An overview of the submission details for the drug under review is provided in .
Introduction
Crohn disease (CD) is a chronic form of inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal tract, but most commonly affects the ileum (small intestine), colon (beginning of the large intestine), and rectum. Common gastrointestinal symptoms experienced by patients with CD include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.1,2 CD-associated inflammation can also manifest outside the gastrointestinal tract, affecting the joints, eyes, and skin of the patient. Complications associated with CD can include fever, malnutrition, weight loss, anemia, bowel obstructions, fistulas, anal fissures, intra-abdominal and other abscesses, and ulcers.2,3 In addition, patients with colonic CD have been shown to have an increased risk of developing colon cancer.2 The predicted prevalence of CD in 2018 was 368 per 100,000 population, thus there are approximately 135,000 Canadians living with CD.4,5
Currently there is no cure for CD. Therapeutic goals include inducing and maintaining clinical and endoscopic remission. Pharmaceutical treatments for CD include aminosalicylates, immunosuppressants, corticosteroids, tumour necrosis factor alpha (TNF alpha) antagonists, interleukin (IL) inhibitors, and integrin inhibitors. 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. Most drugs have important adverse effects that may have short-term or long-term consequences.2,3
Vedolizumab is a humanized immunoglobin G1 monoclonal antibody that binds exclusively to alpha 4 beta 7 integrin on pathogenic gut-homing lymphocytes and selectively inhibits adhesion of these cells to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), which is primarily localized to blood vessels within intestinal muscosa and gut-associated lymphoid tissue. Vedolizumab is available as powder for solution for IV infusion, 300 mg per vial, or solution for subcutaneous (SC) injection, 108 mg/0.68 mL pre-filled syringe or pen.6 Vedolizumab SC has been approved by Health Canada for the treatment of adult patients with CD and a Notice of Compliance was issued on November 19, 2020. Vedolizumab SC has also been approved for the treatment of adult patients with moderately to severely active ulcerative colitis.
Vedolizumab IV has been approved by Health Canada for the treatment of adult patients with moderately to severely active CD who have had an inadequate response with, lost response to, or were intolerant to immunomodulators or a TNF alpha antagonist; or have had an inadequate response, intolerance, or demonstrated dependence on corticosteroids.6 The dosing of vedolizumab IV recommended by Health Canada for CD is 300 mg at 0, 2, and 6 weeks, and then every 8 weeks thereafter. When vedolizumab SC is used as a maintenance treatment following at least 2 IV infusions, the recommended dose regimen is 108 mg administered by SC injection once every 2 weeks.
Vedolizumab IV received CADTH Canadian Drug Expert Committee (CDEC) recommendations to reimburse with criteria and conditions for ulcerative colitis (UC) in October 2015 and for CD in October 2016. CDEC issued a recommendation to reimburse vedolizumab SC with criteria and conditions for UC in May 2020.
The objective of the current review was to perform a review of the beneficial and harmful effects of vedolizumab SC in adult patients with moderately to severely active CD who have had an inadequate response with, lost response to, or were intolerant to immunomodulators or a TNF alpha antagonist; or have had an inadequate response, intolerance, or demonstrated dependence on corticosteroids.
The clinical and pharmacoeconomic evidence for the review were provided through the CADTH tailored review process. A tailored review consists of an appraisal of the clinical evidence and a pharmacoeconomic evaluation filed by the sponsor using a CADTH-provided review template that is specific to the type of drug product to be reviewed.
Stakeholder Engagement
The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from a clinical expert consulted by CADTH for the purpose of this review.
Patient Input
Two patient groups submitted input for this review: (1) the Gastrointestinal Society (GI Society) and (2) Crohn’s and Colitis Canada (CCC). The GI Society is a national registered charity that is committed to improving the lives of patients with GI and liver conditions by supporting research, advocating for patient access to health care, and promoting overall GI and liver health. A national, volunteer-based charity, CCC is focused on finding cures for CD and UC and improving the lives of people affected by these diseases.
Patient input from these 2 groups was obtained through surveys, direct contact with patients affected with IBD, interviews, patient roundtables, telephone calls, emails, and social media, or via published reports. From the patients’ point of view, CD is a chronic GI condition that primarily affects the small intestine and colon. The most frequent symptoms associated with CD are persistent diarrhea, rectal bleeding, abdominal pain, and weight loss. These symptoms vary from person to person and may change over time. Patients with CD may also experience symptoms outside of the GI tract. Fever, fatigue, and anemia are common. Serious complications such as fistula can occur. In addition to the physical symptoms, the patient groups stated that CD has a profound effect on patients’ emotional and social lives. Both patient groups indicated that patients are constantly concerned about future flare-ups, which can be unpredictable and severely disruptive.
