Background

Tildrakizumab is a humanized immunoglobulin G1 kappa monoclonal antibody indicated for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.¹ Tildrakizumab is available as a solution for subcutaneous injection in a single-dose, pre-filled syringe containing 100 mg/mL of product. The recommended dose is 100 mg administered via subcutaneous injection at weeks, 0, 4, and every 12 weeks thereafter.¹ At the sponsor’s submitted price of $4,935 per pre-filled syringe,² the annual cost of tildrakizumab is $24,675 in the first year and $21,385 thereafter.

The sponsor submitted a cost-utility analysis based on a Markov model comparing tildrakizumab with the following biologic therapies reimbursed in Canada for moderate-to-severe plaque psoriasis: adalimumab, brodalumab, etanercept subsequent entry biologic (SEB), guselkumab, infliximab SEB, ixekizumab, secukinumab, ustekinumab, and risankizumab.² The analysis was conducted from a Canadian publicly funded health care payer perspective using 2-week cycles over a 10-year time horizon. The model had 2 time periods: the induction period (from treatment initiation to the initial assessment of treatment response, i.e., 10 to 16 weeks), and the maintenance period. Four states were defined by the following Psoriasis Area and Severity Index (PASI) response categories: a PASI of less than 50, 50 to 74, 75 to 89, and 90 to 100. Treatment response was defined as achieving a PASI response score of 75 (PASI 75) or greater. Following the induction period, patients who achieved a PASI 75 response continued treatment in the maintenance phase until discontinuation due to loss of response or death; those who did not respond or who discontinued therapy were switched to another active therapy, as determined by the physician (second-line treatment), which included biologics (50% of patients), systemic immunosuppressants, and phototherapy. Patients who did not achieve a PASI 75 response after receiving second-line treatment and a 12-week induction period were switched to best supportive care (BSC), which comprised topical therapies. Patients continuing first- or second-line treatment were assumed to maintain the same level of PASI response and remain in the same health state until discontinuation. Once patients reached the BSC state, they remained in that state until death or the end of the model time horizon.

The probabilities of PASI 75 response were based on the tildrakizumab reSURFACE clinical trials³ and on a network meta-analysis (NMA) published by the Institute for Clinical and Economic Reviews (ICER).⁴ Discontinuation rates for both the first year of therapy and for the following years were also based on the report published by ICER.⁴ Utility values were stratified according to the PASI response categories.

In the sponsor’s probabilistic base case, tildrakizumab was dominated by brodalumab (i.e., tildrakizumab was more costly and associated with fewer quality-adjusted life-years [QALYs]). At a willingness-to-pay (WTP) threshold of $50,000 per QALY, tildrakizumab had a 0% probability of being cost-effective. Etanercept SEB had the lowest costs and fewest QALYs followed by brodalumab and risankizumab.

Summary of Identified Limitations and Key Results

CADTH identified several key limitations with the model submitted by the sponsor. CADTH clinical reviewers noted that even though the trials reported efficacy outcomes up to week 52 or week 64, conclusions on the comparative efficacy of tildrakizumab could only be drawn from the induction period due to the design of the studies and, as such, there is significant uncertainty around the long-term clinical effectiveness of tildrakizumab. Additionally, any efficacy outcomes reported after week 12 were reported descriptively based on observed case data, which could potentially inflate the effects of tildrakizumab (see CADTH Clinical Review Report for further details). The sponsor assumed that the clinical efficacy of treatment at the end of the induction period continues beyond the induction period; no consideration was given to the waning of treatment effects. Furthermore, the clinical expert consulted by CADTH advised that PASI 75 response is not consistent with how treatment success is measured in clinical practice, as PASI 90 is now the preferred response score to measure treatment success. The use of a PASI 90 response may lead to different conclusions about both absolute and relative efficacy and result in different conclusions about the cost-effectiveness, as indirect evidence suggests that tildrakizumab may be less effective in inducing PASI 75 and PASI 90 responses compared with IL-17 inhibitors, IL-23 inhibitors, and infliximab. Unfortunately, this limitation could not be addressed through reanalysis of the model due to a lack of long-term data and the lack of flexibility with the model structure. Discontinuation rates, which were sourced from the ICER report, were based on US claims data on patients receiving adalimumab and etanercept; no evidence was provided for the remaining biologics, including tildrakizumab. Furthermore, claims data may be subject to coverage changes (as noted by ICER) and, therefore, might not fully reflect clinical practice. This is an important assumption, as the use of different discontinuation rates, along with the assumption that patients who discontinue second-line treatment switch to BSC (instead of another active treatment), favours tildrakizumab, which has the lowest discontinuation rate in the model. Additionally, the model included the use of different time points for the initial assessment of treatment response in different comparators, which is not consistent with clinical practice; an assessment time point of 16 weeks for all treatments was more reflective of clinical practice, according to the clinical expert consulted by CADTH.

