Reimbursement Review

Guselkumab (Tremfya)

Sponsor: Janssen Inc.

Therapeutic area: Crohn disease

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 the Application Submitted for Review

NOC = Notice of Compliance.

Source: Product monograph for Tremfya.¹

Introduction

Crohn disease (CD) is a chronic form of inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal tract, but most commonly affects the ileum (i.e., small intestine), colon (i.e., the beginning of the large intestine), and rectum.^2,3 CD is typically diagnosed in adolescents and young adults, most commonly between the ages of 20 years and 30 years.⁴ In 2023, the incidence of IBD in Canada was estimated at 30 per 100,000 individuals, with CD accounting for 12.2 per 100,000.⁵ CD can manifest in 3 phenotypical forms: inflammatory, stricturing, and penetrating (fistulas and abscesses).⁶ Common symptoms of CD include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.^4,7,8 Potential complications of CD include malnutrition, anemia, bowel obstructions, fistulas, anal fissures, and intra-abdominal or other abscesses and ulcers.^2,3 Risk factors for CD include cigarette smoking, a family history of IBD, prior infectious gastroenteritis, and frequent use of nonsteroidal anti-inflammatory drugs.⁹

The diagnosis of CD is established through a comprehensive assessment that integrates clinical evaluation with endoscopic, histological, radiological, and/or biochemical investigations.⁹ Therapeutic goals include inducing and maintaining clinical and endoscopic remission. Pharmaceutical treatments for CD include immunosuppressants, corticosteroids, tumour necrosis factor (TNF) alpha antagonists, interleukin inhibitors, Janus kinase inhibitors, and integrin inhibitors. The medical management of CD generally follows a stepwise approach, in which therapies are initiated sequentially and escalated to more advanced drugs or higher doses in cases of inadequate response. Not all patients respond to available treatments and their disease may become refractory to the current treatment regimens.

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 in the treatment of adult patients with moderately to severely active CD. The recommended induction dosage of guselkumab is either 200 mg administered by IV infusion, or 400 mg of guselkumab administered by subcutaneous (SC) injection at week 0, week 4, and week 8. For maintenance therapy, the recommended dosage of guselkumab is 100 mg administered by SC injection at week 16 and every 8 weeks thereafter, or 200 mg administered by SC injection at week 12 and every 4 weeks. The indication for guselkumab is for the treatment of adult patients with moderately to severely active CD, and the sponsor’s submitted reimbursement criteria align with this indication.

Perspectives of Patient, Clinicians, and Drug Programs

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

Patient Input

Two patient inputs were summarized for this review. The Gastrointestinal Society (GI Society) is a national charity with programs and services that support research, advocate for appropriate patient access to health care, and promote gastrointestinal and liver health. Crohn’s and Colitis Canada is a national, volunteer-based health charity focused on finding the cures for CD and ulcerative colitis. Information from both inputs was gathered from varied sources, which included published perspectives, online surveys, interviews with patients, and questionnaires.

The patient groups noted that CD often has a profound effect on patients’ quality of life, affecting physical, emotional, and social factors of patients at home, at school, or in the workplace. Disease severity may fluctuate, thus requiring routine testing, reassessments, and medication changes. The GI Society noted that patients with CD preferred sustained remission and treatment response over relieving any 1 symptom. In a survey conducted by Crohn’s and Colitis Canada, most respondents with moderate IBD (53%) and severe IBD (60%) believed that access to different treatment options could make them feel better. Both groups noted that treating CD requires a multifaceted strategy that allows for the management of symptom and disease consequences with therapies that target and reduce the underlying inflammation. Respondents in both patient group inputs highlighted that they had exposure to the following treatment options: systemic steroids, biologics and biosimilars, immunomodulators and antibiotics, sulfasalazine, 5-aminosalicylates, and nonsystemic steroids. The majority of patients with moderate to severe CD who participated in the surveys expressed that they continued to experience symptoms with current treatment options. Both patient groups expressed that patients need effective treatment options that mitigate symptoms and improve quality of life, are convenient, and can be accessed in a timely manner. Patients expressed that they desired fewer medications and treatments that are safe, can minimize the use of steroids, can be administered at home, and can be taken as pills.

Major concerns regarding the existing treatments identified by the GI Society included limited access to adequate treatment supplies and continuity of care given that some patients respond differently to various medications, and in some cases may stop responding to medications after using them for some time. Both groups noted that patients have varied preferences for medication administration, influenced by a range of factors. One group noted the importance of varied treatment options that can cater to individual needs, without a requirement to trial conventional therapies before accessing targeted treatments. Therefore, there is a need for new, effective treatments for patients that could improve quality of life and eliminate symptoms, pain, frustration, and hardship.

Clinician Input

Input From Clinical Experts Consulted for This Review

According to the clinical experts consulted by CDA-AMC, although a variety of treatment options are available for CD, not all patients respond adequately to existing therapies. The clinical experts consulted emphasized the importance of introducing highly effective treatments early in the disease treatment to optimize patient outcomes. Furthermore, the clinical experts identified a significant barrier to accessing biologics; a requirement was for patients whose disease had demonstrated an inadequate response to or inability to tolerate conventional therapy (i.e., immunomodulators) before initiating biologic treatment. Additionally, the clinical experts noted that the absence of clear guidance on the optimal sequencing of biologic therapies contributes to clinical uncertainty, often leading to treatment decisions being made without the support of robust comparative evidence.

The clinical experts indicated that guselkumab is unlikely to dramatically shift the current treatment paradigm for CD and is expected to be used similarly to other biologic therapies. Nonetheless, the clinical experts agreed that guselkumab should be accessible as a treatment option for patients with moderately to severely active CD and that it should not be reserved only for those who are intolerant of or have contraindications to other biologic drugs. The clinical experts also highlighted that a favourable safety profile makes it a viable alternative for patients who have experienced adverse effects with other therapies, such as anti-TNF drugs. According to the clinical experts consulted, guselkumab is considered appropriate for a broad population, including both patients with no prior exposure to biologics and patients with previous exposure to biologics — particularly those whose disease has not demonstrated improvement with or is intolerant of conventional therapies or other biologics. Patients best suited should have an established diagnosis of CD based on an ileocolonoscopy with active disease.

The clinical expert noted the following outcomes are used to determine patient response to treatment: clinical response or remission, endoscopic response or remission, and improved health-related quality of life (HRQoL). According to the clinical experts consulted, clinicians monitor response using a combination of symptom burden, endoscopic assessment, and biomarkers such as fecal calprotectin and C-reactive protein (CRP). The clinical experts indicated that the discontinuation of guselkumab may be considered in cases of primary nonresponse, worsening patient-reported outcomes (PROs), rising biomarkers, or adverse events (AEs) that cannot be adequately managed. The clinical experts emphasized that patients receiving guselkumab should be diagnosed, treated, and monitored by a specialist, such as a gastroenterologist or an internal medicine physician.

Clinician Group Input

No clinical group input was submitted 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:

• relevant comparators

• consideration for the initiation of therapy

• consideration for the continuation or renewal of therapy

• consideration of the discontinuation of therapy

• consideration for the prescribing of therapy.

The clinical experts consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug programs.

Clinical Evidence

Systematic Review

Description of Studies

Three multicentre, double-blind, randomized controlled trials (RCTs) — the GALAXI 2 study (N = 508), the GALAXI 3 study (N = 513), and the GRAVITI study (N = 347) — were included in the sponsor-submitted systematic literature review (SLR).

The GALAXI 2 and GALAXI 3 trials are identically designed, phase III, randomized, double-blind, placebo- and active-controlled (versus ustekinumab), parallel-group, multicentre trials. The primary objectives of both trials were to evaluate the clinical and endoscopic efficacy, and safety, of guselkumab in patients with moderately to severely active CD that has demonstrated an inadequate response to or failure to tolerate previous conventional therapy (oral corticosteroids and/or immunomodulators) or biologic therapy. Each trial included a 48-week main treatment phase, consisting of a 12-week induction period followed by a 36-week maintenance period. In both trials, patients in the guselkumab group received an induction dose of 200 mg intravenously every 4 weeks, followed by maintenance treatment with either 100 mg subcutaneously every 8 weeks (guselkumab regimen 1 [low dose]) or 200 mg SC every 4 weeks (guselkumab regimen 2 [high dose]). In the active control group, patients received a single weight-based IV dose of ustekinumab at week 0 (approximately 6 mg/kg), followed by SC maintenance dosing of 90 mg every 8 weeks. Patients were enrolled at 186 centres from 36 countries or territories (including 31 sites in Canada) in the GALAXI 2 trial, and 198 centres across 39 countries or territories (including 31 sites in Canada) in the GALAXI 3 trial.

The GRAVITI trial is a phase III, randomized, double-blind, placebo-controlled, parallel-group, multicentre study. The primary objectives of the GRAVITI trial were to evaluate the efficacy and safety of guselkumab in patients with moderately to severely active CD whose disease had demonstrated an inadequate response or intolerance to prior conventional therapy or biologic treatments. The 24-week main treatment phase included a 12-week induction period followed by a 12-week maintenance period; this was then followed by the extension treatment phase that included a 72-week maintenance period. During the GRAVITI trial, patients received guselkumab at a dose of 400 mg SC at week 0, week 4, and week 8 for induction, followed by either 100 mg SC every 8 weeks (guselkumab regimen 1 [low dose]) or 200 mg SC every 4 weeks (guselkumab regimen 2 [high dose]) for maintenance. Patients were enrolled at 143 centres from 23 countries or territories, including 5 sites in Canada.

Efficacy Results

Clinical Response at Week 12 and Clinical Remission at Week 48

GALAXI 2 and GALAXI 3 studies (IV induction and SC maintenance): In the GALAXI 2 study, the adjusted between-group difference compared to placebo was 38.1% (95% confidence interval [CI], 27.3% to 48.9%; P value < 0.001) for guselkumab regimen 1 (low dose) and 42.8% (95% CI, 31.6% to 53.9%; P value < 0.001) for guselkumab regimen 2 (high dose). In the GALAXI 3 study, the adjusted between-group difference compared to placebo was 34.2% (95% CI, 23.2% to 45.3%; P value < 0.001) for guselkumab regimen 1 and 35.0% (95% CI, 23.5% to 46.5%; P value < 0.001) for guselkumab regimen 2. Sensitivity, supportive, and subgroup analyses — including those conducted in patients with a history of biologic therapy inadequate response or intolerance (BIO-Failure group) and those with a history of conventional therapy inadequate response or intolerance (CON-Failure group) — were consistent with the primary analyses in both trials.

Clinical Response at Week 12 and Endoscopic Response at Week 48

GALAXI 2 and GALAXI 3 studies (IV induction and SC maintenance): In the GALAXI 2 study, the adjusted between-group difference compared to placebo was 33.7% (95% CI, 24.1% to 43.2%; P value < 0.001) for guselkumab regimen 1 and 32.9% (95% CI, 23.5% to 42.4%; P value < 0.001) for guselkumab regimen 2. In the GALAXI 3 study, the adjusted between-group difference compared to placebo was 27.9% (95% CI, 18.7% to 37.1%; P value < 0.001) for guselkumab regimen 1 and 30.8% (95% CI, 21.3% to 40.3%; P value < 0.001) for guselkumab regimen 2. Sensitivity, supportive, and subgroup analyses —including those conducted in the BIO-Failure and CON-Failure analysis subpopulations — were consistent with the primary analyses in both trials.

Clinical Response at Week 12 and 90-Day, Corticosteroid-Free Clinical Remission at Week 48

GALAXI 2 and GALAXI 3 studies (IV induction and SC maintenance): In the GALAXI 2 study, the adjusted between-group difference compared to placebo was 38.7% (95% CI, 28.4% to 48.9%; P value < 0.001) for guselkumab regimen 1 and 41.3% (95% CI, 30.6% to 52.0%; P value < 0.001) for guselkumab regimen 2. In the GALAXI 3 study, the adjusted between-group difference compared to placebo was 32.6% (95% CI, 21.7% to 43.6%; P value < 0.001) for guselkumab regimen 1 and 31.5% (95% CI, 20.1% to 42.8%; P value < 0.001) for guselkumab regimen 2.

Clinical Response at Week 12 and Endoscopic Remission at Week 48

GALAXI 2 and GALAXI 3 studies (IV induction and SC maintenance): In the GALAXI 2 study, the adjusted between-group difference compared to placebo was 24.0% (95% CI, 15.8% to 32.2%; P value < 0.001) for guselkumab regimen 1 and 30.0% (95% CI, 21.4% to 38.5%; P value < 0.001) for guselkumab regimen 2. In the GALAXI 3 study, the adjusted between-group difference compared to placebo was 18.2% (95% CI, 9.5% to 26.9%; P value < 0.001) for guselkumab regimen 1 and 16.7% (95% CI, 8.0% to 25.4%; P value < 0.001) for guselkumab regimen 2.

Clinical Remission at Week 12

GALAXI 2 and GALAXI 3 studies (IV induction and SC maintenance) and GRAVITI trial (SC induction and SC maintenance): In the GALAXI 2 study, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 25.1% (95% CI, 14.1% to 36.2%; P value < 0.001) compared to placebo. In the GALAXI 3 study, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 31.2% (95% CI, 21.1% to 41.3%; P value < 0.001) compared to placebo.

In the GRAVITI trial, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 34.9% (95% CI, 25.1% to 44.6%; P value < 0.001) compared to placebo. Sensitivity and subgroup analyses — including those in the BIO-Failure and CON-Failure analysis subpopulations — were consistent with the primary analyses.

Clinical Remission at Week 48

GRAVITI study (SC induction and SC maintenance): In the GRAVITI study, the adjusted between-group difference compared to placebo was 42.8% (95% CI, 31.6% to 54.0%; P value < 0.001) for guselkumab regimen 1 and 48.9% (95% CI, 37.9% to 59.9%; P value < 0.001) for guselkumab regimen 2.

Endoscopic Response at Week 12

GALAXI 2 and GALAXI 3 studies (IV induction and SC maintenance) and GRAVITI trial (SC induction and SC maintenance): In the GALAXI 2 study, the combined guselkumab induction dose group showed an adjusted between-group difference of 27.7% (95% CI, 19.3% to 36.1%; P value < 0.001) compared to placebo. In the GALAXI 3 study, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 22.1% (95% CI, 12.2% to 31.9%; P value < 0.001) compared to placebo.

In the GRAVITI trial, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 19.9% compared to placebo (95% CI, 10.2% to 29.6%; P value < 0.001). Sensitivity and subgroup analyses — including those conducted in the BIO-Failure and CON-Failure analysis subpopulations — were consistent with the primary analyses.

Endoscopic Response at Week 48

GRAVITI study (SC induction and SC maintenance): The adjusted between-group difference compared to placebo was 37.5% (95% CI, 27.3% to 47.7%; P value < 0.001) for guselkumab regimen 1 and 44.6% (95% CI, 34.1% to 55.0%; P value < 0.001) for guselkumab regimen 2.

Endoscopic Remission at Week 48

GRAVITI study (SC induction and SC maintenance): The adjusted between-group difference compared to placebo was 24.5% (95% CI, 15.2% to 33.9%; P value < 0.001) for guselkumab regimen 1 and 32.4% (95% CI, 22.6% to 42.3%; P value < 0.001) for guselkumab regimen 2.

Clinical Response at Week 12

GRAVITI study (SC induction and SC maintenance): The combined guselkumab induction dose group demonstrated an adjusted between-group difference of 40.3% compared to placebo (95% CI, 29.9% to 50.7%; P value < 0.001).

Deep Remission at Week 48

GRAVITI study (SC induction and SC maintenance): The adjusted between-group difference compared to placebo was 21.8% (95% CI, 13.1% to 30.6%; P value < 0.001) for guselkumab regimen 1 and 29.8% (95% CI, 20.5% to 39.2%; P value < 0.001) for guselkumab regimen 2.

Patient-Reported Outcomes

Inflammatory Bowel Disease Questionnaire (IBDQ) remission at week 12, GALAXI 2 and GALAXI 3 studies (IV induction and SC maintenance) and GRAVITI trial (SC induction and SC maintenance): In the GALAXI 2 study, the adjusted between-group difference compared to placebo was 19.1% (95% CI, 6.7% to 31.5%; P value = 0.003) for guselkumab regimen 1 and 10.5% (95% CI, –2.3% to 23.2%; P value = 0.108) for guselkumab regimen 2. In the GALAXI 3 study, the adjusted between-group difference compared to placebo was 23.7% (95% CI, 11.1% to 36.4%; P value < 0.001) for guselkumab regimen 1 and 16.5% (95% CI, 3.0% to 30.1%; P value = 0.017) for guselkumab regimen 2. In the GRAVITI trial, the adjusted between-group difference compared to placebo was 29.2% (95% CI, 17.4% to 41.0%; P value < 0.001) for guselkumab regimen 1 and 20.8% (95% CI, 9.2% to 32.4%; P value < 0.001) for guselkumab regimen 2.

IBDQ remission at week 48, GRAVITI study (SC induction and SC maintenance): The adjusted between-group difference compared to placebo was 36.6% (95% CI, 25.4% to 47.8%; P value < 0.001) for guselkumab regimen 1 and 30.7% (95% CI, 19.2% to 42.1%; P value < 0.001) for guselkumab regimen 2.

Patient-reported outcome 2 (PRO-2) remission at week 48, GRAVITI study (SC induction and SC maintenance): At week 48, the adjusted between-group difference compared to placebo was 41.1% (95% CI, 30.1% to 52.1%; P value < 0.001) for guselkumab regimen 1 and 53.2% (95% CI, 42.6% to 63.7%; P value < 0.001) for guselkumab regimen 2.

Summary of Efficacy Outcomes (Guselkumab Versus Ustekinumab)

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance)

Clinical Remission at Week 48 and Endoscopic Response at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 7.8% (95% CI, 0.1% to 15.6%; P value = 0.049) for guselkumab regimen 1 and 13.6% (95% CI, 5.9% to 21.3%; P value < 0.001) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was 2.8% (95% CI, –0.6% to 21.0%) for guselkumab regimen 1 and 10.2% (95% CI, –0.6% to 21.0%) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 12.7% (95% CI, 1.7% to 23.7%) for guselkumab regimen 1 and 16.9% (95% CI, 5.8% to 27.9%) for guselkumab regimen 2.

Clinical Remission at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 2.6% (95% CI, –5.1% to 10.2%; P value = 0.512) for guselkumab regimen 1 and 7.3% (95% CI, –0.2% to 14.8%; P value = 0.058) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was –0.6% (95% CI, –11.6% to 10.5%) for guselkumab regimen 1 and 9.5% (95% CI, –0.7 % to 19.8%) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 5.6% (95% CI, –5.2% to 16.5%) for guselkumab regimen 1 and 5.0% (95% CI, –6.1% to 16.1%) for guselkumab regimen 2.

Endoscopic Response at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 10.6% (95% CI, 2.7% to 18.5%; P = 0.009) for guselkumab regimen 1 and 15.6% (95% CI, 7.9% to 23.4%; P < 0.001) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was 7.0% (95% CI, –4.4% to 18.3%) for guselkumab regimen 1 and 14.5% (95% CI, 3.6% to 25.4%) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 14.1% (95% CI, 2.9% to 25.2%) for guselkumab regimen 1 and 16.8% (95% CI, 5.7% to 28.0%) for guselkumab regimen 2.