The patient groups described treatment of CD as multifaceted as it involves managing symptoms and consequences of the disease, as well as trying to reduce the underlying inflammation. Many respondents have experienced multiple medications over many years. When one medication fails to treat their disease, patients switch to another type. Even though different treatment options are available, many patients still have difficulties obtaining remission and/or adequate symptom relief. Patients reporting experience with vedolizumab noted both benefits and side effects associated with this drug.
Both patient groups emphasized the importance of symptom relief, quality-of-life improvements, and achieving remission in patients with CD, as well as the importance of having access to a variety of treatment options, as patients respond differently to treatments. They also expressed concerns about the challenges in receiving medication for CD via infusion at clinics due to the significant time commitment and time away from work and school. A self-administered option, such as the SC formulation of vedolizumab, is desirable.
Clinician Input
Based on current standards of practice with existing therapies, the clinical expert consulted by CADTH identified several areas of unmet need where vedolizumab SC may play a role:
As primary maintenance therapy for CD for patients who experience primary non-response to either conventional therapy with immunomodulators or TNF alpha antagonists
In the setting of secondary non-response during maintenance therapy; an important proportion of CD patients will lose response to TNF alpha antagonist therapy during maintenance, either due to formation of anti-drug antibodies or to inflammatory mechanisms that are independent of TNF
As salvage therapy for patients responding to immunomodulation therapy or TNF alpha antagonists who develop adverse effects to therapy; while immunomodulators such as azathioprine and methotrexate are generally safe medications, well-known side effects include the development of pancreatitis, neutropenia, hepatitis, and neoplasia (e.g., skin cancers); in addition, TNF alpha antagonists can be associated with severe allergic reactions, psoriatic skin diseases, neurological complications, congestive heart failure, lupus, and severe infections.
Patients with moderate to severe CD require treatment with biologic therapies (typically starting with the TNF alpha antagonists infliximab and adalimumab) after not meeting treatment goals with aminosalicylates, immunosuppressants, and corticosteroids. Biologic treatments are usually administered in combination with an immunosuppressant such as azathioprine or methotrexate. Patients who respond to this approach continue with biologic treatment for several years. However, some patients experience a reduction in response over time (e.g., due to the development of antibodies to a particular biologic treatment) or become intolerant of biologic treatment (e.g., due to side effects such as an allergic reaction or other drug-related complications), which necessitates a change in the treatment regimen to maintain clinical responsiveness. At present, patients who experience a loss of response to either infliximab or adalimumab can be switched to the other TNF alpha antagonist, although this is often associated with a weaker clinical response compared with the response in patients who have not been exposed previously to a TNF alpha antagonist. Therefore, patients with moderate to severe CD who are no longer responsive to or intolerant of TNF alpha antagonists may benefit from a drug with a different mechanism of action.
Vedolizumab is an integrin inhibitor, and therefore represents a different class of biologic compared to the TNF alpha antagonists and the IL-12 and IL-23 inhibitor ustekinumab.
There are no barriers to identifying patients for whom vedolizumab treatment would be appropriate in a consistent manner, although a specialized diagnostic test, such as endoscopy, computed tomography scan, abdominal ultrasound, or magnetic resonance enterography, is usually required to assess disease activity and severity in all patients who require biologic therapy, in accordance with standard clinical practice. The following are also advisable to assess prior to initiating treatment:
Clinical Evidence
Pivotal Studies
Description of Studies
One phase III, double-blind, placebo-controlled, randomized controlled trial (RCT), VISIBLE 2 (N = 410), was submitted by the sponsor.7 VISIBLE 2 was designed to evaluate the efficacy and safety of maintenance treatment with vedolizumab SC injection in adult patients with moderately to severely active CD who achieved a clinical response at week 6 to open-label therapy with 300 mg vedolizumab IV infusion at weeks 0 and 2. Patients with a clinical response at week 6 were randomized to maintenance treatment with vedolizumab SC (108 mg vedolizumab SC every 2 weeks), or placebo in a 2:1 ratio. The primary outcome was the proportion of patients with clinical remission, defined as a Crohn’s Disease Activity Index (CDAI) score of 150 or less at week 52. To control for an overall type I error rate in the comparison between vedolizumab SC and the placebo for the primary and secondary end points, a hierarchical approach was applied to the statistical testing.
