Indication: For the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy
Sponsor: Bristol-Myers Squibb
Final recommendation: Do not reimburse
Summary
What Is the CADTH Reimbursement Recommendation for Sotyktu?
CADTH recommends that Sotyktu not be reimbursed by public drug plans for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Why Did CADTH Make This Recommendation?
The evidence from 2 clinical trials was insufficient to determine that Sotyktu offered treatment benefits over the currently available advanced treatments in Canada for the treatment of moderate to severe plaque psoriasis in adults.
No evidence was found that directly compared Sotyktu to newer interleukin (IL)-17 and IL-23 biologics, and the indirect evidence suggested that Sotyktu was less effective at improving skin plaques than several biologics (including IL-17 and IL-23 biologics) that are available and reimbursed in Canada.
CADTH concluded that there was not enough evidence to show that Sotyktu met the needs of patients with moderate to severe plaque psoriasis not already addressed by other available treatments.
Additional Information
What Is Plaque Psoriasis?
Plaque psoriasis is a skin disease that causes red, flaky, crusty patches of skin that may be itchy and painful and can lead to negative impacts on social and work life. Up to 1 million people in Canada are living with psoriasis, a third of whom have moderate to severe disease.
Unmet Needs in Plaque Psoriasis
Although many treatments are approved in Canada for moderate to severe plaque psoriasis, some patients may not respond to these treatments. Other treatment options are needed for these patients.
How Much Does Sotyktu Cost?
Treatment with Sotyktu is expected to cost $14,409 per patient per year.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that deucravacitinib not be reimbursed for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
There is a lack of robust evidence to sufficiently demonstrate that deucravacitinib exhibits a comparable therapeutic benefit relative to the treatments for plaque psoriasis that are currently used in clinical practice in Canada. Evidence from 2 double-blind, randomized controlled trials (RCTs), POETYK PSO-1 (N = 666) and POETYK PSO-2 (N = 1,020), in adults with moderate to severe plaque psoriasis showed that deucravacitinib was associated with statistically significant improvements in skin clearance (Psoriasis Area and Severity Index [PASI] score reduced by 75% [PASI 75] or 90% [PASI 90] or a static Physician’s Global Assessment [sPGA] of clear or almost clear) at week 16 versus apremilast and placebo. In the trials, 53% to 58% of patients in the deucravacitinib groups achieved a PASI 75 response, 27% to 36% achieved a PASI 90 response, and 10% to 14% achieved a PASI score reduced by 100% (PASI 100) response at week 16. However, the clinical relevance of these results within the Canadian treatment landscape is uncertain. Based on clinical expert input, although PASI 75 is accepted as a clinically relevant minimal response threshold in clinical trials, available biologics are expected to achieve a PASI 90 or PASI 100 response in clinical practice. Finally, patients in the POETYK PSO-1 and POETYK PSO-2 trials were not required to fail on conventional treatment options before enrolment, and, as a result, it is uncertain if the outcomes demonstrated in these trials can be extrapolated to the advanced treatment clinical landscape.
Direct evidence comparing newer IL-17 and IL-23 biologics and deucravacitinib was not identified by CADTH for this review. The only direct comparative evidence included deucravacitinib and apremilast. Indirect evidence from 1 sponsor-submitted network meta-analysis (NMA) suggested that deucravacitinib was less effective in producing skin improvement than several biologics (including IL-17 and IL-23 biologics) that are available and reimbursed in Canada.
Patients expressed a need for treatments that improve skin clearance, symptoms of psoriasis, and health-related quality of life (HRQoL), as well as a need for treatments that are convenient and have minimal adverse effects. CDEC concluded that there was insufficient evidence to demonstrate that deucravacitinib meets needs that are not already addressed by other available treatments.
The sponsor requested a reconsideration of the initial CDEC draft recommendation to not reimburse deucravacitinib for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. CDEC discussed each of the issues identified by the sponsor in their Request for Reconsideration, which included that the sponsor does not agree that the committee fully considered the unmet need for the patient population or that the original recommendation was supported by the evidence for deucravacitinib. CDEC re-examined the limitations of the available evidence for this review.