Endoscopic Remission at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 8.5% (95% CI, 1.1% to 15.9%; P = 0.024) for guselkumab regimen 1 and 12.3% (95% CI, 4.9% to 19.7%; P = 0.001) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group treatment difference compared to ustekinumab was 6.4% (95% CI, –4.3% to 17.1%) for guselkumab regimen 1 and 17.9% (95% CI, 7.3% to 28.4%) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 10.5% (95% CI, 0.1% to 20.9%) for guselkumab regimen 1 and 6.9% (95% CI, –3.3% to 17.0%) for guselkumab regimen 2.

Deep Remission at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 7.4% (95% CI, 0.3% to 14.6%; P = 0.040) for guselkumab regimen 1 and 11.3% (95% CI, 4.2% to 18.5%; P = 0.002) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was 4.2% (95% CI, –6.2% to 14.7%) for guselkumab regimen 1 and 13.0% (95% CI, 2.7% to 23.4%) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 10.4% (95% CI, 0.4% to 20.4%) for guselkumab regimen 1 and 9.6% (95% CI, –0.1% to 19.4%) for guselkumab regimen 2.

IBDQ Remission at Week 48

In the GALAXI 2 study, the adjusted between-group difference compared to ustekinumab was 1.6% (95% CI, –9.9% to 13.2%; P value = 0.783) for guselkumab regimen 1 and 5.6% (95% CI, –5.5% to 16.7%; P value = 0.322) for guselkumab regimen 2. In the GALAXI 3 study, the adjusted between-group difference compared to ustekinumab was 10.1% (95% CI, –1.2% to 21.5%; P value = 0.080) for guselkumab regimen 1 and 2.1% (95% CI, –9.4% to 13.6%; P value = 0.725) for guselkumab regimen 2.

Harms Results

GALAXI 2 and GALAXI 3 Studies: IV Induction and SC Maintenance

Induction Period

In the GALAXI 2 study, the proportion of patients experiencing at least 1 AE was 38.5% in the guselkumab regimen 1 group, 47.3% in the guselkumab regimen 2 group, 48.3% in the ustekinumab group, and 40.8% in the placebo group. In the GALAXI 3 study, the proportion of patients experiencing at least 1 AE was 51.7% in the guselkumab regimen 1 group, 50.7% in the guselkumab regimen 2 group, 44.6% in the ustekinumab group, and 55.6% in the placebo group. In the GALAXI 2 study, the proportion of patients experiencing at least 1 serious adverse event (SAE) was 3.5% in the guselkumab regimen 1 group, 1.4% in the guselkumab regimen 2 group, 2.4% in the ustekinumab group, and 2.6% in the placebo group. In the GALAXI 3 study, the proportion of patients experiencing at least 1 SAE was 3.5% in the guselkumab regimen 1 group, 2.7% in the guselkumab regimen 2 group, 5.4% in the ustekinumab group, and 9.7% in the placebo group. In the GALAXI 2 trial, the proportion of patients who discontinued study treatment due to an AE was 2.6% in the placebo group, 0% in the guselkumab regimen 1 group, 1.4% in the guselkumab regimen 2 group, and 2.1% in the ustekinumab group. In the GALAXI 3 trial, the discontinuation rates due to AE were 6.9% in the placebo group, 2.8% in the guselkumab regimen 1 group, 3.3% in the guselkumab regimen 2 group, and 3.4% in the ustekinumab group. No deaths occurred during the induction period in either trial.

Maintenance Period

In the GALAXI 2 trial, the proportion of patients experiencing at least 1 AE was higher in the guselkumab regimen 1 group (74.1%), the guselkumab regimen 2 group (78.8%), and the ustekinumab group (78.3%) compared with the placebo group (50.0%). In the GALAXI 3 trial, the proportion of patients experiencing at least 1 AE was higher in the guselkumab regimen 1 group (79.0%), the guselkumab regimen 2 group (76.7%), and the ustekinumab group (79.1%) compared with the placebo group (56.9%). In the GALAXI 2 trial, the proportion of patients experiencing at least 1 SAE was higher in the guselkumab regimen 1 and ustekinumab groups (12.6% each) compared to the guselkumab regimen 2 group (4.1%) and placebo group (7.9%). In the GALAXI 3 trial, the proportion of patients experiencing at least 1 SAE was 8.4% in the guselkumab regimen 1 group, 10.0% in the guselkumab regimen 2 group, 10.8% in the ustekinumab group, and 13.9% in the placebo group. In the GALAXI 2 study, the proportion of patients who discontinued study treatment due to an AE during the maintenance period was 6.6% in the placebo group, 5.6% in the guselkumab regimen 1 group, 4.1% in the guselkumab regimen 2 group, and 6.3% in the ustekinumab group. In the GALAXI 3 study, the discontinuation rates due to an AE were 11.1% in the placebo group, 8.4% in the guselkumab regimen 1 group, 8.7% in the guselkumab regimen 2 group, and 8.8% in the guselkumab regimen 2 group. No deaths occurred during the maintenance period in either trial.

Notable Harms

In the GALAXI 2 study, 1 patient (0.7%) in the guselkumab regimen 1 group experienced major adverse cardiovascular events and 1 patient (0.7%) in the ustekinumab group experienced venous thromboembolism. In the GALAXI 3 study, 1 (0.7%) patient in the guselkumab regimen 1 group experienced active tuberculosis and 1 (0.7%) patient experienced a malignancy in the guselkumab regimen 2 group. Additionally, 4 patients experienced opportunistic infections, including 1 (1.4%) in the placebo group, 1 (0.7%) in the guselkumab regimen 1 group, and 2 (1.3%) in the guselkumab regimen 2 group.

GRAVITI Study: SC Induction and SC Maintenance

Induction Period

The proportion of patients who experienced at least 1 AE was 49.6% in the placebo group, 51.3% in the guselkumab regimen 1 group, and 41.7% in the guselkumab regimen 2 group. The proportion of patients experiencing at least 1 SAE was 2.6% in the guselkumab regimen 1 group, 1.7% in the guselkumab regimen 2 group, and 7.7% in the placebo group. The proportion of patients who discontinued study treatment during the induction period was 2.6% in the placebo group, 0% in the guselkumab regimen 1 group, and 0.9% in the guselkumab regimen 2 group. No deaths occurred during the induction period in the GRAVITI trial.

Maintenance Period

The proportion of patients who experienced at least 1 AE was 65.8% in the placebo group, 82.6% in the guselkumab regimen 1 group, and 80.0% in the guselkumab regimen 2 group. The proportion of patients experiencing at least 1 SAE during the maintenance period was 13.0% in the regimen 1 guselkumab group, 7.8% in the guselkumab regimen 2 group, and 13.7% in the placebo group. The proportion of patients who discontinued study treatment was 8.5% in the placebo group, 3.5% in the guselkumab regimen 1 group, and 2.6% in the guselkumab regimen 2 group. During the maintenance period, 1 (0.9%) patient died in the guselkumab regimen 1 group.

Notable Harms

In the GRAVITI study, 1 (0.7%) patient in the regimen 1 guselkumab group experienced a malignancy while in the placebo group, 1 (0.9%) patient experienced an opportunistic infection, and 1 (0.9%) patient experienced a venous thromboembolism.

Critical Appraisal

Randomization and allocation concealment for all 3 studies were conducted using appropriate methodology. A stratified, computerized randomization scheme was employed, and allocation concealment was ensured using interactive web response technology. Although there was some imbalance in baseline characteristics across the treatment groups in the GALAXI and GRAVITI trials (e.g., race, sex, several disease characteristics), these did not systematically favour any treatment group, and clinical experts did not believe these would impact the results of the pivotal trials. Additionally, they noted that the stratification factors used across all 3 trials (e.g., baseline Crohn’s Disease Activity Index [CDAI] and Simple Endoscopic Score for Crohn’s Disease [SES-CD] scores, prior biologic exposure) were deemed appropriate for minimizing confounding and ensuring balanced treatment groups. Major protocol deviations occurred in 17.5% of patients in the GALAXI 2 trial and 23.3% of patients in the GALAXI 3 trial. These deviations were balanced across treatment groups and did not appear to be related to the trial context. In the GRAVITI trial, major protocol deviations were reported in 36.8% of patients in the placebo group, 26.1% of patients in the guselkumab regimen 1 group, and 24.3% of patients in the guselkumab regimen 2 group through week 48. The uneven distribution of protocol deviations across treatment groups may potentially result in imbalanced comparisons of efficacy and safety of guselkumab relative to placebo. However, patients who received prohibited concomitant medications were addressed using a composite strategy, under which they were classified as nonresponse; this approach was considered reasonable by the review team.

The GALAXI and GRAVITI trials used a treat-through design, whereby participants remained on their assigned treatment regimen beyond the initial induction phase without rerandomization. Additionally, all 3 trials were conducted using a double-blind design, where patients, investigators, and outcome assessors were masked to treatment allocation from the time of randomization until unblinding as specified in the study protocols. In all 3 trials, the rate of treatment discontinuation before week 48 was higher in the placebo group compared to the active treatment groups. In both GALAXI trials, 49 patients crossed over to ustekinumab at week 12 due to clinical nonresponse but were still analyzed as part of the as-randomized placebo group at week 48, despite having received ustekinumab treatment from week 12 onward. In the GRAVITI trial, 44 patients in the placebo group meeting predefined criteria received guselkumab rescue treatment at week 12 or week 16. As a result, in all 3 trials, patients in the guselkumab groups who completed the study were exposed to treatment for a longer duration, potentially providing more opportunity to demonstrate efficacy or experience safety events. Dropouts for various reasons were reflected as intercurrent events (ICEs) within the trial estimands and typically considered as nonresponse, which was thought to be appropriate in most cases. Some dropouts were not clearly related to a lack of efficacy, and the nonresponse imputation (NRI) could have introduced bias, though rates of such ICEs were relatively limited in the GALAXI trials. At longer time points in the GRAVITI study, dropouts due to reasons potentially unrelated to a lack of response were increased in the placebo group compared to the guselkumab groups, which could have inflated the treatment effect estimates. After consideration of the ICEs, there were few missing data.

In general, the end points reported in all 3 trials were validated for use in patients with moderately to severely active CD. The statistical methods used to analyze the primary and secondary outcomes across all 3 trials were deemed appropriate. Multiplicity adjustments were adequately implemented for primary and secondary outcomes across all 3 trials. However, in the GALAXI trials, formal statistical testing of the long-term secondary end points comparing guselkumab with ustekinumab within the individual trials was precluded due to failure of the hierarchical testing strategy. Subgroup analyses, including those conducted in the BIO-Failure and CON-Failure analysis subpopulations, of the coprimary end points were conducted in all 3 trials as part of this review. However, the subgroup analyses were not adjusted for multiplicity and were likely underpowered to detect differences between subgroups; therefore, the findings should be considered supportive only. In all 3 trials, the use of concomitant therapies was generally balanced across treatment groups and, according to clinical experts, was unlikely to have confounded the study results. Overall, the proportion of patients who experienced SAEs was low across all 3 trials, with similar rates observed among all treatment groups.

In terms of external validity, the inclusion and exclusion criteria across all 3 trials were generally appropriate and reflective of patients eligible for guselkumab treatment in clinical practice. The clinical experts consulted noted that while certain exclusion criteria, such as strictures or a previous colectomy, are considered typical for clinical trials, they do not always reflect real-world practice where treatment decisions are often based on individual clinical judgment and may include patients typically excluded from trials. The Health Canada indication for guselkumab is for the treatment of adult patients with moderately to severely active CD. However, the GALAXI and GRAVITI trials included patients with moderately to severely active CD whose disease had demonstrated an inadequate response to or inability to tolerate previous conventional therapy or biologic therapy. The clinical experts noted that the trial design reflects real-world clinical practice; however, they emphasized that the distribution of patients with no prior exposure to biologics versus patients with previous exposure to biologics may differ between community and tertiary care settings. In the GALAXI 2 and GALAXI 3 trials, guselkumab was evaluated against both an active comparator (ustekinumab) and placebo. The active comparator used in these trials was appropriate because ustekinumab is currently used in clinical practice. The end points included in the trials were considered appropriate by the clinical experts, although they noted that the Harvey-Bradshaw Index is more commonly used in Canadian clinical practice than the CDAI score. Although there is a disconnect between tools used in trials and in clinical practice, clinical experts emphasized that the use of CDAI in trials does not pose a barrier to applying the results, because clinicians are well familiar with its components. The clinical experts considered the 48-week maintenance period following the 12-week induction period to be appropriate and sufficient for evaluating the long-term efficacy and safety of guselkumab in patients with CD.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^10,11

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence¹² consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• guselkumab compared with placebo — clinical response at week 12 and clinical remission at week 48, clinical response at week 12 and endoscopic response at week 48, clinical response at week 12 and 90-day, corticosteroid-free clinical remission at week 48, clinical response at week 12 and endoscopic remission at week 48, IBDQ remission at week 12, clinical remission at week 12 and week 48, endoscopic response at week 12 and week 48, endoscopic remission at week 48, IBDQ remission at week 48, and PRO-2 remission at week 48

• guselkumab compared with ustekinumab — clinical remission at week 48, endoscopic response at week 48, endoscopic remission at week 48, clinical remission and endoscopic response at week 48, and IBDQ remission at week 48

• harms — SAEs.

Results of GRADE Assessments

Table 2 and Table 3 present the GRADE summary of findings for guselkumab versus placebo (IV induction and SC maintenance, high and low dose) in the GALAXI trials and the GRAVITI study (SC induction and SC maintenance, high and low dose), respectively. Table 4 presents the GRADE summary of findings for guselkumab versus ustekinumab in the GALAXI 2 and GALAXI 3 trials (IV induction and SC maintenance, high and low dose).

Table 2: Summary of Findings for Guselkumab vs. Placebo for Patients With Crohn Disease — GALAXI Trials, IV Induction and SC Maintenance (Regimen 1 and Regimen 2)

AP = abdominal pain; CD = Crohn disease; CDA-AMC = Canada’s Drug Agency; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; MID = minimal important difference; NR = not reported; PRO-2 = patient-reported outcome 2; RCT = randomized controlled trial; SAE = serious adverse event; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency.

Notes: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the 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 2 footnotes.

The statistical testing for IBDQ remission and PRO-2 remission was not adjusted for multiplicity in either GALAXI trial and should be considered as supportive evidence.

^aClinical response was defined as either a reduction of 100 or more points from baseline in the CDAI score or a CDAI score of less than 150.

^bClinical remission was defined as a CDAI score of less than 150.

^cCombined guselkumab induction dose group: 200 mg every 4 weeks, administered via IV injection. Guselkumab regimen 1 (low dose) = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 (high dose) = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^dIncluded patients in the placebo group who crossed over to ustekinumab after week 12.

^eAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^fEndoscopic response was defined as at least a 50% improvement from baseline in the SES-CD score or a SES-CD score of 2 or higher.

^gEndoscopic remission was defined as a SES-CD score 4 or less and at least a 2-point reduction from baseline and with no subscore greater than 1 in any individual component.

^hA 90-day, corticosteroid-free clinical remission was defined as not receiving corticosteroids for 90 days.

ⁱIBDQ remission was defined as an IBDQ total score of at least 170. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^jThe level of evidence was rated down 1 level for imprecision. Based on the MID identified by clinical experts (a difference of 5% between the groups), the 95% CI for the between-group difference crossed the MID threshold (i.e., included the possibility of little to no difference) for guselkumab regimen 2 in both GALAXI trials. Additionally, notable between-group imbalances in missing data were observed after applying the intercurrent event handling strategies.

^kAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 3% to 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome. The level of evidence was rated down 2 levels for imprecision and indirectness; the estimate was informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening CD and other CD-related events such as an SAE. This complicates interpretation.

^lAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 3% to 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome. The level of evidence was rated down 2 levels for imprecision and indirectness; the estimate was informed by a very low number of events and may be unstable. There was some inconsistency in the result for regimen 1. Additionally, there was indirectness related to the inclusion of worsening CD and other CD-related events such as an SAE. This complicates interpretation because it is difficult to explain findings such as lower SAE rates with guselkumab compared with placebo at week 48 in the GALAXI 3 trial. A greater number of patients in the placebo group discontinued treatment while discontinuation rates were lower in the guselkumab groups; therefore, differences in treatment discontinuation and exposure between the study groups may influence the interpretation of harms outcomes.

Sources: Clinical Study Report for the GALAXI 2 trial¹² and Clinical Study Report for the GALAXI 3 trial.¹³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 3: Summary of Findings for Guselkumab vs. Placebo for Patients With Crohn Disease — GRAVITI Trial, SC Induction and SC Maintenance (Regimen 1 and Regimen 2)

AP = abdominal pain; CD = Crohn disease; CDA-AMC = Canada’s Drug Agency; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; ICE = intercurrent event; MID = minimal important difference; NR = not reported; PRO-2 = patient-reported outcome 2; RCT = randomized controlled trial; SAE = serious adverse event; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency.

Notes: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the 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 3 footnotes.

The statistical testing for IBDQ remission was not adjusted for multiplicity in the GRAVITI trial and should be considered as supportive evidence.

The statistical testing for endoscopic remission was not adjusted for multiplicity in the GRAVITI trial and should be considered as supportive evidence.

In the GRAVITI trial, the week 12 end points were based on comparisons between the combined guselkumab induction dose group and the placebo group. The end points assessed after week 12 were based on comparisons between each individual guselkumab group and the placebo group.

ICE category 5 methodology was used to handle treatment discontinuations (using a composite strategy), which is an approach accepted by regulatory authorities. However, because the exact reasons for discontinuations were not always clearly reported (e.g., whether they were linked to a lack of efficacy), there remains some uncertainty regarding potential bias. No downgrading for a risk of bias was applied for the end points at week 48, although some risk may have existed. Additional context is provided in the Executive Summary section.

^aClinical remission was defined as a CDAI score of less than 150. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 12% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^bCombined guselkumab induction dose group: 400 mg SC at week 0, week 4, and week 8, administered via SC injection. The guselkumab SC regimen 1 (low dose) equals guselkumab 400 SC every 4 weeks, followed by 100 mg SC every 8 weeks; the guselkumab SC regimen 2 (high dose) equals guselkumab 400 SC every 4 weeks, followed by 200 mg SC every 4 weeks.

^cIncludes placebo patients who were rescued with guselkumab after week 12.

^dEndoscopic response was defined as at least a 50% improvement from baseline in the SES-CD score. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^eEndoscopic remission was defined as an SES-CD score of 4 or less and at least a 2-point reduction from baseline and with no subscore greater than 1 in any individual component. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical expert consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^fIBDQ remission was defined as an IBDQ total score of at least 170. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical expert consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^gThe level of evidence was rated down 1 level for serious study limitations. Notable between-group imbalances in missing data were observed after applying the ICE handling strategies.

^hPRO-2 remission was defined as an AP mean daily score equal to or less than 1 and an SF mean daily score equal to or less than 3, and no worsening of the AP or SF score from baseline. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

ⁱAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 3% to 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome. The level of evidence was rated down 2 levels for imprecision and indirectness; the estimate was informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening CD and other CD-related events such as an SAE. This complicates interpretation because it is difficult to explain findings such as lower SAE rates with guselkumab compared with placebo.

^jAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 3% to 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome. The level of evidence was rated down 2 levels for imprecision and indirectness; the estimate was informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening CD and other CD-related events such as an SAE. This complicates interpretation because it is difficult to explain findings such as lower SAE rates with guselkumab compared with placebo. A greater number of patients in the placebo group discontinued treatment while discontinuation rates in the guselkumab groups were lower; therefore, differences in treatment discontinuation and exposure between the study groups may influence the interpretation of harms outcomes.

Sources: Clinical Study Report for the GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 4: Summary of Findings for Guselkumab (Regimen 1 and Regimen 2) vs. Ustekinumab With Crohn Disease — GALAXI Trials, IV Induction and SC Maintenance

AP = abdominal pain; CD = Crohn disease; CDA-AMC = Canada’s Drug Agency; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; MID = minimal important difference; NR = not reported; PRO-2 = patient-reported outcome 2; RCT = randomized controlled trial; SAE = serious adverse event; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency.

Notes: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the 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.

In the GALAXI trials, the hierarchical testing strategy precluded formal statistical testing of the long-term secondary end points comparing guselkumab with ustekinumab because the adjusted treatment difference for clinical remission at week 48 did not reach statistical significance.

In both GALAXI trials, all long-term end points comparing guselkumab relative to ustekinumab were analyzed separately, comparing each individual guselkumab regimen against ustekinumab.

^aClinical remission was defined as a CDAI score of less than 150. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 12% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^sEndoscopic response was defined as at least a 50% improvement from baseline in the SES-CD score or a SES-CD score of 2 or higher. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^cEndoscopic remission was defined as an SES-CD score of 4 or less and at least a 2-point reduction from baseline and with no subscore greater than 1 in any individual component. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^dIBDQ remission was defined as an IBDQ total score of at least 170.

^eData were pooled for each guselkumab treatment group from the GALAXI 2 and GALAXI 3 studies and compared with the ustekinumab treatment group.

^fUstekinumab: Approximately 6 mg/kg IV, followed by 90 mg SC every 8 weeks.

^gGuselkumab regimen 1 (low dose) = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 (high dose) = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^hThe level of evidence was rated down 1 level for serious imprecision. An empirically derived MID was not identified for the between-group difference for this outcome. Based on the MID identified by clinical experts (a difference of 12% between the groups), the point estimate suggests little to no difference, and the 95% CI for the between-group difference crossed the MID threshold.

ⁱThe level of evidence was rated down 2 levels for serious imprecision and inconsistency. An empirically derived MID was not identified for the between-group difference for this outcome. Based on the MID identified by clinical experts (a difference of 5% between the groups), the point estimate suggests a benefit, and the 95% CI for the between-group difference crossed the MID threshold to include little to no difference. Additionally, inconsistency was observed between studies — while 1 study demonstrated a benefit based on the point estimate, the other study showed little to no difference. This inconsistency reduces the overall certainty of the evidence.

^jThe level of evidence was rated down 1 level for serious imprecision. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical expert consulted by CDA-AMC as a threshold of clinical importance for this outcome, the point estimate suggested a benefit, and the 95% CI for the between-group difference crossed the MID threshold to include little to no difference.

^kThe level of evidence was rated down 2 levels for serious imprecision and inconsistency. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome, and the 95% CI for the between-group difference crossed the MID threshold. Additionally, inconsistency was observed between studies — while 1 study demonstrated a benefit based on the point estimate, the other study showed little to no difference. This inconsistency reduces the overall certainty of the evidence.

^lThe level of evidence was rated down 1 level for study limitations. An empirically derived MID was not identified for the between-group difference for this outcome. Based on the MID identified by clinical experts (a difference of 5% between the groups), the 95% CI for the between-group difference crossed the MID threshold. Notable between-group imbalances in missing data were observed after applying the intercurrent event handling strategies.

^mAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 3% to 5% between the groups was identified by the clinical experts consulted by CDA-AMC as a threshold of clinical importance for this outcome. The level of evidence was rated down 2 levels for imprecision and indirectness; the estimate was informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening CD and other CD-related events such as an SAE. This complicates interpretation.

Sources: Clinical Study Report for the GALAXI 2 trial¹² and Clinical Study Report for the GALAXI 3 trial.¹³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

Description of Studies

The parent pivotal studies, the GALAXI 2 and GALAXI 3 trials, were randomized, double-blind, placebo- and active-controlled, parallel-group, multicentre studies to evaluate the efficacy and safety of guselkumab in patients with moderately to severely active CD. The long-term extensions (LTEs) were designed to evaluate the long-term efficacy of clinical and endoscopic outcomes, and safety, to evaluate the benefit of treatment adjustment for patients with inadequate response between week 52 and week 80, and the impact of guselkumab on HRQoL. Patients continued with their assigned treatments throughout the LTE phase. Patients on guselkumab or ustekinumab maintained their dosages while those on placebo were discontinued after unblinding at week 48. The studies are ongoing and week 96 results are presented.

Efficacy Results

In the primary efficacy analysis set (all randomized patients with a screening SES-CD score of ≥ 6 [or ≥ 4 for participants with isolated ileal disease] who received ≥ 1 [partial or complete] dose of the study drug), rates of clinical remission were 59.4% in the pooled regimen 1 group (guselkumab 200 mg IV every 4 weeks to 100 mg SC every 8 weeks), 63.2% in the pooled regimen 2 group (guselkumab 200 mg IV every 4 weeks to 200 mg SC every 4 weeks), and █████ in the ustekinumab group at week 96. The rates of patients with corticosteroid-free clinical remission were 57% in the pooled regimen 1 group, 60.8% in the pooled regimen 2 group, and █████ in the pooled ustekinumab group at week 96. The rates of patients with endoscopic response were 44.1%, 44.6%, and █████ in the pooled regimen 1, regimen 2, and ustekinumab groups, respectively, at week 96. The rates of patients with clinical remission and endoscopic response were 40.6% and 41.6% in the pooled regimen 1 and regimen 2 groups, respectively, compared to █████ in the pooled ustekinumab group at week 96. In the primary efficacy analysis set, the rates of patients with deep remission (clinical remission and endoscopic response) were 26.2%, 29.4%, and ███ in the pooled regimen 1, regimen 2, and ustekinumab groups at week 96. Data on HRQoL was not presented.

In the LTE efficacy analysis set (consisting of all patients who had entered the LTE and had received ≥ 1 [partial or complete] dose of the study drug during the LTE), the rates of patients with clinical remission were 75.1%, 78.1%, and █████ in the pooled regimen 1, regimen 2, and ustekinumab groups, respectively, at week 96. The rates of patients with endoscopic response were 53.6%, 55.4%, and █████ in the pooled regimen 1, regimen 2, and ustekinumab groups at week 96. The rate of patients with endoscopic remission was 34.6%, 39.3%, and █████ in the pooled regimen 1, regimen 2, and ustekinumab groups at week 96.

Harms Results

In the LTE safety analysis set (consisting of randomized patients who entered the LTE and received ≥ 1 dose of study intervention [including a partial dose] during the LTE phase), 61.4%, 58.8%, and █████ of patients in the regimen 1, regimen 2, and ustekinumab groups, respectively, reported at least 1 AE. In total, 5.2%, 5.8%, and ████ of patients reported at least 1 SAE in the regimen 1, regimen 2, and ustekinumab groups, respectively. AEs leading to discontinuation were generally similar across treatment groups in the LTE. In total, 2%, 1.6%, ████ in the regimen 1, regimen 2, and ustekinumab groups, respectively, discontinued treatments in the LTE. There were no deaths reported in the guselkumab treatment groups. In total, ||| patient died in the ustekinumab group. Notable harms were not reported in the guselkumab treatment groups in the LTE phase. ███ ████████ ██ ███ ███████████ ████████ █ ██ ████ █████████████ ███ █ ███████

Critical Appraisal

Both pivotal studies of the LTEs (the GALAXI 2 and GALAXI 3 trials) were randomized, double-blind, placebo-controlled, parallel-group trials. There is a risk for selection bias for the main estimand (LTE patients) because only patients with continued treatment benefit (approximately 80% of randomized patients) in the opinion of the investigator were included.

The LTE phase was unblinded at week 48, which may have introduced bias in patient management, the reporting of AEs, and the assessment of subjective clinical outcomes. Concomitant treatments were provided or adjusted at the discretion of the investigator; the impact on estimates of efficacy cannot be quantified.

Overall, the statistical methods in the LTEs were appropriate. The strategy used to handle ICEs for the main estimands (LTE patients) was relevant and aligned with the guidance of regulatory bodies. However, it is not clear how many patients discontinued for reasons other than a lack of efficacy or an AE (ICE category 3) or who chose not to enter the LTE (ICE category 7). Because these ICEs are not clearly related to a lack of efficacy, imbalances in these occurrences could introduce bias in the randomized comparisons. However, no information was reported to adequately access the proportion of patients with these ICEs. There was no defined hierarchical testing procedure for the LTE phases in both LTEs and statistical analyses were not controlled for multiplicity. Thus, the results were considered exploratory. Rates of study discontinuation were generally low in both LTE studies and similar between groups, and were mostly attributed to withdrawal by patients, AEs, and a lack of efficacy. NRI was performed for missing data in the primary LTE analysis. The extent of missing data was not clear; therefore, any potential for a risk of bias arising from the imputation methods used cannot be ascertained.

In general, the population requested for reimbursement aligns with that of the Health Canada indication. The dosing and administration of guselkumab in the LTEs were consistent with the product monograph. According to the clinical experts, the patient eligibility criteria and baseline characteristics of the parent studies were generalizable to adults with moderately to severely active CD in the Canadian clinical setting. However, HRQoL was not reported in the LTE. Therefore, the impact of guselkumab on HRQoL in the long term is uncertain.

Indirect Comparisons

Description of Studies

A sponsor-submitted indirect treatment comparison (ITC) evaluated guselkumab versus relevant comparators (including adalimumab, infliximab, vedolizumab, ustekinumab, risankizumab, and upadacitinib) for moderately to severely active CD. An SLR (July 2023) identified 58 unique RCTs; of these, 37 double-blind RCTs informed the network meta-analysis (NMA). Analyses considered adults with a history of CON-Failure and/or BIO-Failure, assessed induction (approximately 12 weeks) and maintenance (approximately 1 year), and examined clinical remission, clinical response, endoscopic response, and a joint outcome of remission plus endoscopic response. The ITC used Bayesian random-effects NMAs, often adjusted for differences in baseline placebo response during induction. No safety data were included in these indirect comparisons.

Efficacy Results

During induction, results showed that in both the CON-Failure and BIO-Failure analysis populations, no active comparator significantly outperformed guselkumab. There were instances in which guselkumab appeared numerically more effective than vedolizumab or ustekinumab, albeit with wide credible intervals that highlight uncertainty in these estimates.

In the maintenance phase (with or without patients with a delayed response), numerical trends suggested that guselkumab may potentially exceed the efficacy of some comparators (e.g., vedolizumab, certain doses of upadacitinib); no significant advantage for any other active treatment over guselkumab was observed. Overall, there was no clear evidence showing any comparator to be more efficacious. However, wide credible intervals in several comparisons suggested that caution is needed when interpreting the relative treatment effects.

Harms Results

No safety or harms outcomes were included in the sponsor’s submitted ITC.

Critical Appraisal

The SLR’s search was last conducted in July 2023 and the NMA restricted evidence to double-blind RCTs, which may have excluded relevant open-label trials and more recent evidence. The GRAVITI trial was not included in the NMA, precluding conclusions about SC induction. Maintenance analyses incorporated complex normalization of different trial designs, including rerandomization, but relied on untested assumptions that may affect interpretability. Baseline risk adjustment was only applied during induction, despite potentially greater heterogeneity in the maintenance phase. Variations across trials — encompassing population differences, definitions of response, and outcome time points ranging from 4 weeks to 64 weeks — further introduced potential bias due to the violation of the underlying transitivity assumption and imprecision. Safety end points were not evaluated, limiting any comparative benefit-risk assessment. Additionally, data extraction and risk-of-bias assessment were conducted by a single reviewer with only secondary validation, which may have introduced human error bias. Several included trials had risk-of-bias concerns.

Studies Addressing Gaps in the Evidence From the Systematic Review

GALAXI 1 Study LTE Phase

Description of Studies

The GALAXI 1 study is a phase II, randomized, double-blind, placebo- and active-controlled, multicentre trial with an LTE component, designed to evaluate the efficacy and safety of guselkumab in adults with moderately to severely active CD. The LTE phase extended treatment to approximately 152 weeks and included patients who continued to derive benefit according to the investigator at the end of the 48-week maintenance period. The study was unblinded at 48 weeks. The study enrolled 220 patients in the guselkumab group and 71 patients in the ustekinumab group, with 151 patients and 48 patients, respectively, entering the LTE. Participants continued on their assigned SC treatment regimens throughout the extension period. The primary end point was clinical remission, defined by a CDAI score of less than 150 at week 144, with additional assessments of PROs and endoscopic end points. The study was not powered to detect differences between guselkumab and ustekinumab, and all outcomes beyond week 12 were considered exploratory. Three cohorts were defined: the all-randomized NRI set, which included every patient dosed from week 0, imputing discontinuations, nonentry, and ICEs as nonresponse; the LTE NRI set, which comprised those dosed during LTE with the same ICE rules plus CD-related surgery and AE-related discontinuation, assessed through week 144 using NRI; and finally, the LTE observed set, which included only patients on treatment without dose changes, reporting observed rates without imputations.

Efficacy Results

By week 144, clinical remission — as measured by the CDAI — remained stable in patients treated with guselkumab. In the LTE NRI cohort, 68.2% (103 of 151) of patients treated with guselkumab had CDAI remission while 54.1% (100 of 185) of patients had remission in the all-randomized NRI cohort and 95.4% (103 of 108) of patients in the LTE observed cohort. Ustekinumab yielded similar results: 64.6% (31 of 48) of patients in the LTE NRI cohort and 83.8% (31 of 37) of patients in the LTE observed cohort, and 46.0% (29 of 63) of patients in the all-randomized NRI analysis were in CDAI remission. PROs (PRO-2 remission) followed the same pattern — 64.2% and 51.4% of patients treated with guselkumab reached PRO-2 remission in the LTE NRI and all-randomized NRI cohorts, respectively, while 58.3% of patients treated with ustekinumab did so in the LTE NRI cohort.

Endoscopic assessments likewise demonstrated maintained benefit through week 144. In the guselkumab group, endoscopic response rates were 43.0% (LTE NRI) and 34.7% (all-randomized NRI), and endoscopic remission rates were 28.9% and 23.3%, respectively. Patients treated with ustekinumab had a 25.5% endoscopic response and 17.0% endoscopic remission in the LTE NRI cohort.

Harms Results

Guselkumab was well tolerated through 152 weeks, with overall AE rates comparable to those of ustekinumab. In the guselkumab group, there were 279.8 events per 100 patient-years (PYs) and 87.3% of patients experienced 1 or more AE; SAEs occurred at 10.6 per 100 PYs in 11.4% of patients, and 13.2% of patients discontinued due to AEs. Infections affected 51.8% of patients treated with guselkumab (65.8 events per 100 PYs), with serious infections in 5.5% of patients (3.3 events per 100 PYs) versus infections in 46.5% of patients (44.7 events per 100 PYs) and serious infections in 7.0% of patients (5.0 events per 100 PYs) in the ustekinumab group.

The most frequent individual AEs for guselkumab were COVID-19 at 15.0% (8.5 events per 100 PYs), headache at 13.6% (10.1 events per 100 PYs), nasopharyngitis at 12.7% (12.9 events per 100 PYs), CD events at 10.9% (7.5 events at 100 PYs), and pyrexia at 9.5% (8.0 events per 100 PYs). By comparison, ustekinumab‐treated patients reported lower rates of COVID-19 at 7.0% (3.6 events at 100 PYs) but similar frequencies of headache at 11.3% (5.7 events per 100 PYs) and nasopharyngitis at 11.3% (7.1 events per 100 PYs).

Critical Appraisal

The GALAXI 1 study’s LTE employed a robust “treat-through” design (i.e., participants remained on their originally randomized therapy through week 152). The prespecified analysis sets (all-randomized NRI, LTE NRI, and LTE observed) ensured methodological transparency. However, because only 80% of randomized patients entered the extension (investigator-judged to be benefiting), the LTE cohort lost its randomized basis and was susceptible to selection bias. Unblinding at week 48 may have influenced patient management, AE reporting, and subjective efficacy assessments while investigator-driven adjustments to concomitant medications further clouds causal inference. Although ICEs were handled per regulatory guidance, the absence of a complete ICE inventory and the unclear extent of missing data mean that imputation methods — and thus overall efficacy estimates — cannot be fully appraised.

Participants included patients with and without prior exposure to biologics with moderate to severe CD, reflecting a real-world treatment landscape and supporting broad applicability of safety and efficacy findings. The exclusion of individuals with certain comorbidities or complex complications limits the relevance of the results to the sickest or those with more severe or multifactorial disease presentations.

Neff-Baro et al. (2024)

Additional evidence by Neff-Baro et al. (2024)⁵⁴ was reviewed to assess the predictive impact of endoscopic response after maintenance treatment (approximately 48 weeks) and long-term outcomes (approximately 96 weeks) in patients with moderately to severely active CD. A pooled post hoc analysis was conducted with data from the treatment groups (placebo excluded) of 2 RCTs (the IM-UNITI trial [a phase III maintenance trial of ustekinumab] and the GALAXI 1 trial [a phase II treat-through trial of guselkumab], total N = 461]), which enrolled adult patients diagnosed with moderately to severely active CD of at least 3 months’ duration (confirmed through CDAI scores).

Efficacy Results

Efficacy results at the end of maintenance (EOM): Overall, 75.3% of patients with endoscopic response at the EOM were in long-term clinical remission (i.e., week 92 for the IM-UNITI study and week 96 for the GALAXI 1 study) compared to 48.5% of patients without endoscopic response. The odds ratio (OR) for endoscopic response at the EOM was 1.91 (95% CI, 1.11 to 3.28). In total, 78.5% of patients with endoscopic response at the EOM were in long-term clinical response compared to 56.9% of patients without endoscopic response (OR = 1.65; 95% CI, 0.97 to 2.83). A total of 75.0% versus 54.4%, respectively, of patients with endoscopic response at the EOM were in long-term IBDQ remission compared to patients without endoscopic response (OR = 1.99; 95% CI, 1.16 to 3.41).

Harms Results

There were no harms results presented.

Critical Appraisal

The pooled post hoc analysis is limited by a lack of prespecification and an increased risk of type I error due to multiple group testing; thus, the evidence is exploratory. The model aimed to provide an indication of the ability of endoscopic response at week 48 to predict later outcomes among individual patients. It is not clear how variables were selected for inclusion within the regression models. It is possible that important predictors (confounders) were missed that might alter the observed associations had they been included. In general, the associations were estimated with imprecision, which indicates uncertainty in the estimated magnitude of association between endoscopic response at week 48 and later outcomes. There is a risk of bias in the estimated associations due to substantial missing data (approximately 15% to 35%) across the available outcomes, which does not appear to have been imputed. Finally, the study provides some information to suggest an association between endoscopic response at 48 weeks and later outcomes. However, the ideal evidence to validate a surrogate end point comes from RCTs that demonstrate the ability of the treatment effect (i.e., guselkumab versus placebo or other comparator) at 48 weeks to predict a clinically relevant treatment effect on patient-important outcomes at later time points.