Efficacy Results
In VISIBLE 2, more patients in the vedolizumab SC group achieved clinical remission at week 52 (primary efficacy end point) when compared to placebo, with an adjusted risk difference of 13.7% (95% confidence interval [CI], 3.8 to 23.7; P = 0.008). In addition, numerically higher enhanced clinical response at week 52 was observed in the vedolizumab SC group compared with the placebo group; however, the between-group difference did not reach statistical significance (52% versus 44.8%; P = 0.167). Consequently, statistical significance cannot be formally claimed for any of the end points ranked after this end point in the hierarchy, such as corticosteroid-free remission at week 52. A numerically higher rate of corticosteroid-free remission at week 52 was reported for the vedolizumab group (45.3%) compared with placebo (18.2%).
For patient-reported outcomes, total scores in the Inflammatory Bowel Disease Questionnaire (IBDQ), a disease-specific tool to assess health-related quality of life (HRQoL), suggested improvements for both treatment groups; change from baseline was 63.3 points in the vedolizumab SC group and 55.1 points in the placebo group. It is unclear whether the between-groups difference can be considered clinically meaningful. Similar results were observed for the results of EuroQol 5-Dimensions questionnaire (EQ-5D) Visual Analogue Scale (VAS) score and index score.
Harms Results
Overall, data from the VISIBLE 2 trial do not provide important concerns in terms of adverse events (AEs) or serious adverse events (SAEs), or harms of special interest established a priori in this review. The incidence of treatment-emergent adverse events (TEAEs) was 73.5% in the vedolizumab SC group and 76.1% in the placebo group. The most common AEs were worsening of CD disease activity, abdominal pain, nasopharyngitis, arthralgia, and upper respiratory tract infections. The incidence of SAEs was comparative between the 2 groups, at 8.4% in the vedolizumab SC group and 10.4% in the placebo group. The incidence of withdrawals due to AEs was higher in the placebo group (8.2%) compared to vedolizumab SC (4%).
Summary of Key Results from Pivotal Studies.
CADTH Critical Appraisal
The only pivotal study included in this review was VISIBLE 2. A hierarchical statistical testing was used to control for the overall type I error rate. As statistical significance was not achieved for one of the secondary efficacy end points, “enhanced clinical response at week 52,” statistical significance cannot be formally claimed for any of the end points ranked after this end point, including “corticosteroid-free remission,” although numerically greater differences in these end points were reported in the vedolizumab SC group compared with the placebo group.
During the maintenance phase, 41% of the participants discontinued treatment, 45.2% in the placebo group and 38.9% in the vedolizumab SC group. The main reason for discontinuation in the maintenance phase was lack of efficacy (with 32% and 28% on placebo and vedolizumab SC, respectively) followed by voluntary withdrawal and AEs. This difference in missing data could bias the results. Sensitivity analyses were conducted to examine the robustness of study findings to missing data assumptions, and the results supported the primary analysis.
Subgroup analyses were performed to examine the consistency of the treatment effect observed for the primary and all secondary outcomes based on age, gender, race, duration of CD, geographic region, baseline disease activity, baseline fecal calprotectin, disease localization, clinical remission status at week 6, prior TNF alpha antagonist therapy, prior immunomodulator and TNF alpha antagonist failure, prior corticosteroid failure, prior immunomodulator failure, concomitant therapies, and worst prior treatment failure. However, conclusions in regard to these subgroups are uncertain due to the ▬▬▬▬▬ in the subgroups. In addition, subgroup analyses were exploratory in VISIBLE 2, and there was also a lack of adjustment for multiplicity. All of these increase uncertainty in interpretation of results in the subgroups. The VISIBLE 2 study was powered to assess the primary outcome of clinical remission after 52 weeks but was not sufficient to assess other secondary end points. This limitation contributed to the findings of numerically greater but not statistically significant differences between treatment arms for all secondary end points, such as enhanced clinical response and corticosteroid-free clinical remission.
Indirect Comparisons
Description of Studies
The sponsor submitted a single network meta-analysis (NMA) aimed at evaluating the comparative efficacy and safety of vedolizumab SC relative to other comparators with similar indications.8
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Efficacy Results
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Little should be inferred regarding the comparative efficacy or safety based solely on this submitted NMA. The applicability of the sponsor’s NMA is affected by the limited size of the evidence base (i.e., small effect sizes and large credible intervals), potential limitations in the submitted analysis and heterogeneity in trial design, and patient populations across trials. Overall, the results of this analysis must be interpreted with caution.
Harms Results
Results of the NMA suggest that ▬▬▬▬▬
CADTH Critical Appraisal
The major concerns with the submitted NMA are related to the limited size of the evidence ▬▬▬▬▬ and heterogeneity across trials in both design and patient baseline characteristics.