CDEC discussed that while improvement in PASI 75 compared to apremilast was noted, the ability to determine a more meaningful improvement for patients, such as PASI 90 and PASI 100, was limited. CDEC considered the comparison to apremilast in the Canadian treatment landscape to be of limited relevance.
During the initial and reconsideration meetings, CDEC discussed the potential benefit of the convenience of an oral therapy like deucravacitinib over injectable therapies along with patient group input that some patients have concerns with self-injection and that options for oral therapy are valued. Cyclosporine and methotrexate are available oral alternatives funded in most jurisdictions. The clinical expert stated that many patients will prefer an infrequent subcutaneous injection of a more efficacious product over a daily oral medication with lesser efficacy. Furthermore, the clinical expert noted that concerns around self-injection can also be overcome by health care provider administration.
In addition to putting a priority on skin clearance, patient groups also indicated the need for a treatment that would improve HRQoL with minimal adverse effects. CDEC discussed that the available data on Dermatology Life Quality Index (DLQI) suggest that deucravacitinib may be associated with short-term benefits in HRQoL versus placebo. In addition, the sponsor-submitted indirect treatment comparison (ITC) did not assess comparative HRQoL or safety. Hence, it is uncertain whether deucravacitinib would improve HRQoL or have a lower rate of adverse events compared with other currently available advanced therapies for the treatment of moderate to severe plaque psoriasis in adults.
During the initial and reconsideration meetings, CDEC discussed that plaque psoriasis requires lifelong treatment and there is uncertainty regarding the long-term effectiveness and safety of deucravacitinib over other currently available treatment options for moderate to severe plaque psoriasis. In addition, there were generalizability issues with the longer-term data in the POETYK PSO-2 trial. The withdrawal period results of the POETYK PSO-2 trial were based on an enriched population whose disease responded to deucravacitinib. As a result, the 52-week skin response rate may be inflated relative to an unselected patient population. The available longer-term extension data were limited by selection bias, lack of a control group, and lack of blinding.
During the reconsideration meeting, CDEC noted that the majority of adults in the POETYK PSO-1 and POETYK PSO-2 trials had received prior systemic therapy for psoriasis but were not required to fail on first-line systemic treatment options nor was there a subgroup analysis assessing those with prior first-line systemic therapy failure. CDEC determined that, based on the pivotal trials submitted by the sponsor, deucravacitinib’s place in therapy does not align with other advanced treatment options. CDEC concluded that although deucravacitinib has a novel mechanism of action, there was no evidence provided that identified an efficacy or safety benefit of deucravacitinib over other common-place comparators (i.e., first-line systemic drugs or biologics).
Plaque psoriasis is a chronic inflammatory skin disease characterized by erythematous inflammatory plaques that may be itchy or painful and are usually covered by silver, flaking scales. In addition to the dermatological symptoms, plaque psoriasis is often associated with psychosocial symptoms and can impact self-esteem, interpersonal relationships, and performance at school or work. Several comorbid conditions have been linked to psoriasis, such as depression, cardiovascular disease, and psoriatic arthritis. It is estimated that up to 1 million people in Canada are living with a type of psoriasis, 90% of whom have plaque psoriasis.
Most patients with moderate to severe plaque psoriasis will require systemic therapies to control their symptoms. Traditional systemic drugs include cyclosporine, methotrexate, and acitretin. Advanced therapy, which is usually reserved for patients who fail on or are intolerant of traditional systemic therapies, include apremilast and biologic drugs (tumour necrosis factor alpha inhibitors, IL-23 inhibitors, IL-12 and IL-23 inhibitors, and IL-17 inhibitors).
Deucravacitinib is a tyrosine kinase 2 inhibitor that impedes the release of proinflammatory cytokines and chemokines. Deucravacitinib was approved by Health Canada for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. It is available as a 6 mg oral tablet and the dosage recommended in the product monograph is 6 mg daily.
