Reimbursement Recommendation

Guselkumab (Tremfya)

Indication: For the treatment of adult patients with moderately to severely active Crohn disease

Sponsor: Janssen Inc.

Final recommendation: Reimburse with conditions

What Is the Reimbursement Recommendation for Tremfya?

Canada’s Drug Agency (CDA-AMC) recommends that Tremfya be reimbursed by public drug plans for the treatment of adult patients with moderately to severely active Crohn disease if certain conditions are met.

Which Patients Are Eligible for Coverage?

Tremfya should only be covered according to the reimbursement criteria used by public drug plans for other advanced therapies for the treatment of adult patients with moderately to severely active Crohn disease.

What Are the Conditions for Reimbursement?

Tremfya should only be reimbursed if the cost of Tremfya is reduced so that it does not cost the drug programs more than the least costly available advanced therapy that is reimbursed for the treatment of moderately to severely active Crohn disease.

Why Did CDA-AMC Make This Recommendation?

• Evidence from 3 clinical trials demonstrated that at week 48, treatment with Tremfya (IV or subcutaneous induction followed by subcutaneous maintenance) resulted in improvements in clinical remission and response as well as endoscopic remission and response, when compared with placebo or ustekinumab. These outcomes were observed in patients with moderately to severely active Crohn disease who had either an inadequate response or were intolerant to prior conventional or biologic therapies. Additionally, treatment with Tremfya likely improves health-related quality of life at weeks 12 and 48 compared to placebo.

• Tremfya may meet some needs that are important to patients, such as achieving clinical response and remission, achieving endoscopic response and remission, improving health-related quality of life, and offering an additional advanced therapy option. It provides patients with a subcutaneous formulation option that may be convenient for them to administer.

• Based on the CDA-AMC assessment of the health economic evidence, Tremfya does not represent good value to the health care system at the public list price. The Canadian Drug Expert Committee determined that there is not enough evidence to justify a greater cost for Tremfya compared with other treatments that are currently reimbursed for treating moderately to severely active Crohn disease in adults.

• Based on public list prices, Tremfya is estimated to cost the public drug plans approximately $15 million over the next 3 years.

Additional Information

What Is Crohn Disease?

Crohn disease is a chronic condition that causes swelling and irritation in the digestive system. It can affect any part of the gastrointestinal tract, but it most often impacts the small intestine, colon, and rectum. People with Crohn disease may have symptoms that come and go, and disease severity can vary widely over time. Common Crohn disease symptoms include diarrhea, stomach pain, fatigue, fever, rectal bleeding, loss of appetite, weight loss, and poor nutrition. There is no cure for Crohn disease, and many people live with these symptoms on and off throughout their lives. In 2023, it was estimated that approximately 12 out of every 100,000 individuals in Canada were newly diagnosed with Crohn disease.

Unmet Needs in Crohn Disease

Patients with Crohn disease expressed a need for effective treatments that can reduce symptoms, keep the disease under control over time, reduce the use of steroids, improve their overall quality of life, are convenient to administer, and have few side effects.

How Much Does Tremfya Cost?

Treatment with Tremfya is expected to cost between $23,016 and $49,092 per patient in the first year and between $19,957 and $39,913 per patient in subsequent years.

Recommendation

The Canadian Drug Expert Committee (CDEC) recommends that guselkumab be reimbursed for the treatment of adult patients with moderately to severely active Crohn disease, only if the conditions listed in Table 1 are met.

Rationale for the Recommendation

Two phase III, double-blind, placebo- and active-controlled (versus ustekinumab) trials (GALAXI 2, N = 523; GALAXI 3, N = 525) along with 1 phase III, placebo-controlled trial (GRAVITI, N = 347) demonstrated that treatment with guselkumab — administered as either a 200 mg IV or 400 mg subcutaneous induction, followed by 100 mg subcutaneous (SC) maintenance (regimen 1) or 200 mg SC maintenance (regimen 2) — results in added clinical benefits in adults with moderately to severely active Crohn disease who had an inadequate response to, or were unable to tolerate, previous conventional or advanced therapy. Comparative evidence versus placebo from the GALAXI 2 and GALAXI 3 trials demonstrated that guselkumab results in a clinically important improvement in clinical response at week 12 and clinical remission at week 48 (adjusted between-group difference = 40.4%; 95% confidence interval (CI), 31.0 to 49.7; and 34.4%; 95% CI, 24.7 to 44.1, respectively), clinical response at week 12, and endoscopic response at week 48 (33.4%; 95% CI, 25.9 to 41.0; and 29.1%; 95% CI, 21.5 to 36.7, respectively). Evidence from the GRAVITI trial demonstrated that, compared to placebo, guselkumab results in a clinically important improvement in clinical remission at weeks 12 (adjusted between-group difference = 34.9%; 95% CI, 25.1 to 44.6) and 48 (45.9%; 95% CI, 36.6 to 55.1) and endoscopic response at week 48 (40.9%; 95% CI, 32.9 to 48.9). Additionally, these trials showed evidence of high certainty that, compared to placebo, guselkumab treatment results in a clinically important improvement in clinical and endoscopic outcomes, clinical response, and 90-day corticosteroid-free clinical remission at weeks 12 and 48; and evidence of moderate-to-high certainty that guselkumab treatment improves health-related quality of life (HRQoL) (as assessed by Inflammatory Bowel Disease Questionnaire [IBDQ] remission and patient-reported outcome 2 [PRO-2] remission) at weeks 12 and 48. Comparative evidence versus ustekinumab from the pooled analysis of the GALAXI 2 and GALAXI 3 trials showed added benefits with guselkumab treatment with respect to endoscopic response, endoscopic remission, and combined clinical remission and endoscopic response at week 48; however, based on the analyses of individual trials, clinically important benefits with guselkumab treatment was not consistently observed for some outcomes, which reduces certainty of the evidence. Further, evidence from the GALAXI trials suggested that there is little to no clinically important difference between guselkumab and ustekinumab in clinical remission at week 48 (moderate certainty) and IBDQ remission at week 48 (low and moderate certainty for regimen 1 and 2, respectively).

