselkumab, despite both citing the same sources of information. In the ADT-naive population, 49.7% and 47.8% of patients received guselkumab 200 mg every 4 weeks in the CUA and BIA, respectively. In the ADT-experienced population, 50.3% and 53.3% of patients received guselkumab 200 mg every 4 weeks in the CUA and BIA, respectively. While the clinical expert feedback for this review noted it is reasonable to assume that half of all patients will be treated with high-dose guselkumab in clinical practice, the inconsistencies between the sponsor’s CUA and BIA must be noted because the proportions influence drug acquisition costs.

  Secondly, in some instances, the proportions of patients using high versus low doses for comparators did not align with the clinical expert feedback received by CDA-AMC for this review. For example, for adalimumab, the experts predicted 50% of those in the ADT-naive population would receive the high dose rather than the 30% assumed by the sponsor; for vedolizumab, the experts predicted 50% of those in the ADT-naive population would receive the high dose rather than the 30% assumed by the sponsor and, for upadacitinib, the experts predicted 80% of those in the ADT-naive population would receive the high dose rather than the 44% assumed by the sponsor. Finally, the clinical expert feedback received by CDA-AMC for this review indicated some use of off-label dosing for some comparators. For golimumab, the experts indicated that approximately 10% of ADT-experienced patients would receive 100 mg every 2 weeks. For ustekinumab, the experts indicated that most patients, irrespective of ADT experience, would receive 90 mg every 4 weeks. Therefore, there is uncertainty in the dosing for comparator treatments, introducing uncertainty in comparator costs.

  • In the ADT-naive population, the overall conclusions regarding the cost-effectiveness of guselkumab are unlikely to change if the doses for comparators were adjusted. If a greater proportion of patients used the high dose for adalimumab, vedolizumab, and upadacitinib, guselkumab would remain dominated by ustekinumab. If all patients receiving ustekinumab received the 90 mg every 4 weeks dosage, guselkumab would remain dominated by upadacitinib. If both steps are combined, then guselkumab remains off the frontier because it would be extendedly dominated by tofacitinib.

  • In the ADT-experienced population, the overall conclusions regarding the cost-effectiveness of guselkumab are unlikely to change if the doses for comparators were adjusted. If all patients receiving ustekinumab received the 90 mg every 4 weeks dosage, then guselkumab would remain dominated by etrasimod and ozanimod.

Additional limitations were identified but were not considered to be key limitations. These limitations are outlined subsequently.

• The sponsor’s model had additional issues: During the review process, additional issues were identified with the sponsor’s model but these were not prioritized, given the uncertainty in the comparative clinical evidence. For example, the lack of long-term evidence available, the remission utility value implying that those in remission with UC have a better quality of life than the general public in Canada, the assumption of no vial sharing, and uncertainty in the impact of subsequent therapy on efficacy and costs.

  • Addressing these limitations would not resolve the uncertainty in the clinical evidence that precludes drawing conclusions regarding the comparative safety and efficacy of guselkumab versus comparators.

Issues for Consideration

• CADTH previously reviewed guselkumab for plaque psoriasis and psoriatic arthritis, both of which received a recommendation to reimburse with clinical criteria and/or conditions.^34,35 In both reviews, the Canadian Drug Expert Committee recommended that guselkumab be reimbursed with the condition that the drug plan cost for guselkumab not exceed the drug plan cost of treatment with the least costly biologic reimbursed for the treatment of the respective conditions.^34,35 In both reviews, the sponsor-submitted price for guselkumab was aligned with the submitted price for this review.^34,35

• Ustekinumab biosimilars, adalimumab biosimilar, infliximab biosimilar, vedolizumab, golimumab, ozanimod, tofacitinib, mirikizumab, and upadacitinib have successfully completed negotiations with the pan-Canadian Pharmaceutical Alliance for UC and are listed on public formularies;³⁶ etrasimod is currently under active negotiation.³⁶ Therefore, the price paid by the drug plans for comparators may be lower than the price incorporated in the sponsor’s pharmacoeconomic model.

• According to the drug plan input received for this review, coverage of UC treatments varies across drug plans, and not all drug plans may cover all of the treatments considered in the sponsor’s analysis.

• The sponsor’s proposed indication for guselkumab does not restrict use to patients who have experienced an inadequate response or failure to tolerate conventional therapy or ADT (i.e., the target population of the CUA). The clinical expert input received by CDA-AMC indicated that patients who had not been previously treated with conventional therapy would likely not be considered for treatment with guselkumab; however, the cost-effectiveness among patients who are naive to conventional therapy is unknown, owing to a lack of clinical data.