To make its recommendation, the committee considered the following information:
a review of 2 randomized controlled clinical studies in adults with moderate to severe plaque psoriasis
patients’ perspectives gathered by patient groups, Canadian Psoriasis Network (CPN) and the Canadian Association of Psoriasis Patients (CAPP)
input from public drug plans that participate in the CADTH review process
1 clinical specialist with expertise diagnosing and treating patients with plaque psoriasis
a review of the pharmacoeconomic model and report submitted by the sponsor
information submitted as part of the Request for Reconsideration (described in the following).
Two patient groups submitted a joint input: CPN and the CAPP. The patient input was based on English and French surveys that received a total 22 responses and another survey entitled “2022 Survey of People with Psoriatic Disease in Canada and their Caregivers,” which was commissioned by the CPN and collected responses from 502 patients. The symptoms most frequently experienced by patients were flaking, itching, pain and burning, silvery scaly plaques, and dry skin that may crack or bleed. Many patients indicated that psoriasis negatively affected their mental health, self-esteem, social life, ability to exercise, and sleep. Furthermore, some patients were financially impacted and missed work due to psoriasis.
The patient groups emphasized that the complexity and chronic nature of plaque psoriasis lead to a continuing need for treatment options that consider the needs of individual patients. Regarding patients’ expectations for new medications, improved symptoms, better quality of life, and reduced side effects were mentioned. Other responses included “affordable” and “easier to take, e.g., dosing schedule, route of administration.”
According to the clinical expert consulted by CADTH, the goals of treatment are to reduce signs and symptoms of psoriasis, and to improve quality of life and function. With available treatments, 80% to 90% of patients achieve a PASI 90 response and approximately 50% to 60% achieve a PASI 100 response. About 10% of patients may not respond to initial induction therapy with a biologic (i.e., primary failure) or may lose response over time (secondary failure). The expert indicated that there is an unmet need for treatments that can be remittive and allow drug discontinuation or are intermittent (rather than continuous) therapy, as well as for treatments that can modify the disease pathophysiology and have a beneficial effect on its natural history.
The clinical expert indicated that deucravacitinib does not address any of the unmet needs in plaque psoriasis and did not anticipate that it would cause a shift in the current treatment paradigm. The expert stated that it would be difficult to define a role for deucravacitinib except as an oral alternative to the biologics for patients who prefer oral treatment.
Advanced therapy, such as deucravacitinib, should be reserved for patients who have failed first-line traditional systemics (e.g., methotrexate, acitretin, cyclosporine), according to the clinical expert. Treatment response is usually assessed after 12 to 16 weeks and then at 1 year. Deucravacitinib should be discontinued if patients experience a significant adverse effect (e.g., hypersensitivity, serious infection). In addition, the expert stated that deucravacitinib ought to be discontinued if it fails to provide at least a PASI 75 response. Like biologics, the expert stated that deucravacitinib should be prescribed by dermatologists.
No input was received from clinician groups.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for deucravacitinib:
relevant comparators
considerations for initiation of therapy
considerations for continuation or renewal of therapy
considerations for discontinuation of therapy
considerations for prescribing of therapy.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Two 52-week double-blind RCTs met the inclusion criteria for the systematic review. POETYK PSO-1 (N = 666) and POETYK PSO-2 (N = 1,020) used a parallel study design, with POETYK PSO-2 adding a randomized withdrawal design for responders at week 24. The studies enrolled adults (≥ 18 years) who had moderate to severe plaque psoriasis and were candidates for systemic psoriasis therapy and/or phototherapy. Patients were required to have a baseline PASI score of 12 or higher, with more than 10% of body surface area affected, and with a static sPGA score of at least 3 on a 5-point scale.
Both studies randomized eligible patients (2:1:1) to deucravacitinib 6 mg daily, apremilast 30 mg twice daily, or placebo. All patients in the placebo groups switched to deucravacitinib at week 16. Both studies included a 24-week crossover to deucravacitinib for patients in the apremilast group who did not show an adequate response to therapy (i.e., did not achieve a PASI 50 response in the POETYK PSO-1 trial or a PASI 75 in the POETYK PSO-2 trial). At week 24 in the POETYK PSO-2 study, patients in the deucravacitinib group who achieved a PASI 75 response were rerandomized to placebo or to continue deucravacitinib, and patients in the apremilast group who achieved a PASI 75 response were switched to placebo.