The sponsor-submitted indirect treatment comparison (ITC) demonstrated that guselkumab frequently showed potential superiority over vedolizumab in achieving clinical remission and response; however, comparisons with other agents — such as adalimumab, infliximab, ustekinumab, risankizumab, and upadacitinib — yielded more inconsistent results. Due to limitations of the ITC and imprecision in the treatment effect estimates, no definitive conclusions can be drawn regarding the relative efficacy of guselkumab compared with other relevant comparators.

Patients identified a need for accessible and effective treatment options that provide a convenient route of administration, reduce symptoms, achieve clinical remission (including corticosteroid-free remission), improve HRQoL, and minimize side effects. CDEC concluded that guselkumab met some of the important needs identified by patients, such as achieving clinical response and remission, achieving endoscopic response and remission, improving HRQoL, and offering an additional advanced therapy option. CDEC noted that no new safety signals were identified and that the safety profile of guselkumab was consistent with that of the drug class.

At the sponsor-submitted price for guselkumab and the publicly listed price for comparators, guselkumab was more costly than most other reimbursed advanced therapies for adult patients with moderately to severely active Crohn disease who have an inadequate response to or failure to tolerate conventional or advanced therapy. Given that no definitive conclusions can be drawn regarding the relative efficacy of guselkumab compared to other advanced therapies, the total drug cost of guselkumab should not exceed the total drug cost of the least costly relevant advanced therapy reimbursed in this patient population.

Table 1: Reimbursement Conditions and Reasons

CDA-AMC = Canada’s Drug Agency; CDEC = Canadian Drug Expert Committee; NMA = network meta-analysis.

Discussion Points

• Unmet need: Patients and clinicians identified a need for additional effective advanced therapy options for Crohn disease. The clinical experts consulted by Canada’s Drug Agency (CDA-AMC) indicated that in clinical practice, some patients have inadequate response or loss of response to currently available advanced therapies and require alternative treatments. CDEC noted that currently, there are several approved advanced therapies available for Crohn disease. Based on the submitted evidence, CDEC concluded that guselkumab does not meet the unmet needs identified by patients when compared to other advanced therapies. However, the evidence is supportive of guselkumab as an additional effective treatment option for patients with moderately to severely active Crohn disease, specifically in those who have disease that failed conventional or advanced therapy as per the GALAXI 2, GALAXI 3, and GRAVITI trial populations. CDEC also acknowledged that the availability of SC formulation for induction therapy may be an advantage, given that it may be more convenient to administer than the IV formulation.

• Direct comparative efficacy versus placebo: CDEC highlighted that the evidence from the GALAXI 2 and GALAXI 3 trials (IV induction followed by SC maintenance) was of high certainty, per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment that guselkumab, compared with placebo, results in a clinically important improvement in the following outcomes: clinical response at week 12 and clinical remission at week 48, clinical response at week 12 and endoscopic response at week 48, as well as clinical response at week 12 and 90-day corticosteroid-free clinical remission at week 48, and clinical response at week 12 and endoscopic remission at week 48. Compared with placebo, evidence from the GRAVITI trial (SC induction followed by SC maintenance) demonstrated with high certainty that guselkumab results in a clinically important increase in achieving clinical remission at weeks 12 and 48, endoscopic response at weeks 12 and 48, endoscopic remission at week 48, and clinical remission and endoscopic response at week 48. In the GALAXI and GRAVITI trials, IBDQ remission was evaluated as an exploratory outcome. In the GALAXI trials, there is high-certainty evidence that guselkumab regimen 1 (100 mg maintenance) results in a clinically meaningful improvement in IBDQ remission at week 12 compared with placebo. For guselkumab regimen 2 (200 mg maintenance), there is moderate-certainty evidence suggesting it likely results in a clinically important increase in the proportion of patients achieving IBDQ remission at week 12 compared with placebo. In the GRAVITI trial, there is moderate-certainty evidence that guselkumab likely results in a clinically meaningful improvement in IBDQ remission at week 48 and high-certainty evidence that guselkumab results in a clinically meaningful improvement in PRO-2 remission at week 48, compared to placebo.

