Introduction

Crohn’s disease is a chronic form of inflammatory bowel disease that can affect any part of the gastrointestinal tract but most commonly affects the ileum, colon, and rectum. Common gastrointestinal symptoms experienced by patients with Crohn’s disease include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.^1–3 According to Crohn’s and Colitis Canada, there are approximately 129,000 Canadians living with Crohn’s disease (one in 150 people), and it is estimated that 5,700 new cases of Crohn’s disease are diagnosed each year.¹

Ustekinumab (Stelara) is a fully human immunoglobulin G1 kappa monoclonal antibody that binds to the shared p40 subunit of interleukin (IL)-12 and IL-23.⁴ Ustekinumab is already approved by Health Canada for the treatment of adults with chronic moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and for the treatment of adult patients with active psoriatic arthritis, alone or in combination with methotrexate.⁴

The current indication under review is for the treatment of adult patients with moderately to severely active Crohn’s disease, who have had an inadequate response with, loss of response to, or intolerance to either immunomodulators or one or more tumour necrosis factor (TNF) alpha antagonists, or have had an inadequate response with, intolerance to, or demonstrated dependence on corticosteroids. The recommended dosage for ustekinumab in the treatment of Crohn’s disease is an initial single intravenous (IV) induction dose based on body weight (approximating 6 mg/kg), followed by a 90 mg subcutaneous (SC) maintenance dose eight weeks later, then one dose every eight weeks thereafter as maintenance treatment. For some patients (e.g., “those with low inflammatory burden,” per the product monograph), an alternative maintenance regimen of ustekinumab 90 mg SC every 12 weeks may be administered at the discretion of the treating physician. Patients who inadequately respond to the 90 mg SC every 12 weeks regimen may be switched to the every eight weeks regimen. Immunomodulators and/or corticosteroids may be continued during treatment with ustekinumab. The product monograph recommends that, in patients who have responded to treatment with ustekinumab, corticosteroids may be reduced or discontinued in accordance with standard of care.⁴

The objective of this report is to perform a systematic review of the beneficial and harmful effects of ustekinumab in accordance with the Health Canada–approved indication for the treatment of Crohn’s disease. Only Health Canada–approved dosage regimens for ustekinumab for Crohn’s disease were included in this review. Ustekinumab has been previously reviewed through the CADTH Common Drug Review (CDR) for the treatment of plaque psoriasis and psoriatic arthritis.^5,6

Results and Interpretation

Efficacy

Clinical Remission

A statistically significantly higher proportion of patients treated with ustekinumab 6 mg/kg (20.9% and 40.2%) than with placebo (7.3% and 19.6%) were in remission at week 8 in UNITI-1 and UNITI-2, respectively (Table 1). Likewise, statistically significantly higher proportions of patients treated with ustekinumab every 12 weeks (48.8% and 42.6%) and ustekinumab every eight weeks (53.1% and 46.9%) were in clinical remission and corticosteroid-free remission, respectively, at week 44 of IM-UNITI than with placebo (35.9% and 29.8%) (Table 2). ▬ The clinical expert consulted by CDR noted that, although the between-group differences are not large, they likely represent clinically meaningful results, especially in UNITI-1, in which patients had experienced a failure of TNF antagonist treatment.

Table 1

Summary of Key Results From the Induction Studies.

Table 2

Summary of Key Results From the Maintenance Study.

Clinical Response

The primary outcome for the UNITI induction studies was achieved: the proportion of patients with a clinical response at week 6 was statistically significantly higher in the ustekinumab groups (33.7% and 55.5%) than in the placebo groups (21.5% and 28.7%) in UNITI-1 and UNITI-2, respectively (Table 1).

Almost 60% of patients randomized to ustekinumab maintenance treatments in IM-UNITI were responders at week 44, whereas 44% of those assigned to placebo achieved clinical response. The comparison versus placebo was statistically significant for both ustekinumab regimens (Table 2).

The results from CERTIFI were supportive of these.

Health-Related Quality of Life, Functional and Disability Outcomes

▬ (Table 1). ▬ (Table 2).