The coprimary outcomes in both studies were the proportion of patients who achieved an sPGA score of 0 or 1 (with at least a 2-point change from baseline) and PASI 75 response at week 16, compared with placebo. The sPGA is a composite score of the physician’s assessment of the overall severity of the patient’s psoriatic lesions using a 5-point scale, described as clear (0), almost clear (1), mild (2), moderate (3), or severe (4). PASI grades the extent and severity of psoriatic lesions and combines an assessment of the body surface area affected with the severity of desquamation, erythema, and plaque induration or infiltration. It is scored from 0 to 72, with higher scores representing more severe disease. A PASI response is the percentage improvement in PASI score, with PASI 75 considered the minimum clinically relevant change.
Key secondary outcomes included other PASI or sPGA response thresholds, HRQoL, and symptoms of psoriasis for deucravacitinib versus placebo or apremilast at week 16, 24, or 52. The POETYK PSO-2 study also evaluated the time to relapse among patients in the deucravacitinib group who achieved a PASI 75 response at week 24.
The mean age of patients enrolled in the pivotal trials ranged from 44.7 years (standard deviation [SD] = 12.1) to 47.9 years (SD = 14.0) per treatment group. The majority of patients were men (62% to 71%) and the minority were women (29% to 38%). Most patients were white (77% to 93%), with fewer patients who were Asian (3% to 21%), Black (1% to 4%), or other races (≤ 2%). The patients enrolled had been diagnosed with psoriasis for a median of 13.4 years to 18.2 years, with a mean PASI score at baseline ranging from 20.7 (SD = 8.0) to 21.8 (SD = 8.6). The majority of patients had received prior systemic therapy for psoriasis (54% to 66%), including biologics (31% to 39%).
In the POETYK PSO-1 study, 53.6%, 7.2%, and 32.1% of patients in the deucravacitinib, placebo, and apremilast groups, respectively, met the sPGA 0 or 1 response criteria at week 16. The between-group differences favoured deucravacitinib versus placebo (risk difference [RD] = 46.7%; 95% confidence interval [CI], 40.2% to 53.2%; P < 0.0001) and versus apremilast (RD = 21.4%; 95% CI, 12.7% to 30.1%; P < 0.0001). The proportion of responders was 49.5%, 8.6%, and 33.9% in the deucravacitinib, placebo, and apremilast groups, respectively, of the POETYK PSO-2 study. The between-group risk difference was 40.9% (95% CI, 35.4% to 46.4%) for deucravacitinib versus placebo and 15.8% (95% CI, 8.8% to 22.9%) versus apremilast. For both comparisons, the difference favoured deucravacitinib, with P values less than 0.0001.
The proportion of patients in POETYK PSO-1 who achieved a PASI 75 response at week 16 was 58.4%, 12.7%, and 35.1% in the deucravacitinib, placebo, and apremilast groups, respectively, with a risk difference of 46.1%, (95% CI, 38.9% to 53.2%) for deucravacitinib versus placebo (P < 0.0001) and 23.0% (95% CI, 14.1% to 31.8%) versus apremilast (P < 0.0001). The results were similar in the POETYK PSO-2 study, with 53.0%, 9.4%, and 39.8% of patients in the deucravacitinib, placebo, and apremilast groups, respectively, achieving a PASI 75 response at week 16. The risk difference was 43.7% (95% CI, 38.0% to 49.3%; P < 0.0001) for deucravacitinib versus placebo and 13.4% (95% CI, 6.2% to 20.7%; P = 0.0004) versus apremilast.