• Direct comparative efficacy versus ustekinumab: The results of the prespecified, multiplicity-controlled pooled analysis of the GALAXI 2 and GALAXI 3 trials demonstrated that both dosing regimens of guselkumab were favoured over ustekinumab across secondary end points, including endoscopic response, endoscopic remission, and combined clinical remission and endoscopic response at week 48. However, results from the analyses of individual trials did not consistently suggest clinically important benefits with guselkumab treatment for some outcomes, which reduces the certainty of the evidence. Per the GRADE assessment, evidence showed clinically important improvements in endoscopic response and combined clinical remission and endoscopic response at week 48 (low certainty for 100 mg maintenance; high certainty for 200 mg maintenance) and endoscopic remission at week 48 (moderate certainty) with guselkumab treatment, compared to ustekinumab. Additionally, the evidence suggests that, compared with ustekinumab, guselkumab results in little to no difference in clinical remission at week 48 (moderate certainty) and IBDQ remission at week 48 (low certainty for 100 mg maintenance; moderate certainty for 200 mg maintenance).

• Long-term evidence: The long-term safety and efficacy of guselkumab were evaluated in the long-term extension (LTE) phase of the GALAXI trials, with comparative assessments relative to ustekinumab. However, these findings were considered exploratory and only supportive of the primary trial results, given that the outcomes assessed in the LTE phase were not subject to formal hypothesis testing and no adjustments were made for multiplicity in the statistical analyses. Similar limitations were identified with the LTE of the GALAXI 1 trial, with up to 152 weeks of data submitted by the sponsor.

• Indirect evidence: The results of the sponsor-submitted network meta-analysis (NMA) 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 agents — 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. No comparative evidence was presented for SC guselkumab induction.

• Safety: In all 3 randomized controlled trials (RCTs), serious treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation of treatment, notable harms (i.e., infections), and deaths were infrequent and similar across the treatment groups. CDEC agreed with the clinical experts that there were no new safety signals identified and that the safety of guselkumab was consistent with the known safety profile of the drug class. No safety outcomes were included in the NMA; therefore, CDEC could not draw any conclusions about the safety of guselkumab compared to relevant comparators based on this analysis.

• Induction and maintenance regimens: CDEC discussed that 2 maintenance dosing regimens (100 mg and 200 mg) of guselkumab were evaluated. CDEC considered input from the clinical experts that, in clinical practice, clinicians would typically initiate treatment with the 100 mg maintenance dose, reserving the 200 mg dose for patients with more severe disease characteristics, such as higher endoscopic activity, perianal disease, or a history of prior intestinal surgery. CDEC acknowledged that the availability of 2 maintenance dosing options may offer flexibility to tailor treatment based on individual patient needs and response to therapy.

• Implementing the price condition: Guselkumab has different dosing regimens to achieve dose optimization. CDEC discussed that there is no clinical evidence of a dose response between the maintenance dosing regimens (i.e., 100 mg every 8 weeks and 200 mg every 4 weeks) or evidence comparing the different routes of administration of guselkumab (i.e., IV and SC). CDEC noted that the clinical experts consulted on the review expected that 60% of patients would receive low-dose guselkumab maintenance therapy, whereas the remainder would be on high-dose guselkumab maintenance therapy. This information should be considered when negotiating the price of guselkumab to ensure that the total cost of treatment is no more costly than the least costly relevant comparator (i.e., advanced therapy) reimbursed for adults with moderately to severely active Crohn disease.

Background

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

The diagnosis of Crohn disease is established through a comprehensive assessment that integrates clinical evaluation with endoscopic, histological, radiological, and/or biochemical investigations. Therapeutic goals include inducing and maintaining clinical and endoscopic remission. Pharmaceutical treatments for Crohn disease include immunosuppressants, corticosteroids, tumour necrosis factor alpha (TNF alpha) antagonists, interleukin (IL) inhibitors, Janus kinase inhibitors (JAK) inhibitors, and integrin inhibitors. Medical management of Crohn disease generally follows a stepwise approach, in which therapies are initiated sequentially and escalated to more advanced agents 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 indication under review for guselkumab is for the treatment of adult patients with moderately to severely active Crohn disease, and the sponsor’s submitted reimbursement criteria align with this indication. The recommended induction dosage of guselkumab is either 200 mg administered by IV infusion or 400 mg of guselkumab administered by SC injection at weeks 0, 4, and 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 thereafter.

Sources of Information Used by the Committee

To make its recommendation, the committee considered the following information:

• a review of 3 phase III, double-blind, RCTs in adults with moderately to severely active Crohn disease

• 1 LTE study

• 1 ITC

• 2 additional studies addressing gaps in evidence

• patients’ perspectives gathered by 2 patient groups, Crohn’s and Colitis Canada and the Gastrointestinal Society

• input from public drug plans that participate in the reimbursement review process

• 2 clinical specialists with expertise in diagnosing and treating patients with Crohn disease

• a review of the pharmacoeconomic model and report submitted by the sponsor.

Perspectives of Patients, Clinicians, and Drug Programs

Patient Input

Two patient input submissions were summarized for this review. The Gastrointestinal Society is a national charity that runs various programs and services, supports research, advocates for appropriate patient access to health care, and promotes gastrointestinal and liver health. Crohn’s and Colitis Canada is a national, volunteer-based health charity focused on finding cures for Crohn disease and ulcerative colitis. Information from both input submissions was gathered from varied sources, which included published perspectives, online surveys, interviews with patients, and questionnaires.