Conclusions

Evidence from 3 phase III, double-blind RCTs — the GALAXI 2 and GALAXI 3 studies (IV induction, then SC maintenance), and the GRAVITI study (SC induction, then SC maintenance) — evaluated outcomes considered important to both patients and clinicians. These studies demonstrated high-certainty evidence that treatment with guselkumab results in a clinically important improvement in clinical and endoscopic outcomes, clinical response, and 90-day, corticosteroid-free clinical remission, as well as PRO-2 remission, at week 12 and week 48 compared with placebo in adults with moderately to severely active CD. Both GALAXI studies demonstrated moderate-certainty evidence that treatment with guselkumab likely results in a clinically important improvement in endoscopic remission at week 48, and little to no difference in clinical remission at week 48, when compared with ustekinumab. However, in both GALAXI trials, heterogeneity in the efficacy of guselkumab was observed between the 2 dosing regimens with respect to IBDQ remission at week 12 when compared with both placebo and ustekinumab, as well as a composite of clinical remission and endoscopic response at week 48 when compared with ustekinumab. Both GALAXI studies demonstrated high-certainty evidence for regimen 1 and moderate-certainty evidence for regimen 2 that treatment with guselkumab likely results in a clinically meaningful improvement in IBDQ remission at week 12 when compared with placebo. When compared with ustekinumab, both GALAXI studies demonstrated low-certainty evidence for regimen 1 and moderate-certainty evidence for regimen 2 that treatment with guselkumab likely results in little to no difference in IBDQ remission at week 48. Of note, in the analyses of the individual GALAXI 2 and GALAXI 3 trials, these end points were not formally tested.

Although the Health Canada indication is broader than the patient populations enrolled in the trials (i.e., trial patients whose disease had inadequate response or was unable to tolerate conventional or advanced therapy), the clinical experts consulted by CDA-AMC did not consider this discrepancy to affect the generalizability of the findings. No new safety signals were identified across the trials and the safety profile of guselkumab was considered consistent with that of other advanced therapies used in the management of CD based on expert opinion. The LTE phase of the GALAXI trials provided additional information on the longer-term benefits of guselkumab beyond 48 weeks for key efficacy and safety outcomes; however, because no formal inferential analyses were conducted, the findings are considered exploratory.

The results of the sponsor-submitted ITC demonstrated that, compared with active treatments, guselkumab often showed potential superiority over vedolizumab in achieving clinical remission and response; however, its comparative efficacy against other drugs — such as ustekinumab, risankizumab, and upadacitinib — was more variable, with results differing across specific analyses and outcome measures. Due to limitations of the ITC primarily related to the heterogeneity across studies, unverifiable assumptions made in the analysis, and imprecision in the treatment effect estimates, no definitive conclusions can be drawn regarding the relative efficacy of guselkumab compared with other relevant comparators. The sponsor-submitted ITC did not include the GRAVITI trial, precluding conclusions about the efficacy of SC induction versus relevant comparators. Additionally, there was not any comparative safety data.

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 in the treatment of adult patients with moderately to severely active CD.

Disease Background

The content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

CD is a chronic form of IBD that can affect any part of the gastrointestinal tract, but most commonly affects the ileum (i.e., the small intestine), colon (i.e., the beginning of the large intestine), and rectum.^2,3 CD is most commonly diagnosed in adolescents and young adults, typically between the ages of 20 years and 30 years.⁴ In 2023, the incidence of IBD in Canada was estimated at 30 per 100,000 individuals, including 12.2 per 100,000 for CD.⁵ These rates correspond to more than 11,700 new cases of IBD diagnosed in 2023, including approximately 4,800 new cases of CD.⁵ CD can manifest in 3 phenotypic forms: inflammatory, stricturing, and penetrating (fistulas and abscesses).⁶ Common symptoms of CD include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.^4,7,8 CD may also cause complications in patients over time such as malnutrition, weight loss, anemia, bowel obstructions, fistulas, anal fissures, intra-abdominal and other abscesses, and ulcers.^2,4 In addition, patients with colonic CD have an increased risk of developing colon cancer.⁴ Smoking, a family history of IBD, infectious gastroenteritis, and frequent use of nonsteroidal anti-inflammatory drugs have been identified as risk factors for CD.⁹

While some patients experience continuous and progressively active disease, approximately 20% of patients may enter a prolonged remission following initial presentation.⁷ Disease severity is measured using the CDAI, SES-CD, and Harvey-Bradshaw Index, which are designed to evaluate bowel-related symptoms including stool frequency, abdominal pain, arthritis or arthralgia, uveitis, skin or mouth lesions, and perianal disease. The classification of CD severity, as defined by the American College of Gastroenterology using the CDAI and the SES-CD, is summarized in Table 5. The diagnosis of CD is based on a combination of clinical evaluation and endoscopic, histological, radiological, and/or biochemical investigations.⁹ An ileocolonoscopy with multiple biopsy specimens is the first-line procedure for diagnosing CD.⁹ The endoscopic hallmark of CD is the patchy distribution of inflammation, with skip lesions, defined as areas of inflammation interposed between normal-appearing mucosa.⁹ Cross-sectional imaging using MRI and CT enterography and transabdominal ultrasonography are complementary to endoscopy and offer the opportunity to detect and stage inflammatory, obstructive, and fistulizing CD.⁹ The American College of Gastroenterology guidelines recommend routine laboratory evaluation for CD, including stool testing, an ileocolonoscopy with biopsies, and small bowel imaging to confirm diagnosis of CD.² In alignment with this approach, the joint European Crohn’s and Colitis Organisation and the European Society of Gastrointestinal and Abdominal Radiology recommend a comprehensive diagnostic strategy incorporating clinical assessment, biochemical markers, stool testing, endoscopy, cross-sectional imaging, and histological evaluation.¹⁵ No companion diagnostic testing and no specific diagnostic technology is required for guselkumab and its comparators within the CD treatment landscape.

Table 5: Classification of Disease Severity in Crohn Disease

CDAI = Crohn’s Disease Activity Index; SES-CD = Simple Endoscopic Score for Crohn’s Disease.

Source: American College of Gastroenterology.²

Standards of Therapy

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

The treatment of CD is individualized based on disease location, extent, phenotype, and severity. Treatment goals for CD, as outlined in Canadian and American clinical practice guidelines,^16,17 include inducing and maintaining clinical remission, reducing reliance on long-term corticosteroid use, and minimizing treatment-related side effects. Long-term goals include endoscopic healing, preventing disability, and normalizing HRQoL, while short- to intermediate-term goals focus on normalizing biomarkers of disease activity, such as CRP and fecal calprotectin. According to the clinical experts consulted by CDA-AMC, the key therapeutic goals for the treatment of CD include clinical response and remission, endomucosal remission, and histological remission. Several drug classes are used in the treatment of CD, including Janus kinase inhibitors, immunosuppressants (e.g., azathioprine, cyclosporine, methotrexate, 6-mercaptopurine), corticosteroids (e.g., prednisone), TNF alpha antagonists (e.g., infliximab, adalimumab), interleukin inhibitors, and integrin inhibitors (e.g., vedolizumab).² With the exception of the TNF alpha antagonists, interleukin inhibitors, and vedolizumab, all are commonly referred to as conventional therapies. Treatment options highlighted are consistent with the input from the clinical experts consulted by CDA-AMC for this review. Current medical management follows a stepwise approach in which treatments are used sequentially, with escalation to newer therapies or higher doses when an adequate response is not achieved at each prior step.¹⁸ Surgical intervention, including total colectomy and ileostomy, may be considered for patients with severe complications or those whose disease does not respond adequately to medical therapy.² According to the clinical experts consulted by CDA-AMC, despite the availability of multiple treatment options, there remains a need for more effective therapies for moderate to severe CD. The clinical experts emphasized that the early initiation of appropriate therapy is critical because the first advanced treatment often provides the greatest benefit; however, evidence to guide the optimal sequencing of biologic therapies remains limited.

Drug Under Review

Key characteristics of guselkumab are summarized in Table 6 with other treatments available for CD.

Guselkumab is a human immunoglobulin G lambda monoclonal antibody that selectively binds to the p19 subunit of interleukin-23 (IL-23) through the antigen-binding site, thereby inhibiting IL-23’s interaction with cell-surface IL-23 receptors.¹⁹ IL-23 is a naturally occurring cytokine involved in normal inflammatory and immune responses, and its levels are elevated in the colonic tissue of patients with CD.²⁰ By blocking IL-23 signalling, guselkumab inhibits the downstream release of proinflammatory cytokines and chemokines, including interleukin-17A, interleukin-17F, and interleukin-22. Guselkumab is the only dual-acting selective IL-23 inhibitor shown to potently neutralize IL-23 through 2 mechanisms: it binds directly to soluble IL-23 and also to CD64 (FcγRI), a high-affinity Fc receptor expressed on cells that produce IL-23.^19,20 This dual binding allows guselkumab to capture IL-23 at the site of production within the same cell, enhancing its local inhibitory effect.

The recommended induction dosage of guselkumab is 200 mg administered by IV infusion over a period of at least 1 hour, or 400 mg of guselkumab administered by SC injection at week 0, week 4, and week 8. For the SC formulation, each 400 mg dose is given as 2 injections of 200 mg. The recommended maintenance dosage of guselkumab is 100 mg administered by SC injection at week 16 and every 8 weeks thereafter. A dose of 200 mg administered by SC injection at week 12 and every 4 weeks thereafter may be considered for patients whose disease does not show adequate therapeutic benefit from guselkumab, or according to clinical judgment.¹

The indication of guselkumab is for the treatment of adult patients with moderately to severely active CD. The reimbursement request aligns with the indication. The drug underwent a standard review by Health Canada, with a Notice of Compliance granted on July 7, 2025.

Guselkumab (Tremfya) has been previously approved by Health Canada for use in adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy,¹ and was reviewed by CDA-AMC for this indication.

Table 6: Key Characteristics of Treatments Used for Crohn Disease

Anti-TNF = anti–tumour necrosis factor; CD = Crohn disease; CS = corticosteroid; IgG = immunoglobin G; IgG1 = immunoglobin G1; IL-12 = interleukin-12; IL-17 = interleukin-17; IL-23 = interleukin-23; JAK = Janus kinase; SC = subcutaneous; TNF = tumour necrosis factor.

^aHealth Canada–approved indication.

Sources: Product monographs of guselkumab (Tremfya),¹ risankizumab (Skyrizi),²¹ vedolizumab (Entyvio),²² infliximab (Remicade and Inflectra),²³ ustekinumab (Stelara),²⁴ adalimumab (Humira),²⁵ and upadacitinib (Rinvoq).²⁶

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received by CDA-AMC are available in the consolidated patient and clinician 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 inputs were summarized for this review. The GI Society is a national charity with programs and services that support research, advocate for appropriate patient access to health care, and promote gastrointestinal and liver health. Crohn’s and Colitis Canada is a national, volunteer-based health charity focused on finding the cures for CD and ulcerative colitis and improving the lives of children and adults affected by these diseases.

Information from both inputs was gathered from varied sources. In addition to information published in the 2023 Impact of Inflammatory Bowel Disease in Canada report, Crohn’s and Colitis Canada conducted online surveys in 2022, gathering information from 1,706 patients living in Canada with CD and ulcerative colitis and caregivers, including 687 patients who identified as having moderate to severe CD. The GI Society gathered information through questionnaires, interviews, and surveys. Information was derived from the following: sources a 2015 survey on biologics and biosimilars completed by 423 people in Canada with IBD (CD or ulcerative colitis); a 2018 survey on unmet needs among people in Canada with IBD completed by 432 people; a 2020 survey completed by 579 respondents regarding unmet patient needs in IBD; a 2020 survey on biosimilars with 145 respondents, most of whom had IBD (some had other inflammatory conditions); a 2022 survey about the IBD patient journey completed by 54 respondents in Canada with IBD; a 2022 focus group that included persons living with IBD; a 2023 review of interviews with 7 individuals living with IBD; and a 2024 survey about the unmet needs of individuals living with IBD, with 514 respondents from Canada. In addition, information from a 2025 round table meeting with a dozen experts, including gastroenterologists and patients and patient groups across Canada, was included. Additional data from a 2020 focus group on people living with IBD and 1-to-1 interviews with patients were also analyzed by the GI Society patient group.

The patient groups noted that CD often has a profound effect on patients’ quality of life, affecting the physical, emotional, and social factors of patients at home, at school, or in the workplace. Disease severity may fluctuate, thus requiring routine testing, reassessments, and medication changes. The GI Society group noted that, “it is never just 1 flare that dominates the impact of the disease, but the constant concern that there will be future flares, possibly worse than the last, at unpredictable times, which can disastrously disrupt their lives.” Crohn’s and Colitis Canada also noted that given that patients are unable to predict when their next flare will occur and how they will control it, isolation, stress, and anxiety are common for these patients. Respondents in 1 patient group expressed concerns such as the fear of running out of medication, anxiety about determining when to go to the emergency department based on symptoms, pain, fear of going out due to disease, decreased quality of life, and fear and worry about being faced with mortality at a young age. When asked about their most common IBD-related symptoms that they had experienced within the past 2 weeks, respondents in the Crohn’s and Colitis Canada input noted that the most common were fatigue (100%), abdominal pain or cramps (99%), pain (98%), constipation (97%), gas (95%), bloating (79%), an urgency to use the bathroom (78%), and diarrhea (73%). The GI Society input highlighted that patients living with CD preferred sustained remission and treatment response over relieving any 1 symptom. In the survey conducted by Crohn’s and Colitis Canada, most respondents with moderate IBD (53%) and severe IBD (60%) believed that access to different treatment options could make them feel better.

Both groups noted that treating CD requires a multifaceted strategy that allows for the management of symptom and disease consequences with therapies that target and reduce the underlying inflammation. Importantly, the severity of their IBD plays an important role in deciding which medications are being used. In the Crohn’s and Colitis Canada 2022 survey, most patients reported having used a combination of medications to manage their CD, with systemic steroids (79%), biologics and biosimilars (83%), immunomodulators (65%), and antibiotics (61%) being the most common, followed by sulfasalazine and 5-aminosalicylates (45%), and nonsystemic steroids (43%). Results from 1 survey conducted by the GI Society reported that 63% of respondents indicated that they had experienced symptom reduction after using a biologic, while 23% of respondents confirmed remission. No patients interviewed had received guselkumab; however, most had received a biologic. Corticosteroids were not particularly supported among patient respondents in the surveys conducted by both groups; they expressed that systemic steroid use was a burden to their disease management. In the 2022 survey conducted by Crohn’s and Colitis Canada, patients expressed that they would take corticosteroids only if necessary and wished they could eliminate systemic steroids from their list of medications.

The majority of patients with moderate to severe CD who participated in the surveys conducted by both patient groups expressed that they continued to experience symptoms with current treatment options. In a 2020 survey conducted by the GI Society, 33% of respondents expressed that their IBD was not well controlled by their current medications. Both groups indicated that patients need effective treatment options that mitigate symptoms and improve quality of life, are convenient, and can be accessed in a timely manner. Patients expressed that they desired fewer medications and wanted treatments that are safe, that can minimize the use of steroids, and that can be administered at home, and taken as pills. Major concerns identified by the GI Society included limited access to adequate treatment supplies and continuity of care given that some patients respond differently to various medications, and in some cases may stop responding to medications after using them for some time. Both groups unanimously noted that patients have varied preferences for medication administration, influenced by a range of factors. One group noted the importance of varied treatment options that can cater to individual needs, without a requirement to trial conventional therapies before accessing targeted treatments. Therefore, there is a need for new, effective treatments for patients that could improve quality of life and eliminate symptoms, pain, frustration, and hardship.

Clinician Input

Input From Clinical Experts Consulted for This Review

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, 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 CD.

Unmet Needs

The clinical experts consulted by CDA-AMC identified several significant unmet needs in the current treatment landscape for CD, particularly among patients with moderate to severe disease. Although a variety of treatment options are available, the clinical experts indicated that not all patients with CD respond adequately to existing therapies. One of the major challenges in managing CD, according to the clinical experts, is primary nonresponse or loss of response to therapy over time. The clinical experts highlighted the need for safe and effective therapies for both patients with no prior exposure to biologics and patients with previous exposure to biologics. The clinical experts consulted emphasized that treatment response and remission rates tend to diminish with each subsequent line of therapy, with the first advanced therapy often providing the most substantial benefit. As such, they underscored the importance of introducing highly effective treatments early in the disease treatment to optimize patient outcomes. Furthermore, the clinical experts identified a significant barrier to accessing biologics: the requirement for patients whose disease had demonstrated an inadequate response to conventional therapies (i.e., immunomodulators) before initiating biologic treatment. Additionally, the clinical experts indicated that the lack of clear guidance on the sequencing of biologic therapies contributes to clinical uncertainty, often resulting in treatment decisions being made in the absence of robust comparative evidence.

Place in Therapy

The clinical experts consulted by CDA-AMC indicated that guselkumab is unlikely to dramatically shift the current treatment paradigm for CD and is expected to be used similarly to other biologic therapies. However, the clinical experts consulted agreed that guselkumab should be available as a treatment option for patients with moderately to severely active CD and that it should not be reserved only for those who are intolerant of or have contraindications to other biologic drugs. The clinical experts emphasized that there is no clinical justification for requiring patients to first try other advanced therapies or conventional treatments — such as azathioprine or methotrexate — before initiating guselkumab. Instead, they supported an approach in which oral corticosteroids may be used initially, as was done in the clinical trials (i.e., 1 of the possible inclusion criteria), but without mandating the prior use of immunomodulators. The clinical experts also highlighted that a favourable safety profile makes it a viable alternative for patients who have experienced adverse effects with other therapies, such as anti-TNF drugs. The clinical experts consulted also suggested that combination therapies may represent a future direction in the management of IBD.

Patient Population

According to the clinical experts, guselkumab is considered appropriate for a broad population, including both patients with no prior exposure to biologics and patients with previous exposure to biologics, particularly those who have had conventional therapy or other biologics failure or intolerance. The clinical experts highlighted that patients best suited for treatment with guselkumab would be those who have a confirmed diagnosis of CD, supported by pathological and endoscopic evidence. According to the clinical experts, patients with stricturing disease — often characterized by fibrosis rather than active inflammation — may be least likely to benefit from treatment with guselkumab. The misdiagnosis of CD is considered extremely rare by clinical experts. The clinical experts highlighted that delays in accessing gastroenterology services and endoscopic procedures can pose significant challenges to timely diagnosis and the initiation of appropriate treatment.

Assessing the Response Treatment

The clinical experts noted that the following outcomes are used to determine response to treatment: clinical response or remission, endoscopic response or remission, and improvements in HRQoL. According to the clinical experts consulted, clinicians monitor response to treatment by integrating endoscopic findings, symptom burden, and biomarkers such as fecal calprotectin and CRP. The clinical experts noted that an initial assessment of treatment response is typically conducted between week 10 and week 12, often using the Harvey-Bradshaw Index in clinical practice. They also indicated that the CDAI is not routinely used in Canadian clinical practice. The clinical experts noted that a more comprehensive evaluation, which may include endoscopic or imaging-based assessments, is typically performed between 48 weeks and 52 weeks. According to the clinical experts, endoscopic evaluation is most commonly conducted between 6 months and 8 months after treatment initiation, although its use is selective due to limited availability and the associated burden on patients.