A significant concern with the NMA presented is that studies included in the analyses were highly heterogeneous in terms of both study design and patient characteristics. Some of the important patient characteristics, such as disease duration and CDAI score at baseline, were reported graphically. Significant differences were noted in these baseline characteristics, including factors that may be associated with disease severity such as C-reactive protein (CRP) levels, disease duration, and CDAI score at baseline. Another major concern with design heterogeneity is how trials transition from induction to the maintenance phase. The evidence base in the maintenance phase is a mix of treat-through trials and re-randomization trials. Re-randomization within some trials, such as VISIBLE 2, occurs at the end of the induction phase. This difference in design may vary the response between groups and may limit the comparability of treatment groups across trials for the maintenance phase. ▬▬▬▬▬, there remain major concerns regarding the validity of conclusions from this NMA due to the differing designs across studies.
Other Relevant Evidence
Description of Studies
An open-label extension (OLE) study (SC-3030) to evaluate the long-term safety and efficacy of vedolizumab SC in patients with CD and UC is ongoing at the time of this review. This study is intended to collect long-term safety data for vedolizumab SC dosing to complement the safety data gathered in VISIBLE 2 of patients with CD and Study SC-3027 of patients with UC.
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Patients are eligible to enter this OLE study if they participated in the SC-3027 (UC) or SC-3031 (CD) study. They receive open-label vedolizumab SC 108 mg either weekly or every 2 weeks. Patients with UC or CD who completed the maintenance phase (week 52) will receive vedolizumab SC 108 mg every 2 weeks. Patients with UC or CD who withdrew early from the maintenance phase due to disease worsening or need for rescue medications will receive vedolizumab SC 108 mg weekly Patients with UC or CD who did not achieve a clinical response at week 6, but after receiving a third vedolizumab IV infusion at week 6 achieved a clinical response at week 14, will receive vedolizumab SC 108 mg every 2 weeks. Participants continue the study drug for up to 5 years.
Results
▬▬▬▬▬. The available efficacy results to date were limited by their descriptive nature and ▬ of evaluable patients.
CADTH Critical Appraisal
The VISIBLE 2 long-term extension study is limited by the open-label administration of the study drug, the absence of an active or placebo comparator group, and the reporting of descriptive summary statistics. Furthermore, the number of evaluable patients at the most recent data cut was low.
▬▬▬▬▬ In addition, patients enrolled in the OLE study ▬▬▬▬▬, making interpretation of results difficult.
Cost Information
The sponsor included the following comparators in its cost comparison, in which differences in annual cost were considered: vedolizumab IV, adalimumab, infliximab, and ustekinumab. The sponsor estimated the reimbursement of vedolizumab SC to be cost-neutral when compared to vedolizumab IV, as the annual costs based on the recommended maintenance dosing regimen were the same between vedolizumab SC and vedolizumab IV.
CADTH identified 2 main limitations in the sponsor’s cost information: The comparative efficacy of vedolizumab SC is uncertain, based on the submitted indirect treatment comparison (ITC).
▬▬▬▬▬. The sponsor also did not consider induction costs, which are expected to be higher in the first year compared with costs associated with maintenance treatment. Total treatment costs for the introduction of vedolizumab SC are therefore likely underestimated versus other comparators.
CADTH also noted a few issues for consideration, including the availability of ustekinumab; historical claims data and pan-Canadian Pharmaceutical Alliance (pCPA) negotiations indicate there may be limited uptake of this treatment for CD by participating public drug plans. In addition, there may be an impact on health care resource utilization from vedolizumab SC, mainly in the form of potential reduction of IV administration costs and increased pharmacy dispensing fees. Last, CADTH considered the outcome of the 2016 submission for vedolizumab IV, which recommended a price reduction such that it not exceed the least-costly alternative biologic treatment. Where participating drug plans were able to negotiate a price reduction for vedolizumab IV, a similar price reduction would be needed for vedolizumab SC to remain cost-neutral.
Conclusions
Based on one trial, subcutaneous injection of vedolizumab is more effective than placebo in achieving clinical remission in patients with moderately to severely active CD. The benefits related to other outcomes assessed in the trial are uncertain based on the failure to detect a statistically significant difference between vedolizumab SC and placebo for the secondary outcome (enhanced clinical response), which was ranked higher than other outcomes in the stepwise analysis procedure. The frequency of AEs was similar between placebo and vedolizumab SC, after 52 weeks of treatment.
Based on one sponsor-submitted review of ITCs, ▬▬▬▬▬.
Results from an ongoing, open-label, long-term study suggest that the ▬▬▬▬▬.
At the submitted price and based on the recommended dosage of 108 mg every 2 weeks, vedolizumab SC has an annual cost of $21,458 per patient in maintenance therapy. This results in cost-neutrality compared to vedolizumab IV on an annual basis; however, the comparative efficacy and safety of vedolizumab SC are uncertain and the exclusion of induction therapy costs underestimates total treatment costs versus other comparators.