The patient groups noted that Crohn disease often has a profound effect on patients’ quality of life, affecting physical, emotional, and social factors of patients at home, school, or workplace. Disease severity may fluctuate, thus requiring routine testing, reassessments, and medication changes. The Gastrointestinal Society noted that patients with Crohn disease 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 Crohn disease requires a multifaceted strategy that allows for the management of symptoms and disease consequences with therapies that target and reduce the underlying inflammation. Respondents from both patient groups highlighted that they had experience with 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 Crohn disease who participated in the surveys mentioned that they continued to experience symptoms with current treatment options. Both patient 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 a desire for fewer medications as well as treatments that are safe, can minimize the use of steroids, and can be administered at home and taken as pills.

Major concerns regarding the existing treatments identified by the Gastrointestinal 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 requiring conventional therapies to be trialled before targeted treatments can be accessed. 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 Crohn disease, 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: the requirement for conventional therapies (i.e., immunomodulators) to fail 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 expert indicated that guselkumab is unlikely to dramatically shift the current treatment paradigm for Crohn disease 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 Crohn disease and that it should not be reserved only for those who are intolerant to or have contraindications for other biologic agents. The clinical experts also highlighted that a favourable safety profile makes guselkumab a viable alternative for patients who have experienced adverse events (AEs) with other therapies, such as anti-TNF agents. According to the clinical experts consulted, guselkumab is considered appropriate for a broad population, including both patients who are naive to and those who have experience with biologics, particularly those who are intolerant to conventional therapies or other biologics or for whom these treatments have failed. Patients are best suited for treatment with guselkumab if they have an established diagnosis of Crohn disease based on ileocolonoscopy with active disease.

The clinical expert noted that the following outcomes are used to determine patient response to treatment: clinical response or remission, endoscopic response or remission, and improved 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. The clinical experts indicated that discontinuation of guselkumab may be considered in cases of primary nonresponse, worsening patient-reported outcomes, rising biomarkers, or AEs that cannot be adequately managed. The clinical expert 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.

Table 2: Responses to Questions From the Drug Programs

AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; CDEC = Canadian Drug Expert Committee; IL = interleukin; SC = subcutaneous; SES-CD = Simple Endoscopic Score for Crohn’s Disease.

Clinical Evidence

Systematic Review

Description of Studies

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

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 the safety of guselkumab in patients with moderately to severely active Crohn disease who were unable to tolerate, or whose disease had not adequately responded to, 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 phase. In both trials, patients in the guselkumab group received an induction dose of 200 mg by IV every 4 weeks, followed by maintenance treatment with either a 100 mg SC dose every 8 weeks (guselkumab regimen 1 [low dose]) or a 200 mg SC dose 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 trials were to evaluate the efficacy and safety of guselkumab in patients with moderately to severely active Crohn disease who were unable to tolerate, or whose disease had not adequately responded 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 and was followed by the extension treatment phase that included a 72-week maintenance period. During the GRAVITI trial, patients received guselkumab at a 400 mg SC dose at weeks 0, 4, and 8 for induction, followed by either a 100 mg SC dose every 8 weeks (guselkumab regimen 1 [low dose]) or a 200 mg SC dose 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

The GALAXI 2 and GALAXI 3 Trials (IV Induction and SC Maintenance)

In GALAXI 2 trial, the adjusted between-group difference compared to placebo was 38.1% (95% CI, 27.3 to 48.9; P < 0.001) for guselkumab regimen 1 (low dose) and 42.8% (95% CI, 31.6 to 53.9; P < 0.001) for guselkumab regimen 2 (high dose). In the GALAXI 3 trial, the adjusted between-group difference compared to placebo was 34.2% (95% CI, 23.2 to 45.3; P < 0.001) for guselkumab regimen 1 and 35.0% (95% CI, 23.5 to 46.5; P < 0.001) for guselkumab regimen 2. Sensitivity, supportive, and subgroup analyses — including those conducted in patients with a history of biologic therapy failure or intolerance (BIO-Failure group) and those with a history of conventional therapy failure 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

The GALAXI 2 and GALAXI 3 Trials (IV Induction and SC Maintenance)

In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 33.7% (95% CI, 24.1 to 43.2; P < 0.001) for guselkumab regimen 1 and 32.9% (95% CI, 23.5 to 42.4; P < 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 < 0.001) for guselkumab regimen 1 and 30.8% (95%CI, 21.3 to 40.3; P < 0.001) for guselkumab regimen 2. Sensitivity, supportive, and subgroup analyses — including those conducted in the BIO-Failure and CON-Failure 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

The GALAXI 2 and GALAXI 3 Trials (IV Induction and SC Maintenance)

In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 38.7% (95% CI, 28.4 to 48.9; P < 0.001) for guselkumab regimen 1 and 41.3% (95% CI, 30.6 to 52.0; P < 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 < 0.001) for guselkumab regimen 1 and 31.5% (95% CI, 20.1 to 42.8; P < 0.001) for guselkumab regimen 2.

Clinical Response at Week 12 and Endoscopic Remission at Week 48

The GALAXI 2 and GALAXI 3 Trials (IV Induction and SC Maintenance)

In the GALAXI 2 trial, the adjusted between-group difference compared to placebo was 24.0% (95% CI, 15.8 to 32.2; P < 0.001) for guselkumab regimen 1 and 30.0% (95% CI, 21.4 to 38.5; P < 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 < 0.001) for guselkumab regimen 1 and 16.7% (95% CI, 8.0 to 25.4; P < 0.001) for guselkumab regimen 2.