Discontinuing Treatment

The experts emphasized that treatment should not be discontinued solely based on limited improvement at week 12, recommending reassessment and consideration of dose escalation, or the addition of immunomodulators or corticosteroids. According to the clinical experts consulted, the assessment of the response to treatment is typically performed between 48 weeks and 52 weeks. Discontinuation may be considered in cases of primary loss of response, worsening PROs, rising biomarkers (e.g., fecal calprotectin), or AEs or symptoms that cannot be managed.

Prescribing Considerations

The clinical experts noted that patients receiving guselkumab should be diagnosed, treated, and monitored by a specialist, such as a gastroenterologist or an internal medicine physician.

Clinician Group Input

No clinician group input was submitted for this review.

Drug Program Input

Drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted for this review are summarized in Table 7.

Table 7: Summary of Drug Plan Input and Clinical Expert Response

AP = abdominal pain; BIA = budget impact analysis; CD = Crohn disease; CDAI = Crohn’s Disease Activity Index; CDEC = Canadian Drug Expert Committee; CRP = C-reactive protein; CTE = computed tomography enterography; IL = interleukin; MRE = magnetic resonance enterography; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of guselkumab in the treatment of adult patients with moderately to severely active CD. In the clinical evidence submitted by the sponsor, the induction dose of guselkumab is 200 mg administered by IV infusion, or 400 mg administered by SC injection at week 0, week 4, and week 8. The maintenance dose of guselkumab is 100 mg administered by SC injection at week 16 and every 8 weeks thereafter, or 200 mg administered by SC injection at week 12 and every 4 weeks thereafter. The focus has been placed on comparing guselkumab to 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 includes sponsor-submitted LTE studies. The third section includes indirect evidence from the sponsor. The fourth section includes an additional study that was considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

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

• three pivotal studies or RCTs identified in the systematic review

• one LTE study

• one ITC

• two additional studies addressing gaps in evidence.

Systematic Review

The content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 8.

Table 8: Details of Studies Included in the Systematic Review

6-MP = 6-mercaptopurine; AE = adverse event; anti-TNF = anti–tumour necrosis factor; AP = abdominal pain; AZA = azathioprine; C-SSRS = Columbia-Suicide Severity Rating Scale; CD = Crohn disease; CDAI = Crohn’s Disease Activity Index; EQ VAS = EQ visual analogue scale; IBDQ = Inflammatory Bowel Disease Questionnaire; IL-12 = interleukin-12; IL-23 = interleukin-23; LTE = long-term extension; MACE = major adverse cardiovascular event; MTX = methotrexate; PRO-2 = patient-reported outcome 2; SAE = serious adverse event; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; vs. = versus; WPAI:CD = Work Productivity and Activity Impairment Questionnaire in Crohn’s Disease.

Notes: Guselkumab IV regimen 1 (low dose) = guselkumab 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab IV regimen 2 (high dose) = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

Guselkumab SC regimen 1 (low dose) = guselkumab 400 mg SC every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab SC regimen 2 (high dose) = guselkumab 400 SC every 4 weeks, followed by 200 mg SC every 4 weeks.

Patients may not have prior exposure to biologic therapy (i.e., infliximab, adalimumab, certolizumab pegol, vedolizumab, or approved biosimilars for these drugs) or may have been exposed to these biologic therapies and their disease did not demonstrate an inadequate response or intolerance.

^aThe GRAVITI study is currently ongoing, and data presented in this report includes data up to March 1, 2024 (the date of the last visit of the last patient in the study through week 48).

^bOne patient was randomized but not treated.

^cThe primary analysis set in the GALAXI trials included all randomized patients who had received at least 1 (partial or complete) dose of study intervention and satisfied the SES-CD eligibility criteria. The full analysis set in the GRAVITI trial included all randomized patients who had received at least 1 dose of study intervention and excluded the 3 randomized patients.

^dRescue criteria included a CDAI score > 220 and < 70-point reduction from the baseline CDAI score at both week 12 and week 16, or a SES-CD score increase by at least 50% from baseline at week 12.

Sources: Clinical Study Report for the GALAXI 2 trial,¹² Clinical Study Report for the GALAXI 3 trial,¹³ Clinical Study Report for the and GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The GALAXI studies program consists of 3 separate studies conducted under a single protocol: a phase II dose-ranging study (the GALAXI 1 trial)²⁷ and 2 identical phase III confirmatory studies (the GALAXI 2 and GALAXI 3 trials).^12,13 The GALAXI 2 and GALAXI 3 trials are pivotal phase III RCTs evaluating the safety and efficacy of guselkumab (IV induction followed by SC maintenance) compared with placebo and an active control (ustekinumab) in patients with moderately to severely active CD. Additionally, the GRAVITI trial¹⁴ is a phase III RCT evaluating the safety and efficacy of guselkumab (SC induction followed by SC maintenance) compared with placebo for patients with moderately to severely active CD. For this review, 3 phase III trials (the GALAXI 2, GALAXI 3, and GRAVITI studies), included in the sponsor's submission, are summarized.

GALAXI 2 and GALAXI 3 Studies

The GALAXI 2 and GALAXI 3 trials are identically designed, phase III, randomized, double-blind, placebo- and active-controlled (versus ustekinumab) parallel-group, multicentre trials. The primary objectives of the GALAXI 2 and GALAXI 3 trials were to evaluate the clinical and endoscopic efficacy, and safety, of guselkumab (IV induction followed by SC maintenance) in patients with moderately to severely active CD whose disease has demonstrated an inadequate response to or an inability to tolerate previous conventional therapy or biologic therapy. Patients were enrolled at 186 centres from 36 countries or territories (including 31 sites in Canada) in the GALAXI 2 trial, and 198 centres across 39 countries or territories (including 31 sites in Canada) in the GALAXI 3 trial.

During the screening period, patients were evaluated for study eligibility in accordance with the study protocol. Following screening, patients were randomized using a permuted block randomization in a 2:2:2:1 ratio to receive 1 of 2 dose regimens of guselkumab (IV induction therapy followed by SC maintenance therapy), ustekinumab, or placebo, respectively. Each active study intervention and its matching placebo were identical in appearance. Allocation to treatment groups was conducted through a central randomization centre using an Interactive Web Response System. Randomization was stratified based on the baseline CDAI score (less than or equal to 300 versus greater than 300), the baseline SES-CD score (less than or equal to 12 versus greater than 12), prior BIO-Failure status (yes versus no), and baseline corticosteroid use (yes versus no). To ensure that the enrolled population was representative of patients with moderately to severely active CD, the diseases of a minimum of 25% and a maximum of 50% of the total enrolled population were required to have demonstrated an inadequate response, or intolerance, to at least 1 conventional CD therapy (CON-Failure).

Both the GALAXI 2 and GALAXI 3 studies employed a treat-through study design, whereby patients were randomized to treatment regimens at week 0 and continued on their assigned regimen through at least week 48 of each trial, unless otherwise specified (Figure 1). The primary and secondary end points of the trials were analyzed using data up to the cut-off date of October 2, 2023, for the GALAXI 2 study and October 16, 2023, for the GALAXI 3 study.

GRAVITI Study

The GRAVITI trial is a phase III, randomized, double-blind, placebo-controlled, parallel-group, multicentre study. The primary objectives of the GRAVITI trial were to evaluate the efficacy and safety of guselkumab (SC induction followed by SC maintenance) in patients with moderately to severely active CD. Patients were enrolled at 143 centres from 23 countries or territories, including 5 sites in Canada. The patients must have shown an inadequate response or intolerance to prior conventional therapy (i.e., oral corticosteroids) or immunomodulators (i.e., azathioprine, 6-mercaptopurine, or methotrexate), or biologic therapy (i.e., TNF antagonists or vedolizumab).

During the screening period, patients were evaluated for study eligibility in accordance with the study protocol. Following screening, patients were randomized using a permuted block randomization in a 1:1:1 ratio to receive 1 of 2 dose regimens of guselkumab (SC induction followed by SC maintenance) or placebo, respectively. Each active study intervention and its matching placebo were identical in appearance. Allocation to treatment groups was conducted through a central randomization centre using an Interactive Web Response System. Randomization was stratified based on the baseline CDAI score (less than or equal to 300 versus greater than 300), the baseline SES-CD score (less than or equal to 12 versus greater than 12), and prior BIO-Failure (yes versus no), defined as having demonstrated an inadequate response, or intolerance, to 1 or more biologic therapies. Patients whose disease had an inadequate response to or an inability to tolerate biologic therapy represented approximately 35% to 65% of the population. The GRAVITI trial employed a treat-through study design, whereby patients were randomized to treatment regimens at week 0 and continued on their assigned regimen through at least week 48, unless otherwise specified (Figure 2). The GRAVITI trial is ongoing, and this report presents 48-week data with a cut-off date of March 1, 2024.

Figure 1: Overview of Study Design of GALAXI 2 and GALAXI 3 Trials

E = endoscopy; LTE = long-term extension; R = randomization; SC = subcutaneous.

Sources: Clinical Study Report for the GALAXI 2 trial¹² and Clinical Study Report for the GALAXI 3 trial.¹³

Figure 2: Overview of Study Design of GRAVITI Trial

BIO-Failure = biologic therapy failure or intolerance; CDAI = Crohn’s Disease Activity Index; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease; q4w = every 4 weeks; q8w = every 8 weeks.

* Stratified by baseline CDAI score, SES-CD score, and prior BIO-Failure status.

† Rescue initiated at week 16 upon meeting rescue criteria.

Source: Clinical Study Report for the GRAVITI trial.¹⁴

Populations

Inclusion and Exclusion Criteria

GALAXI 2 and GALAXI 3 Studies

Patients were eligible for enrolment in the GALAXI 2 and GALAXI 3 trials if they were 18 years or older and diagnosed with moderately to severely active CD for at least 3 months, with colitis, ileitis, or ileocolitis previously confirmed by radiography, histology, and/or endoscopy. Patients were required to have clinically active CD (a baseline CDAI score of greater than or equal to 220 but less than or equal to 450, along with either a mean daily stool frequency count greater than 3 or a mean daily abdominal pain score of greater than 1), and endoscopic evidence of ileocolonic CD (a screening endoscopy SES-CD score equal to or greater than 6, or greater than or equal to 4 for patients with isolated ileal disease). Additionally, to be eligible for enrolment in the trials, patients were required to be receiving oral corticosteroids and/or immunomodulators, have a history of corticosteroid dependence, or have a history of not responding to or tolerating at least 1 of the following therapies: oral corticosteroids, immunomodulators, or biologic therapy.

Patients whose disease demonstrated an inadequate response to or an inability to tolerate ustekinumab were excluded from the trials. Patients who had complications of CD (e.g., symptomatic strictures or stenoses, short gut syndrome) or had prior exposure to interleukin-12 (IL-12) and IL-23 drugs or IL-23 drugs were also excluded from the trials. Patients who received the following therapies within the specified period were not eligible for enrolment: IV corticosteroids received within 3 weeks of baseline, ustekinumab received within 16 weeks of baseline, vedolizumab received within 12 weeks of baseline, cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil received within 8 weeks of baseline, 6-thioguanine received within 4 weeks of baseline, anti-TNF therapy received within 8 weeks of baseline, or other immunomodulatory biologic drugs received within 12 weeks of baseline.

GRAVITI Study

Eligibility criteria for the GRAVITI trial were similar to those of the GALAXI trials, with some differences. To be included in the GRAVITI trial, patients had to have clinically active CD, as defined by a baseline CDAI score of greater than or equal to 220 but less than or equal to 450, along with either a mean daily stool frequency count of greater than or equal to 4 or a mean daily abdominal pain score of greater than or equal to 2. Patients without prior exposure to biologic therapy or with prior exposure to biologic therapy without inadequate response or intolerance were eligible for enrolment in the GRAVITI trial.

Interventions

GALAXI 2 and GALAXI 3 Studies

In the GALAXI 2 and GALAXI 3 trials, the 48-week main treatment phase consisted of a 12-week induction period followed by a 36-week maintenance period. Patients who completed the 48-week treatment phase of the GALAXI 2 and GALAXI 3 trials may have been eligible to enter the LTE phase.

The guselkumab dose regimens in the GALAXI 2 and GALAXI 3 trials were selected based on the efficacy and safety of the induction dose range (i.e., from 200 mg to 1,200 mg IV) and maintenance dose range (i.e., from 100 mg SC every 8 weeks to 200 mg SC every 4 weeks) evaluated in the phase II study (the GALAXI 1 trial).²⁷ Patients were to remain on their assigned treatment regimens throughout the 48-week trial, with the exception of the placebo treatment group, outlined as follows. No other dose adjustments were planned during the GALAXI 2 and GALAXI 3 trials.

In the guselkumab regimen 1 group (low dose), patients received guselkumab 200 mg IV induction every 4 weeks from week 0 through week 8 (i.e., a total of 3 IV doses). At week 12, patients continued treatment with guselkumab 100 mg SC maintenance every 8 weeks through week 44.

In the guselkumab regimen 2 group (high dose), patients received guselkumab 200 mg IV induction every 4 weeks from week 0 through week 8 (i.e., a total of 3 IV doses). At week 16, patients continued treatment with guselkumab 200 mg SC maintenance every 4 weeks through week 40.

In the active control group, patients received a single ustekinumab IV induction dose at week 0 (a weight-based IV dose approximating 6 mg/kg). At week 8, patients received SC maintenance (90 mg of ustekinumab SC every 8 weeks) through week 40. Weight-based dosing for induction was as follows:

• ustekinumab 260 mg (for weight less than or equal to 55 kg)

• ustekinumab 390 mg (for weight greater than 55 kg and less than or equal to 85 kg)

• ustekinumab 520 mg (for weight greater than 85 kg).

In the placebo group, patients received placebo IV every 4 weeks from week 0 through week 8 (i.e., a total of 3 IV doses). At week 12, patients continued treatment based on their clinical response status, which was defined as a reduction from baseline (i.e., week 0) in the CDAI score of 100 points or more or being in clinical remission (a CDAI score of less than 150).

The placebo response group continued placebo treatment from week 12 through week 44.

The placebo nonresponse group received a single ustekinumab IV induction dose at week 12 (with weight-based IV doses approximating 6 mg/kg). At week 20, patients received ustekinumab SC maintenance (90 mg SC every 8 weeks) through week 44.

Matching placebo (IV and SC), which was identical in appearance to the active study intervention, was administered to maintain the blind throughout the duration of the study. To maintain patient blinding, all patients regardless of treatment group were assessed for clinical response status at week 12. Once all randomized patients in the GALAXI trials had either completed the week 48 visit or terminated study participation before week 48, the treatment assignment information was unblinded for all patients in that study and made available for analysis.

GRAVITI Study

The 24-week main treatment phase includes a 12-week induction period followed by a 12-week maintenance period; this is then followed by the extension treatment phase, which comprises a 72-week maintenance period.

Patients were to remain on their assigned treatment regimens throughout the study, with the exception of the placebo treatment group, outlined as follows.

In the guselkumab regimen 1 group (low dose), patients received guselkumab at a dose of 400 mg SC at week 0, week 4, and week 8, followed by guselkumab at a dose of 100 mg SC every 8 weeks starting at week 12.

In the guselkumab regimen 2 group (high dose), patients received guselkumab at a dose of 400 mg SC at week 0, week 4, and week 8, followed by guselkumab at a dose of 200 mg SC every 4 weeks starting at week 16.

In the placebo group, patients received placebo SC every 4 weeks from week 0. All patients in the placebo group who met at least 1 of the rescue criteria at week 12 and week 16 received rescue treatment in a blinded fashion (i.e., guselkumab at a dose of 400 mg SC at week 16, week 20, and week 24, followed by guselkumab at a dose of 100 mg SC every 8 weeks). The rescue criteria were as follows: having a CDAI score of greater than 220 and less than a 70-point reduction from the baseline CDAI score at both week 12 and week 16, or having the SES-CD score increase by at least 50% from baseline at week 12. To maintain the blind, patients randomized to guselkumab who met at least 1 of the rescue criteria continued their assigned treatment regimen and received a blinded “sham” rescue with a matching placebo SC injection at week 16, week 20, and week 24.

Posttreatment Phase

No medications were required during the posttreatment phase to prevent or mitigate the risk of AEs related to guselkumab administration. Patients should consult a health care provider if signs or symptoms of clinically significant chronic or acute infection occur. There is no defined recovery time for guselkumab.

GALAXI 2, GALAXI 3, and GRAVITI Studies

Concomitant Medications

Patients who were receiving oral 5-ASA compounds, oral corticosteroids, conventional immunomodulators (i.e., azathioprine, 6-mercaptopurine, or methotrexate), antibiotics, and/or enteral nutrition for the treatment of CD at baseline should have maintained a stable dose through week 48, with the exception of oral corticosteroids. These therapies should not be initiated during the studies. Therapies could only be discontinued or reduced in dose after week 0 if investigator judgment required it because of toxicity or another medical necessity; even if the toxicity resolved, the therapy should not be restarted.

Corticosteroids had to be maintained at baseline doses through week 12, and all patients had to begin tapering corticosteroids at week 12, unless medically infeasible, as per the following schedule.

• Oral corticosteroid (other than budesonide):

  • Prednisone at a dose of greater than 15 mg per day or equivalent; taper the daily dose by 5 mg per week until receiving 10 mg per day, then continue tapering at 2.5 mg per week until 0 mg per day.

  • Prednisone at a dose of 11 mg to 15 mg per day (or equivalent); taper the daily dose to 10 mg per day for 1 week, then continue at 2.5 mg per week until 0 mg per day.

  • Prednisone at a dose of less than or equal to 10 mg per day (or equivalent); taper the daily dose by 2.5 mg per week until 0 mg per day.

• Oral budesonide: Taper the daily dose by 3 mg every 3 weeks until 0 mg per day.

From week 12 to week 48, patients were allowed to transiently use (i.e., for less than 4 weeks) increased doses of corticosteroids for reasons other than treatment for CD (e.g., stress doses of corticosteroids for surgery, asthma, adrenocortical insufficiency).

Prohibited Medications

Concomitant use of immunomodulatory drugs other than azathioprine, 6-mercaptopurine, or methotrexate, immunomodulatory biologic drugs (including, but not limited to, TNF antagonists, IL-23 antagonists, natalizumab, ustekinumab, rituximab, and vedolizumab), experimental CD medications, and thalidomide or related drugs were prohibited.

Dose Modification

No treatment or dose adjustment was permitted through week 48 in the GALAXI 2 and GALAXI 3 trials.

Discontinuation of Study Intervention

Discontinuation of a patient’s study intervention must be strongly considered under the following conditions:

• persistent inadequate response or worsening of CD:

  • the patient had a change from baseline in the CDAI score of less than 70 points and has a CDAI score greater than 220 at both week 20 and week 24, or

  • the patient experienced AEs consistent with clinically significant worsening of CD at any time during the study.

• The patient developed a serious infection, including but not limited to sepsis or pneumonia.

• The patient reported suicidal behaviour.

• The patient developed a severe injection-site or infusion reaction.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 9, 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 for this review and input from patient and clinician groups and public drug plans. Using the same considerations, CDA-AMC selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. The most important efficacy end points were assessed using GRADE; others are included in the report as supportive information. Select safety outcomes considered important for informing expert committee deliberations were also assessed using GRADE. A description of the efficacy outcome measures and their measurement properties that were used in both the induction and maintenance phases are presented in Table 10.

