1.1. Disease Prevalence and Incidence

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 (i.e., small intestine), colon (i.e., beginning of the large intestine), 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 Crohn’s disease–associated inflammation can also manifest outside the gastrointestinal tract, affecting the joints, eyes, and skin of the patient. Complications associated with Crohn’s disease can include malnutrition, weight loss, anemia, bowel obstructions, fistulas, anal fissures, intra-abdominal and other abscesses, and ulcers.³ In addition, patients with colonic Crohn’s disease have been shown to have an increased risk of colon cancer.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.²

According to patients — based on patient-group input for this review (0) — Crohn’s disease has a profound effect on physical, emotional, and social well-being. It affects interactions with others and patients’ work life.

1.2. Standards of Therapy

Currently, there is no cure for Crohn’s disease, and the therapeutic goals include inducing and maintaining clinical and endoscopic remission, reducing the need for long-term corticosteroid use, and preventing colon cancer. Several drug classes are used in the treatment of Crohn’s disease, including aminosalicylates, immunomodulators (e.g., azathioprine [AZA], cyclosporine, methotrexate [MTX], and 6-mercaptopurine [6-MP]), corticosteroids (e.g., prednisone), tumour necrosis factor (TNF) alpha antagonists (e.g., infliximab and adalimumab), and integrin inhibitors (e.g., vedolizumab).³ With the exception of the TNF alpha antagonists and vedolizumab, all are commonly referred to as conventional therapies. Medical management is based on a stepwise approach, with treatments used sequentially and escalated to either newer therapies or higher doses as patients fail to respond to each step of treatment.¹⁶ Most drugs have important adverse effects that may have short-term or long-term consequences.³ Surgery, including total colectomy and ileostomy, may be considered for patients with serious complications or medically refractory disease.¹⁶

1.3. Drug

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 previously 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 TNF 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 as a 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 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 90 mg SC every 12 weeks may be administered at the discretion of the treating physician. Patients who have an inadequate response with 90 mg SC every 12 weeks 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 product monograph notes that ustekinumab should be used only by physicians who have sufficient knowledge of the indication for which it is being considered (e.g., Crohn’s disease) and who have fully familiarized themselves with the efficacy and safety profile of the drug.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.

1.4. Key Comparators

Ustekinumab is the first IL inhibitor approved for the treatment of Crohn’s disease in Canada. At the time of this review, there are two TNF antagonists (infliximab and adalimumab) and one integrin inhibitor (vedolizumab) approved for the treatment of Crohn’s disease in Canada. Infliximab and vedolizumab are administered via IV infusion only, whereas adalimumab is administered SC only. The Crohn’s disease indications for ustekinumab and vedolizumab are limited to adult patients, which is more restrictive than the indications for infliximab and adalimumab (Table 4). Infliximab currently has the broadest indication for use in the treatment of Crohn’s disease, being approved for use in the treatment of adults, children, and patients with fistulizing Crohn’s disease. Adalimumab is approved for use in both adults and children with Crohn’s disease.

Table 4

Key Characteristics of Ustekinumab, Vedolizumab, Infliximab, and Adalimumab.

The Health Canada–approved dosage regimens are similar for vedolizumab and infliximab, with administration at weeks 0, 2, and 6 during the induction phase and every eight weeks during maintenance treatment.^17–19 Administration of adalimumab is more frequently during maintenance treatment (i.e., once every two weeks).²⁰ The dose of infliximab is calculated based on the patient’s weight (i.e., 5 mg/kg), whereas the dose of vedolizumab and adalimumab is not adjusted based on the weight of the patient. The product monographs for adalimumab and infliximab indicate that the dosage of these products can be escalated in the event of nonresponse, incomplete response, and/or a disease flare.^18–20 In contrast, the dosage and administration section of the product monograph for vedolizumab does not specify that the dosage can be escalated.¹⁷ The product monograph for ustekinumab indicates that the maintenance administration interval may be shortened to every eight weeks among patients who received the every 12 weeks regimen after induction but did not adequately respond. However, the product monograph for ustekinumab does not specify that the dose or interval may be modified (escalated) beyond 90 mg every eight weeks in patients not meeting treatment goals with this regimen.⁴

1.5. Previous Reviews by CADTH Common Drug Review

Ustekinumab has previously been reviewed twice through the CADTH Common Drug Review (CDR) process 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. The former CADTH Canadian Expert Drug Advisory Committee (CEDAC) recommended that ustekinumab be reimbursed for patients with severe, debilitating psoriasis with clinical criteria.⁶ The CADTH Canadian Drug Expert Committee (CDEC) recommended that ustekinumab not be reimbursed at the submitted price for the treatment of psoriatic arthritis.⁵ Adalimumab for the treatment of moderately to severely active Crohn’s disease was reviewed through the CDR process in 2007, and CEDAC recommended that it be reimbursed with clinical criteria and conditions.^21,22 Infliximab (Remicade) has not been reviewed through the CDR process for the treatment of Crohn’s disease. However, a subsequent entry biologic of infliximab (Inflectra) was reviewed by CDR, and a subsequent CDEC recommendation that it be reimbursed for the treatment of Crohn’s disease, with a clinical criterion and conditions, was issued in 2016.²³