Clinical Remission at Week 12

The GALAXI 2 and GALAXI 3 Trials (IV Induction and SC Maintenance) and the GRAVITI Trial (SC Induction and SC Maintenance)

In the GALAXI 2 trial, the combined guselkumab induction dose group demonstrated an adjusted between-group difference of 25.1% (95% CI, 14.1 to 36.2; P < 0.001) compared to placebo. 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 < 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 < 0.001) compared to placebo. Sensitivity and subgroup analyses — including those in the BIO-Failure and CON-Failure subpopulations — were consistent with the primary analyses.

Clinical Remission at Week 48

The GRAVITI Trial (SC Induction and SC Maintenance)

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

Endoscopic Response at Week 12

The GALAXI 2 and GALAXI 3 Trials (IV Induction and SC Maintenance) and the GRAVITI Trial (SC Induction and SC Maintenance)

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 < 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 < 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 < 0.001). Sensitivity and subgroup analysis — including those conducted in the BIO-Failure and CON-Failure subpopulations — were consistent with the primary analyses.

Endoscopic Response at Week 48

The GRAVITI Trial (SC Induction and SC Maintenance)

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

Endoscopic Remission at Week 48

The GRAVITI Trial (SC Induction and SC Maintenance)

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

Clinical Response at Week 12

The GRAVITI Trial (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 < 0.001).

Deep Remission at Week 48

The GRAVITI Trial (SC Induction and SC Maintenance)

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

Patient-Reported Outcomes

IBDQ Remission Week 12

The GALAXI 2 and GALAXI 3 Trials (IV Induction and SC Maintenance) and the GRAVITI Trial (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 = 0.003) for guselkumab regimen 1 and 10.5% (95% CI, –2.3 to 23.2; P = 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 < 0.001) for guselkumab regimen 1 and 16.5% (95% CI, 3.0 to 30.1; P = 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 < 0.001) for guselkumab regimen 1 and 20.8% (95% CI, 9.2 to 32.4; P < 0.001) in guselkumab regimen 2.

IBDQ Remission at Week 48

The GRAVITI Trial (SC Induction and SC Maintenance)

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

PRO-2 Remission at Week 48

The GRAVITI Trial (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 < 0.001) for guselkumab regimen 1 and 53.2 (95% CI, 42.6 to 63.7; P < 0.001) for guselkumab regimen 2.

Summary of Efficacy Outcomes (Guselkumab Versus Ustekinumab)

The GALAXI 2 and GALAXI 3 Trials (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 = 0.049) for guselkumab regimen 1 and 13.6% (95% CI, 5.9 to 21.3; P < 0.001) for 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 = 0.512) for guselkumab regimen 1 and 7.3% (95% CI, –0.2 to 14.8; P = 0.058) for 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 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 differences compared to ustekinumab were 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 differences compared to ustekinumab were 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 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 differences compared to ustekinumab were 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 differences compared to ustekinumab were 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 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 differences compared to ustekinumab were 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 differences compared to ustekinumab were 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 trial, the adjusted between-group differences compared to ustekinumab were 1.6% (95% CI, –9.9 to 13.2; P = 0.783) for guselkumab regimen 1 and 5.6% (95% CI, –5.5 to 16.7; P = 0.322) for guselkumab regimen 2. In the GALAXI 3 trial, the adjusted between-group differences compared to ustekinumab were 10.1% (95% CI, –1.2 to 21.5; P = 0.080) for guselkumab regimen 1 and 2.1% (95% CI, –9.4 to 13.6; P = 0.725) for guselkumab regimen 2.

Harms Results

The GALAXI 2 and GALAXI 3 Trials: IV Induction and SC Maintenance

Induction Period

In the GALAXI 2 trial, the proportions of patients experiencing at least 1 AE were 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 trial, the proportions of patients experiencing at least 1 AE were 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 trial, the proportions of patients experiencing at least 1 serious adverse event (SAE) were 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 trial, the proportions of patients experiencing at least 1 SAE were 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 proportions of patients who discontinued study treatment due to AEs were 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 corresponding discontinuation rates due to AE were 6.9%, 2.8%, 3.3%, and 3.4%, respectively. 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 (74.1%), guselkumab regimen 2 (78.8%), and ustekinumab (78.3%) groups, 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 (79.0%), guselkumab regimen 2 (76.7%), and ustekinumab (79.1%) groups, 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 (4.1%) and placebo (7.9%) groups. In the GALAXI 3 trial, the proportions of patients experiencing at least 1 SAE were 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 trial, the proportions of patients who discontinued study treatment due to AE during the maintenance period were 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 trial, the corresponding discontinuation rates due to AE were 11.1%, 8.4%, 8.7%, and 8.8%, respectively. No deaths occurred during the maintenance period in either trial.

Notable Harms

In the GALAXI 2 trial, 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 trial, 1 patient (0.7%) in the guselkumab regimen 1 group experienced active tuberculosis, and 1 patient (0.7%) 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.