Table 9: Outcomes Summarized From GALAXI 2, GALAXI 3, and GRAVITI Studies

IBDQ = Inflammatory Bowel Disease Questionnaire; NA = not applicable; PRO-2 = patient-reported outcome 2; SC = subcutaneous; vs. = versus.

^aAn outcome that is commonly used in clinical practice to assess patients.

^bAn outcome that is considered important according to patient group input.

^cAn outcome that is considered important according to clinical expert input.

^dStatistical testing for these end points was adjusted for multiple comparisons.

Sources: Clinical Study Report for the GALAXI 2 trial,¹² Clinical Study Report for the GALAXI 3 trial,¹³ Clinical Study Report for the and GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

GALAXI 2 and GALAXI 3 Studies

Coprimary End Points

The GALAXI trials defined 2 composite outcomes as coprimary end points. These were tested within each of the GALAXI 2 trial and the GALAXI 3 trial separately. They were:

• the proportion of patients with clinical response at week 12 and clinical remission at week 48

• the proportion of patients with clinical response at week 12 and endoscopic response at week 48.

Clinical response was defined as either a reduction of 100 or more points from the baseline in the CDAI score or a CDAI score of less than 150.

Endoscopic response was defined as a 50% or greater improvement from baseline in the SES-CD score or an SES-CD score of 2 or less.

Clinical remission was defined as a CDAI score of less than 150.

Crohn’s Disease Activity Index

The CDAI is a validated, multi-item measure of severity of illness derived as a weighted sum of 8 different CD-related components,²⁸ including extraintestinal manifestations, abdominal mass, weight, hematocrit, the use of antidiarrheal drugs and/or opiate, the total number of liquid or very soft stools, abdominal pain or cramps, and general well-being. The average daily stool frequency, average daily abdominal pain score, and well-being were calculated from the patient diary. The items are scored individually and weighted, and do not contribute equally to the overall score. The CDAI score is derived from summing the weighted individual scores of 8 items and ranges from 0 to 600. A higher score indicates more severe disease. No information regarding minimal important difference (MID) of CDAI in patients with CD was identified.

Simple Endoscopic Score for Crohn’s Disease

The SES-CD is a scoring system that assesses 4 endoscopic items, including the size of ulcers, ulcerated surface, affected surface, and the presence of narrowing.²⁸ Each item is to be scored from 0 to 3, with a total score ranging from 0 to 56. Higher scores indicate more severe disease, although no information regarding the MID was identified. SES-CD was demonstrated to have construct validity²⁸ and high interrater reliability.²⁹

Secondary End Points

Secondary end points included 3 sets of comparisons: short-term comparisons between guselkumab and placebo, long-term comparisons between guselkumab and placebo, and long-term comparisons between guselkumab and ustekinumab.

The first set of secondary end points (set 1) included the short-term comparisons between the combined guselkumab induction dose and placebo. The set 1 of secondary end points included the following outcomes that were relevant to this report:

• the proportion of patients with endoscopic response at week 12

• the proportion of patients with endoscopic remission at week 12

• the proportion of patients with clinical remission at week 12

• the proportion of patients with clinical response at week 12.

The second set of secondary end points (set 2) evaluated the long-term efficacy of each individual guselkumab treatment group (i.e., regimen 1 and regimen 2) versus placebo and included the following:

• the proportion of patients with clinical response at week 12 and 90-day, corticosteroid-free clinical remission at week 48

• the proportion of patients with clinical response at week 12 and endoscopic remission at week 48.

The end point 90-day, corticosteroid-free clinical remission was defined as not receiving corticosteroids for a duration of 90 days.

Endoscopic remission was defined as at least a 2-point reduction in the SES-CD score versus baseline, with no individual subcomponent score greater than 1.

The last set of secondary end points (set 3) evaluated the long-term efficacy of each individual guselkumab treatment group (i.e., regimen 1 and regimen 2) versus ustekinumab and included the following:

• the proportion of patients with clinical remission at week 48

• the proportion of patients with endoscopic response at week 48

• the proportion of patients with clinical remission at week 48 and endoscopic response at week 48

• the proportion of patients with endoscopic remission at week 48

• the proportion of patients with deep remission at week 48.

Deep remission was defined as both clinical remission and endoscopic remission.

In addition to the coprimary and secondary end points, exploratory end points related to disease status, inflammatory biomarkers, HRQoL outcomes, and health economics were also analyzed.

GRAVITI Study

Coprimary End Points

The coprimary end points for the GRAVITI trial included:

• the proportion of patients with clinical remission at week 12

• the proportion of patients with endoscopic response at week 12.

Secondary End Points

In the GRAVITI trial, there were 3 secondary end points and 2 multiplicity-controlled end points, including:

• the proportion of patients with clinical remission at week 24, which evaluated the efficacy of each individual guselkumab treatment group (i.e., regimen 1 and regimen 2) versus placebo

• the proportion of patients with PRO-2 remission, which evaluated the combined guselkumab group (400 mg SC) versus placebo

• the proportion of patients with clinical response at week 12, which evaluated the combined guselkumab group (400 mg SC) versus placebo.

Other multiplicity-controlled end points for the GRAVITI trial included the following:

• the proportion of patients with endoscopic response at week 48

• the proportion of patients with clinical remission at week 48.

Clinical remission was defined as a CDAI score of less than 150.

Clinical response was defined as either a reduction of 100 or more points from the baseline in the CDAI score or a CDAI score of less than 150.

In addition to the primary, secondary, and multiplicity-controlled week 48 end points, exploratory end points related to disease status, inflammatory biomarkers, HRQoL outcomes, and health economics were also analyzed.

GALAXI and GRAVITI Trials

Patient-Reported Outcomes

In the GALAXI and GRAVITI trials, PROs included PRO-2 remission and IBDQ remission.

PRO-2 remission was defined as a mean abdominal pain daily score of less than or equal to 1, and a mean stool frequency daily score of less than or equal to 3, and no worsening of abdominal pain or stool frequency from baseline.

IBDQ remission was defined as an IBDQ score of 170 or greater.

32-Item Inflammatory Bowel Disease Questionnaire

The 32-item Inflammatory Bowel Disease Questionnaire tool is a disease-specific, patient-reported, multidimensional HRQoL questionnaire that has been validated for CD. It comprises 32 Likert-scaled items that cover 4 domains: bowel symptoms, systemic symptoms, emotional function, and social function. Each question is scored on a 7-point scale where 1 corresponds to the poorest and 7 to the optimum function. The total score ranges from 32 points to 224 points, with higher scores indicating a better HRQoL. Each individual IBDQ dimension was calculated when 1 or fewer items were missing in the dimension. One study proposed that a clinically meaningful improvement is an increase of greater than or equal to 16 points in the total score or 0.5 points or more per question in patients with CD.^30,31

Harms

The harms outcomes assessed were AEs, SAEs, deaths, withdrawal due to AEs, and AEs of special interest, including malignancy, active tuberculosis, anaphylaxis, infections and opportunistic infections, major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), hepatic disorders, and venous thromboembolism.

Table 10: Summary of Outcome Measures and Their Measurement Properties

CD = Crohn disease; CDAI = Crohn’s Disease Activity Index; CDEIS = Crohn’s Disease Endoscopic Index of Severity; CI = confidence interval; EMA = European Medicines Agency; HRQoL = health-related quality of life; IBD = inflammatory bowel disease; IBDQ = Inflammatory Bowel Disease Questionnaire; IBDQ-32 = 32-item Inflammatory Bowel Disease Questionnaire; ICC = intraclass correlation coefficient; MID = minimal important difference; SES-CD = Simple Endoscopic Score for Crohn’s Disease.

Statistical Analysis

Sample Size and Power Calculation

GALAXI 2 and GALAXI 3 Studies

The sample size for the GALAXI 2 and GALAXI 3 trials was determined to achieve at least 90% power to detect a treatment difference in the coprimary end points, using a chi-square test with a 2-sided significance level of 0.05.

For the coprimary end point of clinical response at week 12 and clinical remission at week 48, in each of the phase III trials, assuming a placebo rate of 8% to 10% and a 40% to 45% difference between guselkumab and placebo based on the phase II trial (the GALAXI 1 study), 140 patients in each guselkumab dose group and 70 patients in the placebo group were to provide greater than 99% power for this end point at the 2-sided significance level of 0.05. For the coprimary end point of clinical response at week 12 and endoscopic response at week 48, in each of the phase III trials, assuming a placebo rate of approximately 2% to 5% and a 30% to 35% difference between guselkumab and placebo based on the phase II trial (the GALAXI 1 study),²⁷ 140 patients in each guselkumab dose group and 70 patients in the placebo group were to provide greater than 99% power for this end point at the 2-sided significance level of 0.05.

GRAVITI Study

The sample size for this trial was determined to achieve at least 90% power to detect a treatment difference in the clinical remission and endoscopic response at week 12 between the combined guselkumab group (400 mg SC followed by 200 mg SC and 400 mg SC followed by 100 mg SC combined) and the placebo group, using a 2-sided chi-square test with a 2-sided significance level of 0.05. Assuming 15% clinical remission for the placebo group and 50% for the guselkumab group as well as a 13% endoscopic response for the placebo group and 30% for the guselkumab group, enrolling 212 patients in the combined guselkumab group and 106 patients in the placebo group was sufficient to achieve the prespecified statistical power.

Statistical Testing and Multiple Testing Procedures

The statistical analysis of efficacy outcomes in the induction and maintenance studies are summarized in sensitivity analyses for the coprimary end points and were conducted to assess the robustness of the findings under different data imputation methods. First, a tipping point analysis using Bernoulli draws was performed to impute missing clinical response status at week 12, clinical remission status at week 48, and endoscopic response status at week 48 in both the GALAXI 2 and GALAXI 3 trials, as well as clinical remission and endoscopic response at week 12 in the GRAVITI trial. These analyses were conducted after applying the ICE rules and were limited to cases where the proportion of missing data 5% or more.in any treatment group. Subsequently, the multiple imputation method was employed to impute missing CDAI and SES-CD scores, assuming the data were missing at random, also following application of the ICE rules.

Supportive Analyses

As a supportive analysis to the coprimary end points analysis, each coprimary end point was analyzed using the all-treated analysis set, defined as all randomized patients who received at least 1 (partial or complete) dose of study intervention, regardless of meeting the SES-CD eligibility criteria.

Statistical Model

GALAXI 2, GALAXI 3, and GRAVITI Studies

The proportion of patients meeting each of the coprimary end points was summarized by treatment group, along with the associated 95% CIs. The adjusted treatment difference (95% CI) between guselkumab and placebo was also presented. A common risk difference test employing Mantel-Haenszel stratum weights was used to compare each guselkumab treatment group (i.e., regimen 1 and regimen 2) to the placebo treatment group, adjusting for the stratification factors. In the GALAXI 2 and GALAXI 3 trials, the stratification variables included the baseline CDAI score (less than or equal to 300 versus greater than 300), the baseline SES-CD score (less than or equal to 12 versus greater than 12), prior BIO-Failure status (yes or no), and baseline corticosteroid use (yes or no). In the GRAVITI trial, the stratification variables included the baseline CDAI score (less than or equal to 300 versus greater than 300), the baseline SES-CD score (less than or equal to 12 versus greater than 12), and prior BIO-Failure status (yes or no). Each primary end point was assigned a 2-sided alpha of 0.05. In the GRAVITI trial, the stratification variables included the baseline CDAI score (less than or equal to 300 versus greater than 300), the baseline SES-CD score (less than or equal to 12 versus greater than 12), and prior BIO-Failure status (yes or no). The secondary end points of the trials were analyzed using the same methods as the coprimary end points.

At each time point, the CDAI score was calculated only if at least 4 of the 8 components were available. When at least 4 components were available, any missing values were imputed by carrying forward the last nonmissing value for that component. The total SES-CD score for each visit was calculated based on all endoscopic components of segments scored during that visit. If the total SES-CD score could not be calculated at a visit (i.e., none of the segments were scored), the score was considered missing. If the CDAI or SES-CD scores could not be calculated at a visit, they were considered missing for that visit. Patients with missing CDAI or SES-CD scores at a visit were considered as not achieving the end point associated with that visit, as measured by the CDAI or SES-CD score (i.e., NRI).

ICEs were taken into account when defining the estimands in the trials. An estimand refers to a precise definition of the primary targeted treatment effect defined by the following 5 attributes: the study intervention, the target population, the end point, ICEs and strategies for handling them, and the population-level summary. The following ICEs and corresponding strategies were considered for this study:

• patients who underwent ICEs, including

  • a CD-related surgery (ICE category 1)

  • a prohibited change in CD medication, including by patients in the placebo group who crossed over to ustekinumab at week 12 (ICE category 2)

  • the discontinuation of the study intervention due to a lack of efficacy, or an AE of the worsening of CD (ICE category 3)

  • the discontinuation of the study intervention due to COVID-19–related reasons (excluding COVID-19 infection) or a regional crisis (ICE category 4)

  • the discontinuation of the study intervention for reasons other than those specified in ICE category 3 and ICE category 4 (ICE category 5).

ICEs in category 1 to category 3 and in category 5 were considered indicative of not achieving the end point and were handled using a composite strategy. For patients who discontinued the study intervention due to COVID-19–related reasons (excluding COVID-19 infection) or a regional crisis, their observed values were included, using a treatment policy strategy, if available. Patients with missing data for all other reasons were classified as the nonresponse group. A population-level summary was defined as the difference in proportions of those with a response between each guselkumab dose group (regimen 1 and regimen 2) and the placebo group.

The secondary end points of the trials, evaluating guselkumab versus placebo or the active comparator (ustekinumab), were analyzed using the same methods as those of the coprimary end points. The same ICEs and corresponding strategies were specified for the secondary end points. In the GALAXI 2 and GALAXI 3 trials, the analysis of the end points included in the first set of secondary end points (set 1, as described earlier) was based on within-study comparisons of the combined guselkumab induction dose group versus the placebo group in each GALAXI trial. The analysis of the end points included in set 2 involved comparisons within each trial of each guselkumab regimen (regimen 1 and regimen 2) versus the placebo group. The end points in set 3 were analyzed based on within-study comparisons of each guselkumab regimen (regimen 1 and regimen 2) versus the ustekinumab group. Additionally, the end points in set 3 were also analyzed using pooled data from the GALAXI 2 and GALAXI 3 trials.

In the GRAVITI trial, the end points at week 12 were based on comparisons of the combined guselkumab induction dose group (which received guselkumab 400 mg SC at week 0, week 4, and week 8) with the placebo group (because the induction dose is the same for each group). The end points assessed after week 12 were based on comparisons between each guselkumab group (regimen 1 and regimen 2) and the placebo group.

Multiplicity Considerations

GALAXI 2 and GALAXI 3 Studies

Within each trial, the type I error rate across the coprimary end points and secondary end points was controlled at a 2-sided significance level of 0.05 using a fixed-sequence testing procedure. The testing procedure began with sequential tests (within each phase III trial) to assess the superiority of each guselkumab dose group compared with placebo for the coprimary end points at the 2-sided significance level of 0.05 for each trial. If all P values were significant (i.e., P value < 0.05), after testing of the coprimary end points, the testing procedure continued with superiority tests for the secondary end points. However, if any of the tests of the coprimary end points within a trial were not significant (i.e., P value ≥ 0.05), all subsequent P values in the testing hierarchy were considered nominal. The secondary end points in both GALAXI trials were grouped into 5 tiers (graphical testing procedures are presented in Appendix 1). For the coprimary and secondary end points in tier 1, tier 4, and tier 5, the study hypotheses were tested separately within each of the GALAXI 2 and GALAXI 3 trials. For the secondary end points in tier 2 and tier 3, the hypotheses were tested for data pooled across both trials. Within each tier, the Hochberg procedure was used to test all end points in that tier with a 2-sided significance level of 0.05. If a test within a tier was not significant but other tests in the same tier met the Hochberg thresholds, other tests were declared significant. However, formal testing ceased and the P values for all end points in subsequent tiers were considered nominal.

IBDQ remission was an exploratory end point and was tested irrespective of the significance of the coprimary and secondary end points. Testing for IBDQ remission was not controlled for multiplicity and nominal P values were presented.

GRAVITI Study

The type I error rate for the comparison between guselkumab and placebo was controlled at a 2-sided significance level of 0.05 over the coprimary, secondary, and 2 week 48 exploratory end points. The testing procedure began with a fixed-sequence testing procedure for the coprimary and secondary end points. If any test of the coprimary and secondary end points in the sequence did not achieve significance at the 2-sided significance level of 0.05, the P values for all subsequent end points were considered nominal. In September 2023, there was a protocol amendment to add 2 multiplicity-controlled exploratory end points at week 48 to the testing hierarchy procedures. These were tested if all prior tests were statistically significant. For the week 48 multiplicity-controlled end points, the Hochberg procedure with a 2-sided significance level of 0.05 was used for all 4 tests and significance was achieved if a test met the Hochberg thresholds.

Subgroup Analyses

The prespecified subgroups of interest across the 3 trials — BIO-Failure and CON-Failure status and BIO-naive status (i.e., no prior exposure to biologic therapies such as TNF antagonists, vedolizumab, or ustekinumab) — were used to evaluate treatment effects for the coprimary and major secondary end points. The common risk difference test employing Mantel-Haenszel stratum weights was used to compare each guselkumab dose group to placebo while adjusting for the stratification factors. Results were shown as the point estimate and 95% CI for treatment differences between the guselkumab group and comparator group, without formal statistical testing. Subgroup analyses in the GALAXI 2 and GALAXI 3 studies were based on the primary analysis set (PAS), while those in the GRAVITI trial were based on the full analysis set.

Sensitivity Analyses

The sensitivity analyses performed for the primary and secondary outcomes are summarized in Table 11.

Sensitivity analyses for the coprimary end points were conducted to assess the robustness of the findings under different data imputation methods. First, a tipping point analysis using Bernoulli draws was performed to impute missing clinical response status at week 12, clinical remission status at week 48, and endoscopic response status at week 48 in both GALAXI trials, as well as clinical remission and endoscopic response at week 12 in the GRAVITI trial. These analyses were conducted after applying the ICE rules and were limited to cases where the proportion of missing data was 5% or more in any treatment group. Subsequently, the multiple imputation method was employed to impute missing CDAI and SES-CD scores, assuming the data were missing at random, also following application of the ICE rules.

Supportive Analyses

As a supportive analysis to the coprimary end points analysis, each coprimary end point was analyzed using the all-treated analysis set, defined as all randomized patients who received at least 1 (partial or complete) dose of study intervention, regardless of meeting the SES-CD eligibility criteria.

Table 11: Statistical Analysis of Efficacy End Points

ATAS = all-treated analysis set; BIO-Failure = biologic therapy failure or intolerance; CDAI = Crohn’s Disease Activity Index; IBDQ = Inflammatory Bowel Disease Questionnaire; PAS = primary analysis set; PRO-2 = patient-reported outcome 2; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease.

Note: The modified PAS included the same population as the PAS but excluded patients who had data that could not be verified as specified by the Global Monitoring Plan due to an inability to access sites because of a major disruption (specifically, the regional crisis in Ukraine and Russia, or COVID-related site restrictions such as site closures, and other potential events that restrict site access).