The sponsor assumed that 50% of the patients on second-line treatment received biologics and the remaining 50% received a combination of methotrexate, cyclosporine, acitretin, and phototherapy. Additionally, the model assumed that patients who discontinue second-line treatment switch to BSC. In clinical practice, patients who discontinue or do not respond to treatment would likely receive a higher dose of the same drug or switch to another active treatment. In clinical practice, BSC is only used prior to patients being eligible for treatment with a biologic. CADTH addressed this limitation by assuming that 100% of the patients on second-line treatment received biologic therapy; however, CADTH was unable to address the limitation of patients receiving BSC upon discontinuation of second-line treatment because of the structural limitations of the model and a lack of evidence on treatment-experienced patients.

A costing study that estimated the direct costs of plaque psoriasis in a Canadian population was available and was a more appropriate source of BSC costs than the average costs of cortical steroids used by the sponsor, as the study also includes the cost of health care provider visits, pharmacotherapy, laboratory tests and procedures, hospitalizations, and non-conventional treatment and management. Additionally, the cost of etanercept was based on the SEB drug price. However, etanercept biosimilars are not approved for the treatment of psoriasis in Canada; therefore, the branded cost should have been used. Finally, outdated prices were used for several of the biologic treatments.

CADTH addressed some of these limitations by: assuming 100% of the patients on second-line treatment received biologic therapy; using a 20% discontinuation rate for all biologics; using the branded price for etanercept and up-to-date costs for the rest of the biologics; using a consistent time point (16 weeks) for the initial assessment of treatment response for all biologics; and, using a Canadian source for BSC costs.

Based on the CADTH reanalysis, tildrakizumab, adalimumab, guselkumab, secukinumab, ixekizumab, and ustekinumab were either dominated or extendedly dominated. Etanercept, infliximab SEB, brodalumab, and risankizumab were the optimal treatments (on the cost-effectiveness efficiency frontier [CEF]). Etanercept was associated with the lowest cost and fewest QALYs, followed by infliximab SEB, brodalumab, and then risankizumab.

Conclusions

Based on CADTH’s reanalysis, tildrakizumab is not cost-effective at a WTP threshold of $50,000 per QALY; CADTH’s findings on the cost-effectiveness of tildrakizumab are aligned with the sponsor’s results. Some biologic drugs provide better efficacy in terms of response at a lower total cost (e.g., adalimumab, brodalumab, and infliximab have better efficacy than tildrakizumab at a lower total cost). At least a 20% reduction in the submitted price would be required for tildrakizumab to be cost-effective at a WTP threshold of $50,000 per QALY. It should be noted there is significant uncertainty around the clinical effectiveness of tildrakizumab; additionally, the economic model did not allow CADTH to assess the impact of assumptions relating to the waning of treatment effect and the use of alternative treatment sequences in clinical practice. This adds to the uncertainty of the cost-effectiveness of tildrakizumab.