The GRAVITI Trial — SC Induction and SC Maintenance

Induction Period

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

Notable Harms

In the GRAVITI trial, 1 patient (0.7%) in the regimen 1 guselkumab group experienced a malignancy, whereas in the placebo group, 1 patient (0.9%) experienced an opportunistic infection and 1 patient (0.9%) experienced 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 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% 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% in the guselkumab regimen 1 group, and 24.3% 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 having disease that did not respond to treatment; this approach was considered reasonable by the review team. Both 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, in which 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 treatment at weeks 12 or 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 considered appropriate in most cases. Some dropouts were not clearly related to 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 trial, the number of dropouts due to reasons potentially unrelated to lack of response was higher in the placebo group compared to the guselkumab groups, which could inflate 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 Crohn disease. 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 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 although certain exclusion criteria, such as strictures or previous colectomy, are considered typical for clinical trials, they do not always reflect real-world practice in which 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 Crohn disease. However, both the GALAXI and GRAVITI trials included patients with moderately to severely active Crohn disease who have demonstrated an inadequate response or failure 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 who are naive to biologics versus those who have experience with 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. These end points included in the trials were considered appropriate by the clinical expert, although they noted that the Harvey-Bradshaw Index is more commonly used in clinical practice in Canada 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 Crohn disease.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform 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 Evidence, 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 weeks 12 and 48, endoscopic response at weeks 12 and 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 3 and Table 4 present the GRADE summary of findings for guselkumab versus placebo (IV induction and SC maintenance, high and low dose) in the GALAXI and GRAVITI trials (SC induction and SC maintenance, high and low dose), respectively. Table 5 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 3: Summary of Findings for Guselkumab Versus Placebo for Patients With Crohn Disease: GALAXI Trials — IV Induction and SC Maintenance (Regimen 1 and Regimen 2)

AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; MID = minimally important difference; NR = not reported; PRO = patient-reported outcome; RCT = randomized controlled trial; SAE = serious adverse event; 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, 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.

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

^aThe clinical response is defined as either a reduction of 100 or more points from the baseline in the CDAI score or achieving a CDAI score of less than 150.

^bClinical remission is defined as 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 subcutaneously every 8 weeks. Guselkumab regimen 2 (high dose): 200 mg IV every 4 weeks followed by 200 mg subcutaneously every 4 weeks.

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

^eAn empirically derived minimally important difference 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 Canada’s Drug Agency as a threshold of clinical importance for this outcome.

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

^gEndoscopic remission is defined as a SES-CD score 4 or less and at least a 2-point reduction from baseline and 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 is defined as an IBDQ total score of at least 170. An empirically derived minimally important difference 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 Canada’s Drug Agency as a threshold of clinical importance for this outcome.

^jAn empirically derived minimally important difference 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 expert consulted by Canada’s Drug Agency as a threshold of clinical importance for this outcome. The level of evidence was rated down 2 levels for imprecision and indirectness; the estimate is informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening Crohn disease and other Crohn disease–related events as an SAE. This complicates interpretation.

^kThe level of evidence was rated down 1 level for imprecision. Based on the minimally important difference identified by clinical experts (a difference of 5% between the groups), the 95% CI for the between-group difference crossed the minimally important difference threshold (i.e., includes 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.

^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 expert 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 is 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 Crohn disease and other Crohn disease–related events 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 harm outcomes.

Source: Clinical study reports for the GALAXI 2 and GALAXI 3 trials. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 4: Summary of Findings for Guselkumab Versus Placebo for Patients With Crohn Disease: GRAVITI Trial — SC Induction and SC Maintenance (Regimen 1 and Regimen 2)

AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; MID = minimally important difference; NR = not reported; PRO = patient-reported outcome; 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, 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.

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

^aClinical remission is defined as a CDAI score 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 expert consulted by Canada’s Drug Agency as a threshold of clinical importance for this outcome.

^bCombined guselkumab induction dose group: 400 mg SC at weeks 0, 4, and 8. Guselkumab SC regimen 1 (low dose) = guselkumab 400 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.

^cIncludes placebo patients who received guselkumab treatment after week 12.

^dEndoscopic response is defined as at least a 50% improvement from baseline in 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 expert consulted by Canada’s Drug Agency as a threshold of clinical importance for this outcome.

^eEndoscopic remission is defined as an SES-CD score of 4 or less and at least a 2-point reduction from baseline and 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 Canada’s Drug Agency as a threshold of clinical importance for this outcome.

^fIBDQ remission is defined as 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 Canada’s Drug Agency 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 intercurrent event handling strategies.

^hPRO-2 remission is defined as an AP mean daily score less than or equal to 1 and an SF mean daily score less than or equal to 3, and no worsening of AP or SF 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 expert consulted by Canada’s Drug Agency 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 expert 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 is informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening Crohn disease and other Crohn disease–related events as an SAE. This complicates interpretation, as 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 expert consulted by CDA-AMC as a threshold of clinical importance for this outcome. The level of evidence was rated down levels for imprecision and indirectness; the estimate is informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening Crohn disease and other Crohn disease–related events 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 were lower in the guselkumab groups; therefore, differences in treatment discontinuation and exposure between the study groups may influence the interpretation of harm outcomes.