Sources: Clinical Study Report for the GALAXI 2 trial,¹² Clinical Study Report for the GALAXI 3 trial,¹³ Clinical Study Report for the GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Safety Analysis

In all 3 trials, safety analyses were carried out using the corresponding safety analysis described in the Analysis Populations section that follows. In general, patients were analyzed according to their assigned treatment group. However, patients originally assigned to placebo or ustekinumab who inadvertently received guselkumab at any point were analyzed as part of the guselkumab group from the time of first guselkumab administration onward.

Analysis Populations

The analysis populations are summarized in Table 12.

Table 12: Analysis Populations of GALAXI 2, GALAXI 3, and GRAVITI Studies

ATAS = all-treated analysis set; FAS = full analysis set; PAS = primary analysis set; PSAS = primary safety analysis set; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease.

^aScreening SES-CD score of at least 6, or at least 4 for patients with isolated ileal disease.

Sources: Clinical Study Report for the GALAXI 2 trial,¹² Clinical Study Report for the GALAXI 3 trial,¹³ Clinical Study Report for the GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

A summary of patient disposition for the GALAXI 2, GALAXI 3, and GRAVITY trials is presented in Table 13, Table 14, and Table 15, respectively.

GALAXI 2 Study

In the GALAXI 2 trial, 524 patients were randomized, of whom 508 received treatment, including 76 patients in the placebo group, 143 patients in the guselkumab regimen 1 group (200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks), 146 patients in the guselkumab regimen 2 group (200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks), and 143 patients in the ustekinumab group. At week 12, 49 (64.4%) patients who had been randomized to placebo crossed over to ustekinumab. The proportion of patients who discontinued study treatment in the induction period was low across treatment groups, ranging from 0.7% to 3.9%. The proportion of patients who discontinued study treatment before completing the maintenance phase was notably higher in the placebo group (37.0%) compared with the guselkumab regimen 1 group (9.8%), the guselkumab regimen 2 group (4.1%), and the ustekinumab group (14.0%). In the placebo group, discontinuation was most commonly due to AEs related to the worsening of CD (18.5%), followed by patient withdrawal (7.4%) and a lack of efficacy (7.4%). These reasons were less frequently reported in the other treatment groups, with discontinuations due to the worsening of CD ranging from 0.7% to 2.8%, patient withdrawal ranging from 0% to 5.6%, and a lack of efficacy ranging from 0.7% to 2.8%.

GALAXI 3 Study

In the GALAXI 3 trial, 525 patients were randomized, of whom 513 received treatment, including 72 patients in the placebo group, 143 patients in the guselkumab regimen 1 group, 150 patients in the guselkumab regimen 2 group, and 148 patients in the ustekinumab group. At week 12, 49 (68.1%) patients who had been randomized to placebo crossed over to ustekinumab. The proportion of patients who discontinued study treatment during the induction period ranged from 1.3% to 4.2% across the treatment groups. The proportion of patients who discontinued study treatment before completing the maintenance phase was notably higher in the placebo group (34.8%) compared with the guselkumab regimen 1 group (15.4%), the guselkumab regimen 2 group (16.7%), and the ustekinumab group (18.2%). In the placebo group, discontinuation was most commonly due to AEs related to the worsening of CD (21.7%), followed by patient withdrawal (8.7%) and a lack of efficacy (4.3%). These reasons were less frequently reported in the other treatment groups, with discontinuations due to the worsening of CD ranging from 1.4% to 3.4%, patient withdrawal ranging from 2.0% to 4.2%, and a lack of efficacy ranging from 2.1% to 4.1%. One patient withdrew from the study due to a protocol deviation.

GRAVITI Study

In the GRAVITI trial, 350 patients were randomized, of whom 347 received the treatment, including 117 patients in the placebo group, 117 patients in the guselkumab regimen 2 group, and 115 patients in the guselkumab regimen 1 group. The proportion of patients who discontinued study treatment during the induction period was higher in the placebo group (10.3%) compared with the guselkumab regimen 1 group (1.7%) and the guselkumab regimen 2 group (0.9%). The proportion of patients who discontinued study treatment before completing the maintenance period was notably higher in the placebo group (26.5%) compared with the guselkumab regimen 2 group (10.4%) and the guselkumab regimen 1 group (4.3%). In the placebo group, discontinuation was most commonly due to patient withdrawal (7.7%), followed by AEs related to the worsening of CD (5.1%), and a lack of efficacy (5.1%). These reasons were less frequently reported in the guselkumab regimen 2 and guselkumab regimen 1 groups, with discontinuations due to patient withdrawal occurring in 1.7% of patients in both groups, due to the worsening of CD in 1.7% and 0.7% of patients, respectively, and due to a lack of efficacy in 0.9% and 2.6% of patients, respectively.

Table 13: Summary of Patient Disposition From GALAXI 2 Study — PAS

ATAS = all-treated analysis set; CD = Crohn disease; NA = not applicable; PAS = primary analysis set; PSAS = primary safety analysis set; SC = subcutaneous.

Note: Guselkumab regimen 1 = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^aThe Placebo column includes all patients randomized to placebo. At week 12, patients who in the clinical response group continued placebo treatment and those in the nonresponse group crossed over to ustekinumab.

^bStudy treatment discontinuation during induction = discontinued treatment before the week 12 visit and the week 8 dose is missing.

^cPatients who did not receive a maintenance dose, and those who received placebo SC during the maintenance period.

^dPatients who were not in clinical response to placebo induction dosing and crossed over to ustekinumab at week 12 and continued to receive ustekinumab SC dosing in the maintenance period.

^eDiscontinuing study treatment before completing maintenance dosing means discontinued treatment before week 48 visit and the week 44 dose is missing.

Sources: Clinical Study Report for the GALAXI 2 trial.¹² Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 14: Summary of Patient Disposition From GALAXI 3 Study — PAS

ATAS = all-treated analysis set; CD = Crohn disease; NA = not applicable; PAS = primary analysis set; PSAS = primary safety analysis set; SC = subcutaneous.

Note: Guselkumab regimen 1 = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^aThe Placebo column includes all patients randomized to placebo. At week 12, patients in the clinical response group continued placebo treatment and those who in the nonresponse group crossed over to ustekinumab.

^bStudy treatment discontinuation during induction = discontinued treatment before the week 12 visit and the week 8 dose is missing.

^cPatients who did not receive a maintenance dose, and those who received placebo SC during the maintenance period.

^dPatients who were not in clinical response to placebo induction dosing and crossed over to ustekinumab at week 12 and continued to receive ustekinumab SC dosing in the maintenance period.

^eDiscontinuing study treatment before completing maintenance dosing = discontinued treatment before the week 48 visit and the week 44 dose is missing.

^fOther major disruption–related includes a regional crisis.

Sources: Clinical Study Report for the GALAXI 3 trial.¹³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 15: Summary of Patient Disposition From GRAVITI Study — FAS

AE = adverse event; CD = Crohn disease; FAS = full analysis set; NA = not applicable; SAS = safety analysis set; SC = subcutaneous.

Note: Guselkumab regimen 1 equals 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 equals 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^aIncludes data from all placebo patients, excluding data after a patient was rescued with guselkumab.

^bIncludes data from placebo patients who were rescued with guselkumab. Data in this group occurred after a patient crossed over to guselkumab.

Sources: Clinical Study Report for the GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Protocol Deviation

In the GALAXI 2 trial, the proportion of major protocol deviations was 10.5% in the placebo group, 20.3% in the guselkumab regimen 1 group, 14.4% in the guselkumab regimen 2 group, and 19.6% in the ustekinumab group through week 48; this was primarily attributed to not meeting eligibility criteria (5.3%, 6.3%, 4.1%, and 4.2%, respectively). In the GALAXI 3 trial, the proportion of major protocol deviations was 19.4% in the placebo group, 18.9% in the guselkumab regimen 1 group, 24.0% in the guselkumab regimen 2 group, and 27.0% in the ustekinumab group through week 48; the most common reasons for protocol deviations included not meeting eligibility criteria (9.7%, 6.3%, 12.0%, and 12.8%, respectively) and receiving the wrong treatment or incorrect dose (0%, 2.8%, 2.0%, and 1.4%, respectively). In the GRAVITI trial, the proportion of major protocol deviations was 36.8% in the placebo group, 26.1% in the guselkumab regimen 1 group, and 24.3% in the guselkumab regimen 2 group through week 48; the most common reasons for protocol deviations included not meeting eligibility criteria (26.5%, 15.7%, and 16.5%, respectively) and receiving prohibited concomitant medication (2.6%, 4.3%, and 6.1%, respectively).

Baseline Characteristics

The baseline characteristics for the GALAXI trials and the GRAVITI trial are outlined in Table 16 and Table 17, respectively.

GALAXI 2 Study

In the GALAXI 2 trial, patients were predominantly white (74.2% vs. 25.8% nonwhite) and male (55.3% versus 44.7% female). The mean age was 36.4 years (standard deviation [SD] = 12.8 years). In the PAS population, the majority of patients were from Eastern Europe (48.4%), followed by Asia (21.5%) and the rest of the world (23.4%). The mean duration of CD was 7.13 years (SD = 6.9 years), the mean CDAI score was 295.0 points (SD = 52.0 points), the mean SES-CD score was 13.1 points (SD = 7.3 points), and the endoscopic disease severity per SES-CD score for most patients (54.1%) was between 7 and 16. The proportion of patients in the BIO-Failure analysis subpopulation was 52.8%, and 50.6% of patients had not experienced improvement with at least 1 TNF antagonist. The proportion of patients in the CON-Failure analysis subpopulation was 47.2%, and 41.9% of patients were in the biologic-naive analysis subpopulation, which was a subset of the CON-Failure analysis subgroup. Baseline characteristics were generally similar across treatment groups, with a few notable differences. The guselkumab regimen 1 group had a lower proportion of male patients (48.3%) compared with the placebo group (53.9%), the guselkumab regimen 2 group (59.6%), and the ustekinumab group (58.7%). The mean duration of CD was shorter in the placebo group at 6.36 years compared with 7.91 years in the guselkumab regimen 1 group, 7.30 years in the guselkumab regimen 2 group, and 6.58 years in the ustekinumab group. Additionally, a higher proportion of patients in the guselkumab regimen 1 group had an SES-CD score of between 7 and 16 (58.0%) compared with the placebo group (50.0%), the guselkumab regimen 2 group (54.1%), and the ustekinumab group (52.4%). Similarly, more patients in the guselkumab regimen 1 group had at least 1 open or draining fistula (14.7%) compared with those in the placebo group (9.2%), the guselkumab regimen 2 group (4.8%), and the ustekinumab group (6.3%). The distribution of patients with prior treatment using anti-TNF drugs, vedolizumab, or both was generally similar across all groups.

GALAXI 3 Study

In the GALAXI 3 trial, patients were predominantly white (74.5%) and male (59.8%). The mean age was 36.6 years (SD = 12.9 years). In the PAS population, the majority of patients were from Eastern Europe (44.1%), followed by Asia (20.3%) and the rest of the world (25.7%). The mean duration of CD was 7.20 years (SD = 7.47 years), the mean CDAI score was 294.7 points (SD = 53.8 points), the mean SES-CD score was 12.8 points (SD = 7.3 points), and the endoscopic disease severity per SES-CD score for most patients (53.0%) was between 7 and 16. The proportion of patients in the BIO-Failure analysis subpopulation (whose disease had a history of inadequate response or intolerance to previous biologic medication treatment) was 51.9%, and approximately half of patients (50.3%) had not experienced improvement with at least 1 TNF antagonist. The proportion of patients in the CON-Failure analysis subpopulation was 48.1%, and 41.5% of patients were in the biologic-naive analysis subpopulation. Baseline characteristics were generally similar across treatment groups, with a few notable differences. The guselkumab regimen 1 group had a lower proportion of male patients (48.3%) compared with the placebo group (53.9%), the guselkumab regimen 2 group (59.6%), and the ustekinumab group (58.7%). The mean duration of CD was shortest in the placebo group at 6.36 years compared with 7.91 years in the guselkumab regimen 1 group, 7.30 years in the guselkumab regimen 2 group, and 6.58 years in the ustekinumab group. Additionally, a higher proportion of patients in the guselkumab regimen 1 group had an SES-CD score between 7 and 16 (58.0%) compared with the placebo group (50.0%), the guselkumab regimen 2 group (54.1%), and the ustekinumab group (52.4%). Similarly, more patients in the guselkumab regimen 1 group had at least 1 open or draining fistula (14.7%) compared with those in the placebo group (9.2%), the guselkumab regimen 2 group (4.8%), and the ustekinumab group (6.3%). The distribution of patients with prior treatment using anti-TNF drugs, vedolizumab, or both was generally similar across all groups.

GRAVITI Study

In the GRAVITI trial, patients were predominantly white (66.0% versus 44.0% nonwhite) and male (58.5% versus 41.5% female). The mean age was 37.5 years (SD = 12.9 years). In the PAS population, the majority of patients were from Eastern Europe (39.8%), followed by Asia (21.3%) and the rest of the world (30.3%). The mean duration of CD was 8.0 years (SD = 8.1 years), the mean CDAI score was 296.9 points (SD = 52.7 points), the mean SES-CD score was 12.0 points (SD = 6.9 points), and the endoscopic disease severity per SES-CD score for most patients (50.1%) was between 7 and 16. The proportion of patients in the BIO-Failure analysis subpopulation (history of inadequate response or intolerance to previous biologic medication treatment) was 46.6%. A total of 53.6% of patients had not experienced improvement with conventional therapies but had experienced improvement with biologic therapy. Additionally, 46.4% of patients had no prior exposure to biologics, which constitutes the majority of the CON-Failure analysis population. Baseline characteristics were generally similar across treatment groups, with a few notable differences. The guselkumab regimen 2 group had a higher proportion of patients from Eastern Europe (43.5%) compared with the placebo and guselkumab regimen 1 groups (35.0% and 40.9%, respectively). The mean duration of CD was 6.96 years (SD = 7.75 years) in the placebo group, 9.17 years (SD = 9.08 years) in the guselkumab regimen 1 group, and 7.89 years (SD = 7.13 years) in the guselkumab regimen 2 group. A higher proportion of patients in the guselkumab regimen 1 group had an SES-CD score of between 7 and 16 (55.7%) compared with those in the placebo group (52.1%) and the guselkumab regimen 2 group (42.6%). The distribution of patients with prior treatment using anti-TNF drugs, vedolizumab, or both was generally similar across all groups.

Table 16: Summary of Baseline Characteristics From GALAXI 2 and GALAXI 3 Studies — PAS, IV Induction and SC Maintenance

AP = abdominal pain; CD = Crohn disease; CDAI = Crohn’s Disease Activity Index; CRP = C-reactive protein; GI = gastrointestinal; IBDQ = Inflammatory Bowel Disease Questionnaire; PAS = primary analysis set; TNF = tumour necrosis factor; SC = subcutaneous; SD = standard deviation; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency.

Note: Guselkumab regimen 1 = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

Sources: Clinical Study Report for the GALAXI 2 trial,¹² Clinical Study Report for the and GALAXI 3 trial.¹³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 17: Summary of Baseline Characteristics From GRAVITI Study — FAS, SC Induction and SC Maintenance

Anti-TNF = anti–tumour necrosis factor; AP = abdominal pain; BIO-Failure = biologic therapy failure or intolerance; CD = Crohn disease; CDAI = Crohn’s Disease Activity Index; CRP = C-reactive protein; FAS = full analysis set; GI = gastrointestinal; IBDQ = Inflammatory Bowel Disease Questionnaire; SC = subcutaneous; SD = standard deviation; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency.

Note: Guselkumab regimen 1 = 400 mg SC at week 0, week 4, and week 8, followed by guselkumab 100 mg SC every 8 weeks. Guselkumab regimen 2 = 400 mg SC at week 0, week 4, and week 8, followed by guselkumab 200 mg SC every 4 weeks.

Sources: Clinical Study Report for the GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Details of exposure to study treatments of the GALAXI 2, GALAXI 3, and GRAVITI trials are summarized in Table 18, Table 19, and Table 20, respectively.

GALAXI 2 Study

In the PAS, all patients received at least 1 dose of study intervention during the IV induction period. During the maintenance period, missed SC treatment doses were reported in 2 (2.6%) patients in the placebo group, 2 (4.1%) patients in the placebo-to-ustekinumab crossover group, 12 (8.4%) patients in the guselkumab regimen 1 group, 4 (2.7%) patients in the guselkumab regimen 2 group, and 7 (4.9%) patients in the ustekinumab group. The main reasons for missed administrations were COVID-19–related disruptions and treatment discontinuation.

GALAXI 3 Study

In the PAS, all patients received the study intervention to which they were randomized during the IV induction period. During the maintenance phase, missed SC treatment doses were reported in 8 (11.1%) patients in the placebo group, 3 (6.1%) patients in the placebo-to-ustekinumab crossover group, 12 (8.4%) patients in the guselkumab regimen 1 group, 13 (8.7%) patients in the guselkumab regimen 2 group, and 10 (6.8%) patients in the ustekinumab group. The main reasons for missed administrations were COVID-19–related disruptions and treatment discontinuation.

GRAVITI Study

In the SAS, all patients received the study intervention to which they were randomized during the IV induction period. During the maintenance period, missed SC treatment doses were reported in 6 (5.1%) patients in the placebo group, 3 (6.8%) patients in the placebo-to-ustekinumab crossover group, and 2 (1.7%) patients in each of the guselkumab regimen 1 and regimen 2 groups. The main reasons for missed administrations were COVID-19–related disruptions and treatment discontinuation.

Table 18: Summary of Patient Exposure From GALAXI 2 Study — PAS, IV Induction and SC Maintenance

PAS = primary analysis set; SC = subcutaneous; SD = standard deviation.

Note: Guselkumab regimen 1 (low dose) = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 (high dose) = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^aMissed events in this column are attributed to those patients randomized to placebo with 1 exception: in the case where a patient is randomized to placebo and crosses over to ustekinumab, missed events occurring after receiving ustekinumab are not counted in this column.

^bPatients who were not in clinical response to placebo induction dosing and crossed over to ustekinumab at week 12 and continued to receive ustekinumab SC dosing in the maintenance period. Missed events counted in this group occurred after the patient had switched to the ustekinumab treatment group.

^cPatients randomized to guselkumab received IV dosing at weeks 0, 4, and 8. Patients randomized to ustekinumab received an IV dosing at week 0.

^dPatients randomized to guselkumab regimen 1 received guselkumab SC at weeks 16, 24, 32, and 40. Patients randomized to guselkumab regimen 2 received guselkumab SC at weeks 12, 16, 20, 24, 28, 32, 36, 40, and 44. Patients randomized to ustekinumab received an SC dosing of ustekinumab at weeks 8, 16, 24, 32, and 40.

^eMissed study intervention administration may include those due to treatment discontinuation.

Sources: Clinical Study Report for the GALAXI 2 trial.¹² Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 19: Summary of Patient Exposure From GALAXI 3 Study — PAS, IV Induction and SC Maintenance

PAS = primary analysis set; SC = subcutaneous; SD = standard deviation.

Note: Guselkumab regimen 1 equals 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 equals 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^aMissed events in this column are attributed to those patients randomized to placebo with 1 exception: in the case where a patient is randomized to placebo and crosses over to ustekinumab, missed events occurring after receiving ustekinumab are not counted in this column.

^bPatients who were not in clinical response to placebo induction dosing and crossed over to ustekinumab at week 12 and continued to receive ustekinumab SC dosing in the maintenance period. Missed events counted in this group occurred after the patient had switched to the ustekinumab treatment group.