▬ Table 2, ▬

▬

Need for Surgery for Crohn’s Disease

▬ (Table 1). ▬

▬ (Table 2).

In the absence of head-to-head trials comparing the efficacy of ustekinumab with TNF antagonists or vedolizumab, CDR examined the comparative effectiveness results of two network meta-analyses (NMAs, Appendix 7).^12,13 The manufacturer submitted an NMA of ustekinumab versus infliximab, adalimumab, and vedolizumab.¹² There were no statistically significant differences between ustekinumab and vedolizumab or adalimumab for clinical response and remission. Infliximab may be superior to ustekinumab for inducing clinical response and remission among patients who have failed conventional therapies. The indirect comparisons between drugs for induction have several limitations, in particular large differences in placebo response rates and a high degree of heterogeneity associated with the adalimumab and especially the infliximab studies compared with the ustekinumab studies. Given the limitations of the available indirect comparisons and the heterogeneity across studies, the effectiveness of ustekinumab compared with infliximab, adalimumab, and vedolizumab is uncertain for the treatment-sequence analysis (induction plus maintenance phases).

Potential Place in Therapy

The information in this section is based on that provided in draft form by the clinical expert consulted by CDR reviewers for the purpose of this review.

Based on current standards of practice with existing therapies, the clinical expert consulted by CDR indicated that there are several areas of unmet need where ustekinumab may play a role:

1. It may provide primary induction therapy for Crohn’s disease for patients who experience primary nonresponse to either conventional therapy with immunomodulators or TNF antagonists.
2. It may also be useful in secondary nonresponse during maintenance therapy. An important proportion of patients with Crohn’s disease lose response to TNF antagonist therapy during maintenance, either owing to formation of anti-drug antibodies or to inflammatory mechanisms that are independent of TNF. Evidence summarized in this review suggests that ustekinumab may provide clinically meaningful benefit in this patient group.
3. It may also provide salvage therapy for patients who respond to therapy with immunomodulators or TNF antagonists but who develop adverse effects. Immunomodulators such as azathioprine and methotrexate are generally safe medications; however, there are well-known side effects, including pancreatitis, neutropenia, hepatitis, and neoplasia (e.g., skin cancers). TNF antagonists can be associated with severe allergic reactions, psoriatic skin diseases, neurological complications, congestive heart failure, lupus, and severe infections. In these situations, ustekinumab therapy may be safer and allow for continued treatment of the disease.

Conclusions

Three phase III, randomized, placebo-controlled, double-blind trials investigated the effects of ustekinumab on treatment induction (UNITI-1 and UNITI-2) or maintenance (IM-UNITI) in patients with moderate-to-severe Crohn’s disease. A single IV dose of ustekinumab (approximating 6 mg/kg) appears to be significantly superior to placebo for inducing clinical response after six weeks of therapy. Likewise, both the ustekinumab 90 mg SC every 12 weeks and every eight weeks maintenance-treatment regimens were statistically significantly superior to placebo in achieving clinical remission and corticosteroid-free remission in patients who had a clinical response at week 8 of induction therapy. Moreover, these results for induction and maintenance therapy with ustekinumab were reported in subpopulations of patients with Crohn’s disease who had experienced failure of failed conventional therapies only or of TNF antagonist therapies. These findings were considered likely to be clinically meaningful by the clinician expert consulted by CDR. ▬

The proportion of patients who experienced at least one adverse event or serious adverse event was similar between the ustekinumab and placebo groups across all of the included studies. Nasopharyngitis and upper respiratory tract infection were reported more frequently in ustekinumab-treated patients than in placebo-treated patients, but these did not lead to discontinuation of treatment. Administration-related reactions were relatively rare.

There were no studies in which ustekinumab has been compared directly with the approved TNF antagonists or vedolizumab for induction or maintenance treatment of Crohn’s disease. Three indirect comparisons reviewed by CDR, including one submitted by the manufacturer, were challenging to interpret because of numerous limitations related to the source data and the NMA methods used to compare treatments. These limitations precluded any definitive conclusions regarding the efficacy and safety of ustekinumab compared with TNF antagonists and vedolizumab.