Source: Clinical study report for the GRAVITI trial. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 5: Summary of Findings for Guselkumab (Regimen 1 and Regimen 2) Versus Ustekinumab With Crohn Disease: GALAXI Trials — IV Induction and SC Maintenance

AP = abdominal pain; CI = confidence interval; HRQoL = health-related quality of life; IBDQ = Inflammatory Bowel Disease Questionnaire; MID = minimally important difference; NR = not reported; PRO = patient-reported outcome; RCT = randomized controlled trial; SAE = serious adverse event; SF = stool frequency.

Notes:

Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

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 is defined as a CDAI score 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 expert consulted by Canada’s Drug Agency as a threshold of clinical importance for this outcome.

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

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

^dGuselkumab 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.

^eThe 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 suggested little to no difference, and the 95% CI for the between-group difference crossed the MID threshold.

^fEndoscopic response is defined as at least a 50% improvement from baseline in 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 expert consulted by CDA-AMC as a threshold of clinical importance for this outcome.

^gThe 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 suggested 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.

^hEndoscopic remission is defined as a SES-CD score 4 or less and at least a 2-point reduction from baseline and 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 Canada’s Drug Agency as a threshold of clinical importance for this outcome.

ⁱThe 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 Canada’s Drug Agency as a threshold of clinical importance for this outcome, 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.

^jThe 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 expert consulted by Canada’s Drug Agency 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.

^kIBDQ remission is defined as an IBDQ total score of at least 170.

^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 expert consulted by Canada’s Drug Agency as a threshold of clinical importance for this outcome. The level of evidence was rated down 2 levels for imprecision and indirectness; the estimate is informed by a very low number of events and may be unstable. Additionally, there was indirectness related to the inclusion of worsening Crohn disease and other Crohn disease–related events as an SAE. This complicates interpretation.

Source: Clinical study reports for the GALAXI 2 and GALAXI 3 trials. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

LTE Studies

Description of Studies

The parent pivotal studies, GALAXI 2 and GALAXI 3, were randomized, double-blind, placebo-controlled, active-controlled, parallel-group, multicentre studies to evaluate the efficacy and safety of guselkumab in patients with moderately to severely active Crohn disease. The LTEs were designed to evaluate the long-term efficacy of clinical and endoscopic outcomes, safety, 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 had their treatment discontinued after unblinding at week 48. The study is 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 at least 6 [or at least 4 for participants with isolated ileal disease] who received 1 or more (partial or complete) doses of the study drug), rates of clinical remission were 59.4% in pooled regimen 1 (guselkumab 200 mg IV every 4 weeks to 100 mg SC every 8 weeks), 63.2% in pooled regimen 2 (guselkumab 200 mg IV every 4 weeks to 200 mg SC every 4 weeks), versus █████ in the ustekinumab group at week 96. The rates of patients achieving 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 who achieved endoscopic response were 44.1%, 44.6%, versus █████ in the pooled regimen 1, regimen 2, and ustekinumab groups, respectively, at week 96. The rates of patients achieving clinical remission and endoscopic response were 40.6%, 41.6% in the pooled regimen 1 and regimen 2 groups compared to █████ in the pooled ustekinumab at week 96. In the primary efficacy analysis set, the rates of patients who achieved deep remission (clinical remission and endoscopic response) were 26.2%, 29.4%, and ███ in the pooled regimen 1, regimen 2, and ustekinumab group at week 96. Data on HRQoL were not presented.

In the LTE efficacy analysis set (consisting of all patients who had entered the LTE and had received 1 or more [partial or complete] doses of the study drug during the LTE), the rates of patients who achieved 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 who achieved endoscopic response was 53.6%, 55.4%, and █████ in the pooled regimen 1, regimen 2, and ustekinumab group at week 96. The rate of patients who achieved endoscopic remission was 34.6%, 39.3%, versus █████ 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 or more doses of the 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 group, respectively reported at least 1 AE. In total, 5.2%, 5.8%, and ████ of patients reported at least 1 serious AE 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 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. ███ patients in the ustekinumab reported 1 or more malignancies, and ██ patient reported a major adverse cardiovascular event.

Critical Appraisal

Both pivotal studies of the LTE studies (GALAXI 2 and 3) 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 introduce 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 treatment for reasons other than lack of efficacy or AE (ICE3) or who chose not to enter the LTE (ICE7). Given that these ICE are not clearly related to lack of efficacy, imbalances in these occurrences could introduce bias in the randomized comparisons. However, no information was reported to adequately assess 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, mostly attributed to withdrawal by patients, AEs, and 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 risk of bias arising from the imputation methods used cannot be ascertained.

In general, the population requested for reimbursement aligns with 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 Crohn disease in the clinical setting in Canada. 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 ITC evaluated guselkumab versus relevant comparators (including adalimumab, infliximab, vedolizumab, ustekinumab, risankizumab, and upadacitinib) for moderately to severely active Crohn disease. A systematic literature review (July 2023) identified 58 unique RCTs; of these, 37 double-blind RCTs informed the NMA. Analyses considered adults with conventional therapy failure (CON-Failure) and biologic therapy failure (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 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 delayed response to treatment), numerical trends suggested that guselkumab may potentially exceed the efficacy of some comparators (for example, vedolizumab or certain doses of upadacitinib). No significant advantage for any other active treatment over guselkumab was observed. Overall, there is no clear evidence showing any comparator to be more efficacious; however, wide credible intervals in several comparisons suggest 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 systematic literature review 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 to 64 weeks — further introduce potential bias due to 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 introduce bias due to human error. Several included trials had risk-of-bias concerns.