^cPatients randomized to guselkumab received IV dosing at weeks 0, 4, and 8. Patients randomized to ustekinumab received an IV dosing at week 0.

^dPatients randomized to guselkumab regimen 1 received guselkumab SC at weeks 16, 24, 32, and 40. Patients randomized to guselkumab regimen 2 received guselkumab SC at weeks 12, 16, 20, 24, 28, 32, 36, 40, and 44. Patients randomized to ustekinumab received an SC dosing of ustekinumab at weeks 8, 16, 24, 32, and 40.

^eMissed study drug administration may include those due to treatment discontinuation.

Sources: Clinical Study Report for the GALAXI 3 trial.¹³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 20: Summary of Patient Exposure From GRAVITI Trial — SAS, SC Induction and SC Maintenance

FAS = full analysis set; SAS = safety analysis set; SC = subcutaneous; SD = standard deviation.

Note: Guselkumab regimen 1 (low dose) = 400 mg SC at weeks 0, 4, and 8, followed by guselkumab 100 mg SC every 8 weeks. Guselkumab regimen 2 (high dose) = 400 mg SC at weeks 0, 4, and 8, followed by guselkumab 200 mg SC every 4 weeks.

^aCompliance data are specific to the FAS with 13 (3.7%) patients of the 347 patients having missed study drug administration: placebo at 6 (5.1%) patients, placebo followed by guselkumab at 3 (6.8%) patients, guselkumab regimen 1 at 2 (1.7%) patients, and guselkumab regimen 2 at 2 (1.7%) patients.

^bIncludes data from all placebo patients, excluding data after a patient is rescued with guselkumab.

^cIncludes data from placebo patients who were rescued with guselkumab. Data in this group occurred after a patient crossed over to guselkumab.

^dIf more than 1 injection was given at a study visit, it was counted as 1 study drug administration.

Sources: Clinical Study Report for the GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Concomitant Medications and Cointerventions

The proportion of patients using concomitant medications for CD in the GALAXI 2, GALAXI 3, and GRAVITI studies are presented in Table 21, Table 22, and Table 23, respectively.

GALAXI 2 Study

The proportion of patients who received concomitant medications for CD was lower in the placebo group (61.8%) compared with the guselkumab regimen 1 group (74.1%), the guselkumab regimen 2 group (74.0%), and the ustekinumab group (76.2%). Notably, a lower proportion of patients in the placebo group received 6-mercaptopurine or azathioprine (23.7%), oral aminosalicylates (30.3%), and oral corticosteroids (32.9%) compared with the corresponding ranges in the other treatment groups: 27.3% to 30.8% for 6-mercaptopurine or azathioprine, 41.8% to 44.8% for oral aminosalicylates, and 37.7% to 39.2% for oral corticosteroids. The mean dose of corticosteroids (excluding budesonide) in the overall population was 17.8 mg, and the mean budesonide dose was 8.0 mg; both were comparable across treatment groups.

GALAXI 3 Study

In the GALAXI 3 trial, the proportion of patients who received concomitant medications for CD was comparable across the treatment groups. A higher proportion of patients in the guselkumab regimen 2 group received immunomodulators (34.0%) compared with the other treatment groups (ranging from 26.4% to 30.8%). Conversely, a lower proportion of patients in the placebo group received oral aminosalicylates (29.2%) compared with the other treatment groups (ranging from 36.7% to 41.3%). The mean dose of corticosteroids (excluding budesonide) was 19.9 mg in the overall population, and the mean dose of budesonide was 7.8 mg; both were comparable across treatment groups.

GRAVITI Study

The proportion of patients who received concomitant medications for CD was lower in the guselkumab regimen 1 group (64.3%) compared with the placebo group (67.5%) and the guselkumab regimen 2 group (73.0%).

A higher proportion of patients in the guselkumab regimen 2 group received corticosteroids (24.3%) compared with the placebo group (15.4%) and the guselkumab regimen 1 group (13.0%). Conversely, a lower proportion of patients in the guselkumab regimen 2 group received budesonide (8.7%) compared with the placebo group (12.8%) and the guselkumab regimen 1 group (14.8%). The mean dose of corticosteroids (excluding budesonide) was 19.7 mg in the overall population, and the mean dose of budesonide was 7.8 mg; both were comparable across treatment groups.

Table 21: Summary of Concomitant Medications for Crohn Disease at Baseline in GALAXI 2 Study — PAS, IV Induction and SC Maintenance

CD = Crohn disease; PAS = primary analysis set; SC = subcutaneous; SD = standard deviation.

Note: Guselkumab regimen 1 (low dose) = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 (high dose) = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks. Ustekinumab treatment = approximately 6 mg/kg IV, followed by 90 mg SC every 8 weeks.

^aExcluding budesonide.

Sources: Clinical Study Report for the GALAXI 2 trial.¹² Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 22: Summary of Concomitant Medications for Crohn Disease at Baseline in GALAXI 3 Study — PAS, IV Induction and SC Maintenance

CD = Crohn disease; PAS = primary analysis set; SC = subcutaneous; SD = standard deviation.

Note: Guselkumab regimen 1 (low dose) = 200 mg IV every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab regimen 2 (high dose) = 200 mg IV every 4 weeks, followed by 200 mg SC every 4 weeks.

^aExcluding budesonide.

Sources: Clinical Study Report for the GALAXI 3 trial.¹³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 23: Summary of Concomitant Medications for Crohn Disease at Baseline in GRAVITI Study — FAS, SC Induction and SC Maintenance

CD = Crohn disease; FAS = full analysis set; SC = subcutaneous; SD = standard deviation.

Note: Guselkumab SC regimen 1 (low dose) = guselkumab 400 mg SC every 4 weeks, followed by 100 mg SC every 8 weeks. Guselkumab SC regimen 2 (high dose) = guselkumab 400 SC every 4 weeks, followed by 200 mg SC every 4 weeks.

^aExcluding budesonide.

Sources: Clinical Study Report for the GRAVITI trial.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

A summary of the key efficacy results for the GALAXI 2, GALAXI 3, and GRAVITI trials is presented in Table 24, Table 25, Table 26, and Table 27. For the GALAXI trials, the efficacy outcomes were analyzed in the PAS whereas for the GRAVITI trial, the analysis was conducted using the FAS.

Summary of Efficacy Outcomes (Guselkumab Versus Placebo)

Clinical Response at Week 12 and Clinical Remission at Week 48

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance)

In both GALAXI trials, the composite coprimary end point of clinical response at week 12 and clinical remission at week 48 favoured both guselkumab regimens versus placebo. In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 38.1% (CI 95%, 27.3% to 48.9%; P value < 0.001) for guselkumab regimen 1 (low dose) and 42.8% (CI 95%, 31.6% to 53.9%; P value < 0.001) for guselkumab regimen 2 (high dose). In the GALAXI 3 trial, the adjusted between-group difference compared to placebo was 34.2% (CI 95%, 23.2% to 45.3%; P value < 0.001) for guselkumab regimen 1 and 35.0% (CI 95%, 23.5% to 46.5%; P value < 0.001) for guselkumab regimen 2. Sensitivity and supportive analyses were consistent with the primary analyses in both trials. Findings from the post hoc subgroup analyses of pooled GALAXI 2 and GALAXI 3 trial data for this end point were consistent with the primary analyses across BIO-Failure and CON-Failure analysis subpopulations.³⁹

Clinical Response at Week 12 and Endoscopic Response at Week 48

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance)

In both trials, the composite coprimary end point of clinical response at week 12 and endoscopic response at week 48 favoured both guselkumab regimens versus placebo. In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 33.7% (95% CI, 24.1% to 43.2%; P value < 0.001) for guselkumab regimen 1 and 32.9% (95% CI, 23.5% to 42.4%; P value < 0.001) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to placebo was 27.9% (95% CI, 18.7% to 37.1%; P value < 0.001) for guselkumab regimen 1 and 30.8% (95% CI, 21.3% to 40.3%; P value < 0.001) for guselkumab regimen 2. Sensitivity and supportive analyses were consistent with the primary analyses in both trials. Findings from the post hoc subgroup analyses of pooled GALAXI 2 and GALAXI 3 trial data for this end point were consistent with those of the primary analyses across BIO-Failure and CON-Failure analysis subpopulations.³⁹

Clinical Response at Week 12 and 90-Day, Corticosteroid-Free Clinical Remission at Week 48

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance)

In both trials, the composite secondary end point of clinical response at week 12 and 90-day, corticosteroid-free clinical remission at week 48 favoured both guselkumab regimens versus placebo. In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 38.7% (95% CI, 28.4% to 48.9%; P value < 0.001) for guselkumab regimen 1 and 41.3% (95% CI, 30.6% to 52.0%; P value < 0.001) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to placebo was 32.6% (95% CI, 21.7% to 43.6%; P value < 0.001) for guselkumab regimen 1 and 31.5% (95% CI, 20.1% to 42.8%; P value < 0.001) for guselkumab regimen 2.

Clinical Response at Week 12 and Endoscopic Remission at Week 48

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance)

In both trials, the composite secondary end point of clinical response at week 12 and endoscopic remission at week 48 favoured both guselkumab regimens versus placebo. In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 24.0% (95% CI, 15.8% to 32.2%; P value < 0.001) for guselkumab regimen 1 and 30.0% (95% CI, 21.4% to 38.5%; P value < 0.001) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to placebo was 18.2% (95% CI, 9.5% to 26.9%; P value < 0.001) for guselkumab regimen 1 and 16.7% (95% CI, 8.0% to 25.4%; P value < 0.001) for guselkumab regimen 2.

Clinical Remission at Week 12

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance) and GRAVITI Study (SC Induction and SC Maintenance)

At week 12, the secondary end point of clinical remission favoured guselkumab over placebo in both the GALAXI 2 and GALAXI 3 trials. In the GALAXI 2 trial, the combined guselkumab induction dose group showed an adjusted between-group difference of 27.6% compared to placebo (95% CI, 14.1% to 36.2%; P value < 0.001). In the GALAXI 3 trial, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 31.2% (95% CI, 21.1% to 41.3%; P value < 0.001) compared to placebo.

At week 12, the coprimary end point of clinical remission favoured guselkumab over placebo in the GRAVITI trial. The combined guselkumab induction dose group demonstrated an adjusted between-group difference of 34.9% (95% CI, 25.1% to 44.6%; P value < 0.001) compared to placebo. Sensitivity and subgroup analyses were consistent with the primary analyses in the GRAVITI trial.

Clinical Remission at Week 48

GRAVITI Study (SC Induction and SC Maintenance)

At week 48, the secondary end point of clinical remission favoured both guselkumab regimens over placebo in the GRAVITI trial. The adjusted between-group difference compared to placebo was 42.8% (95% CI, 31.6% to 54.0%; P value < 0.001) for guselkumab regimen 1 and 48.9% (95% CI, 37.9% to 59.9%; P value < 0.001) for guselkumab regimen 2.

Endoscopic Response at Week 12

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance) and GRAVITI Study (SC Induction and SC Maintenance)

At week 12, the secondary end point of endoscopic response favoured both guselkumab regimens over placebo in all 3 trials. In the GALAXI 2 trial, the combined guselkumab induction dose group showed an adjusted between-group difference of 27.7% (95% CI, 19.3% to 36.1%; P value < 0.001) compared to placebo. In the GALAXI 3 trial, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 22.1% (95% CI, 12.2% to 31.9%; P value < 0.001) compared to placebo.

At week 12, the coprimary end point of endoscopic response favoured guselkumab over placebo in the GRAVITI trial. The combined guselkumab induction dose group demonstrated an adjusted between-group difference of 19.9% compared to placebo (95% CI, 10.2% to 29.6%; P value < 0.001). Sensitivity and subgroup analyses were consistent with the primary analyses in the GRAVITI trial.

Endoscopic Response at Week 48

GRAVITI Study (SC Induction and SC Maintenance)

At week 48, the end point of endoscopic response favoured both guselkumab regimens over placebo in the GRAVITI trial. The adjusted between-group difference compared to placebo was 37.5% (95% CI, 27.3% to 47.7%; P value < 0.001) for guselkumab regimen 1 and 44.6% (95% CI, 34.1% to 55.0%; P value < 0.001) for guselkumab regimen 2.

Endoscopic Remission at Week 48

GRAVITI Study (SC Induction and SC Maintenance)

At week 48, the end point of endoscopic remission favoured both guselkumab regimens over placebo in the GRAVITI trial. The adjusted between-group difference compared to placebo was 37.5% (95% CI, 27.3% to 47.7%; P value < 0.001) for guselkumab regimen 1 and 44.6% (95% CI, 34.1% to 55.0%; P value < 0.001) for guselkumab regimen 2.

Clinical Response at Week 12

GRAVITI Study (SC Induction and SC Maintenance)

At week 12, the secondary end point of clinical response favoured the guselkumab regimens over placebo in the GRAVITI trial. The combined guselkumab induction dose group demonstrated an adjusted between-group difference of 40.3% compared to placebo (95% CI, 29.9% to 50.7%; P value < 0.001).

Deep Remission at Week 48

GRAVITI Study (SC Induction and SC Maintenance)

Deep remission at week 48 was an exploratory end point in the GRAVITI trial. The adjusted between-group difference compared to placebo was 21.8% (95% CI, 13.1% to 30.6%; P value < 0.001) for guselkumab regimen 1 and 29.8% (95% CI, 20.5% to 39.2%; P value < 0.001) for guselkumab regimen 2.

Patient-Reported Outcomes

Patient-reported end points, including IBDQ remission and PRO-2 remission, were considered exploratory in the GALAXI and GRAVITI trials.

IBDQ Remission at Week 12

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance) and GRAVITI Study (SC Induction and SC Maintenance)

In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 19.1% (95% CI, 6.7% to 31.5%; P value = 0.003) for guselkumab regimen 1 and 10.5% (95% CI, –2.3% to 23.2%; P value = 0.108) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to placebo was 23.7% (95% CI, 11.1% to 36.4%; P value < 0.001) for guselkumab regimen 1 and 16.5% (95% CI, 3.0% to 30.1%; P value = 0.017) for guselkumab regimen 2.

In the GRAVITI trial, the adjusted between-group difference compared to placebo was 29.2% (95% CI, 17.4% to 41.0%; P value < 0.001) for guselkumab regimen 1 and 20.8% (95% CI; 9.2% to 32.4%; P value < 0.001) for guselkumab regimen 2.

IBDQ Remission at Week 48

GRAVITI Study (SC Induction and SC Maintenance)

The adjusted between-group difference compared to placebo was 36.6% (95% CI, 25.4% to 47.8%; P value < 0.001) for guselkumab regimen 1 and 30.7% (95% CI, 19.2% to 42.1%; P value < 0.001) for guselkumab regimen 2.

PRO-2 Remission at Week 12 and Week 48

GRAVITI Study (SC Induction and SC Maintenance)

At week 48, the adjusted between-group difference compared to placebo was 41.1% (95% CI, 30.1% to 52.1%; P value < 0.001) for guselkumab regimen 1 and 53.2% (95% CI, 42.6% to 63.7%; P value < 0.001) for guselkumab regimen 2.

Summary of Efficacy Outcomes (Guselkumab Versus Ustekinumab)

GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance)

Clinical Remission at Week 48 and Endoscopic Response at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 7.8% (95% CI, 0.1% to 15.6%; P value = 0.049) for guselkumab regimen 1 and 13.6% (95% CI, 5.9% to 21.3%; P value < 0.001) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy at tier 3 (i.e., pooled analysis of guselkumab versus ustekinumab for clinical remission at week 48). In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was 2.8% (95% CI, –0.6% to 21.0%; P value = 0.620) for guselkumab regimen 1 and 10.2% (95% CI, –0.6% to 21.0%; P value = 0.065) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 12.7% (95% CI, 1.7% to 23.7%; P value = 0.024) for guselkumab regimen 1 and 16.9% (95% CI, 5.8% to 27.9%; P value = 0.003) for guselkumab regimen 2.

Clinical Remission at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 2.6% (95% CI, –5.1% to 10.2%; P value = 0.512) for guselkumab regimen 1 and 7.3% (95% CI, –0.2% to 14.8%; P value = 0.058) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy on this end point. In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was –0.6% (95% CI, –11.6% to 10.5%; P value = 0.920) for guselkumab regimen 1 and 9.5% (95% CI, –0.7% to 19.8%; P value = 0.069) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 5.6% (95% CI, –5.2% to 16.5%; P value = 0.308) for guselkumab regimen 1 and 5.0% (95% CI, –6.1% to 16.1%; P value = 0.378) for guselkumab regimen 2.

Endoscopic Response at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 10.6% (95% CI, 2.7% to 18.5%; P = 0.009) for guselkumab regimen 1 and 15.6% (95% CI, 7.9% to 23.4%; P < 0.001) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was 7.0% (95% CI, –4.4% to 18.3%; P value = 0.230) for guselkumab regimen 1 and 14.5% (95% CI, 3.6% to 25.4%; P value = 0.009) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 14.1% (95% CI, 2.9% to 25.2%; P value = 0.013) for guselkumab regimen 1 and 16.8% (95% CI, 5.7% to 28.0%; P value = 0.003) for guselkumab regimen 2.

Endoscopic Remission at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 8.5% (95% CI, 1.1% to 15.9%; P = 0.024) for guselkumab regimen 1 and 12.3% (95% CI, 4.9% to 19.7%; P = 0.001) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group treatment difference compared to ustekinumab was 6.4% (95% CI, –4.3% to 17.1%; P value = 0.239) for guselkumab regimen 1 and 17.9% (95% CI, 7.3% to 28.4%; P value < 0.001) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 10.5% (95% CI, 0.1% to 20.9%; P value = 0.048) for guselkumab regimen 1 and 6.9% (95% CI, –3.3% to 17.0%; P value = 0.183) for guselkumab regimen 2.

Deep Remission at Week 48

Following the pooling of data from the GALAXI 2 and GALAXI 3 trials, the adjusted between-group differences compared to ustekinumab were 7.4% (95% CI, 0.3% to 14.6%; P = 0.040) for guselkumab regimen 1 and 11.3% (95% CI, 4.2% to 18.5%; P = 0.002) for guselkumab regimen 2. Comparisons from the individual GALAXI 2 and GALAXI 3 trials were not formally tested due to the failure of the statistical testing hierarchy. In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was 4.2% (95% CI, –6.2% to 14.7%; P value = 0.426) for guselkumab regimen 1 and 13.0% (95% CI, 2.7% to 23.4%; P value = 0.014) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 10.4% (95% CI, 0.4% to 20.4%; P value = 0.041) for guselkumab regimen 1 and 9.6% (95% CI, –0.1% to 19.4%; P value = 0.052) for guselkumab regimen 2.

IBDQ Remission at Week 48

In the GALAXI 2 trial, the adjusted between-group difference compared to ustekinumab was 1.6% (95% CI, –9.9% to 13.2%; P value = 0.783) for guselkumab regimen 1 and 5.6% (95% CI, –5.5% to 16.7%; P value = 0.322) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group difference compared to ustekinumab was 10.1% (95% CI, –1.2% to 21.5%; P value = 0.080) for guselkumab regimen 1 and 2.1% (95% CI, –9.4% to 13.6%; P value = 0.725) for guselkumab regimen 2.

Table 24: Key Efficacy Results From GALAXI 2 and GALAXI 3 Studies (IV Induction and SC Maintenance) — Guselkumab vs. Placebo, PAS