Studies Addressing Gaps in the Evidence From the Systematic Review

GALAXI 1 LTE Trial

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 Crohn disease. 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 in the ustekinumab group, with 151 and 48 patients, respectively, entering the LTE. Participants continued on their assigned subcutaneous 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 patient-reported outcomes 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 included every patient dosed from week 0, imputing discontinuations, nonentry, and intercurrent events as indicating that there was a lack of response to treatment; the LTE NRI set comprised those dosed during LTE with the same ICE rules plus Crohn disease–related surgery and AE-related discontinuation, assessed through week 144 using NRI; and lastly, 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% (103/151) of patients treated with guselkumab achieved CDAI remission, while 54.1% (100/185) achieved remission in the all-randomized NRI cohort and 95.4% (103/108) in the LTE observed cohort. Ustekinumab yielded similar results: 64.6% (31/48) of patients in the LTE NRI cohort and 83.8% (31/37) in the LTE observed cohort were in CDAI remission, and 46.0% (29/63) in the all-randomized NRI analysis. Patient-reported outcomes (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 achieved 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 ustekinumab. In the guselkumab group, there were 279.8 events per 100 patient-years, and 87.3% of patients experienced 1 or more AEs; serious AEs occurred at 10.6 per 100 patient-years in 11.4% of patients, and 13.2% discontinued due to AEs. Infections affected 51.8% of patients treated with guselkumab (65.8 events/100 patient-years [PY]), with serious infections in 5.5% (3.3/100 PY), versus 46.5% (44.7/100 PY) and 7.0% (5.0/100 PY) in the ustekinumab group.

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

Critical Appraisal

The GALAXI 1 LTE trial 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, 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 is 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 intercurrent events were handled per regulatory guidance, the absence of a complete ICE inventory and unclear extent of missing data mean that imputation methods — and thus overall efficacy estimates — cannot be fully appraised.

Participants included both patients with moderate-to-severe Crohn disease who are naive to biologics and those who have experience with biologics, 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) 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 Crohn disease. A pooled post hoc analysis was conducted with data from treatment arms (placebo excluded) of 2 RCTs (IM-UNITI [phase III maintenance trial of ustekinumab] and the GALAXI 1 trial [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).

Efficacy Results

Efficacy results at the end of maintenance (EOM): Overall, 75.3% of patients with endoscopic response at EOM were in long-term clinical remission (i.e., week 92 for IM-UNITI and week 96 for the GALAXI 1 trial) compared to 48.5% without endoscopic response. The odds ratio (OR) for endoscopic response at EOM was 1.91 (95% CI 1.11 to 3.28). In total, 78.5% of patients with endoscopic response at EOM were in long-term clinical response compared to 56.9% 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 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 lack of prespecification and a higher 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, which 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.

Economic Evidence

Cost and Cost-Effectiveness

• Guselkumab is available as a solution for injection (100 mg/mL or 200 mg/2mL). At the submitted price of $3,059.74 per vial, the annual cost of guselkumab is expected to range from $23,016 to $49,092 per patient in the first year of treatment and $19,957 to $39,913 per patient in subsequent years (depending on dose), based on the Health Canada–recommended dosage.

• Clinical efficacy in the economic analysis was derived from a sponsor-submitted NMA, with the efficacy of guselkumab informed by the GALAXI trials. Indirect evidence submitted by the sponsor suggests that guselkumab showed potential superiority over vedolizumab in achieving clinical remission and response; although its comparative efficacy against other agents — such as ustekinumab, risankizumab, and upadacitinib — was more variable, with results differing across specific analyses (e.g., by treatment phase [i.e., induction or maintenance], by patient populations [i.e., conventional therapy failure or biologic failure]) and outcome measures. However, owing to the limitations of the NMA relating to the heterogeneity across studies and imprecision in the treatment effect estimates, no definitive conclusions can be drawn regarding the relative efficacy of guselkumab compared with other biologics.

• Whether guselkumab will be associated with higher or lower drug costs to the health care system versus other biologics will depend on the proportion of patients on high versus low doses of guselkumab. Owing to the individualized approach to dosing in clinical practice, the relative total treatment costs of guselkumab compared to other biologics is uncertain.

• The sponsor estimated that the budget impact of reimbursing guselkumab for the treatment of adult patients with moderately to severely active Crohn disease will be $15,264,551 over the first 3 years of reimbursement compared to the amount currently spent on comparators, with an estimated expenditure of $80,378,863 on guselkumab over this period. CDA-AMC was unable to provide a more robust estimate. The actual budget impact of reimbursing guselkumab will depend on the proportion of patients on high- compared to low-dose guselkumab.

CDEC Information

Members of the Committee

Dr. Peter Jamieson (Chair), Dr. Kerry Mansell (Vice Chair), Dr. Sally Bean, Daryl Bell, Dan Dunsky, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Morris Joseph, Dr. Dennis Ko, Dr. Christine Leong, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Dr. Edward Xie, and Dr. Peter Zed.

Meeting date: June 25, 2025

Regrets: Four expert committee members did not attend.

Conflicts of interest: None