The results of the key secondary outcomes, PASI 90 and PASI 100 at week 16, favoured deucravacitinib versus placebo in both studies. In addition, the PASI 90 response also favoured deucravacitinib versus apremilast at week 16. The proportion of patients who achieved a PASI 90 response ranged from 27.0% to 35.5% in the deucravacitinib groups, 2.7% to 4.2% in the placebo groups, and 18.1% to 19.6% in the apremilast groups. Few patients in any group achieved a PASI 100 response at week 16 (deucravacitinib = 10.2% to 14.2%, apremilast = 3.0% to 4.3%, placebo = 1%), and although numerically the proportion of PASI 100 responders was higher for deucravacitinib versus apremilast, this comparison was not controlled for type I error rate.
The DLQI was used to assess the impact of treatment on HRQoL. It is a patient-reported 10-item questionnaire that covers 6 domains: symptoms and feeling, daily activities, leisure, work and school, personal relationships, and bother with psoriasis treatment, each assessed over the past week. The overall DLQI score ranges from 0 to 30, with lower scores indicating better quality of life. A score of 0 or 1 may be interpreted as the disease has no impact on the patient’s HRQoL. The proportion of patients who achieved a DLQI score of 0 or 1 at week 16 was 41.0%, 10.6%, and 28.6% for POETYK PSO-1 and 37.6%, 9.8%, and 23.1% for POETYK PSO-2 in the deucravacitinib, placebo, and apremilast groups, respectively. The between-group differences favoured deucravacitinib versus placebo (POETYK PSO-1: RD = 30.5%; 95% CI, 23.4% to 37.6% and POETYK PSO-2: RD = 27.9%; 95% CI 22.2% to 33.7%), with P values < 0.0001. Although numerically more patients reported a DLQI response in the deucravacitinib groups than in the apremilast groups (RD = 12.3% and 14.6%), these comparisons were not controlled for type I error rate.
The patient-reported Psoriasis Symptoms and Signs Diary (PSSD) was used to evaluate symptom severity in both studies. PSSD symptom score includes 5 symptoms (itch, pain, stinging, burning, and skin tightness) and is scored from 0 to 100, with 0 indicating a complete absence of symptoms. Among patients who have a baseline PSSD symptom score of at least 1, the proportion of patients who had a symptom score of 0 at week 16 was 7.9%, 0.7%, and 4.4% in POETYK PSO-1 and 7.5%, 1.3%, and 4.3% in POETYK PSO-2 in the deucravacitinib, placebo, and apremilast groups, respectively. In both studies, the differences favoured deucravacitinib versus placebo (P < 0.01), but with no statistically significant difference detected for deucravacitinib versus apremilast.
The trials were 52 weeks in duration and analyzed longer-term outcomes for the randomized population (POETYK PSO-1) and for the subgroup of patients who achieved a PASI 75 response at week 24 (POETYK PSO-2). In the POETYK PSO-1 study, 56.3% of patients achieved a PASI 75 response at week 24 and week 52, in comparison to 30.5% of patients who had received apremilast (RD = 25.5%; 95% CI, 16.9% to 34.0%; P < 0.0001). Data from the POETYK PSO-2 study indicate that patients who achieved a PASI 75 response with deucravacitinib, and who remained on treatment, were less likely to relapse than patients who were switched to placebo (P < 0.0001).
During the first 16 weeks of the pivotal trials (before any treatment switching), the frequency of adverse events was generally similar across groups, with 53% and 58% of patients in the deucravacitinib groups, 42% and 54% of patients in the placebo groups, and 55% and 59% in the apremilast groups reporting 1 or more adverse event. The most commonly reported events in the deucravacitinib group were nasopharyngitis (6% to 11%), upper respiratory tract infection (5% to 6%), and diarrhea and headache (each reported in 4% to 5%). The frequency of these events was comparable in the placebo and apremilast groups, except for gastrointestinal adverse events, which appeared to be more common among patients who received apremilast.
The frequency of serious adverse events was generally low during the trials, with 2% of patients in the deucravacitinib group, 1% to 5% in the placebo group, and 0.4% to 2% in the apremilast group reporting an event during the first 16 weeks. Among patients who received deucravacitinib at any time during the 52-week trials, 3% to 6% of patients experienced a serious adverse event, compared with 1% to 4% of those who received apremilast at any time. A total of 4 patients died during the studies. One patient in the placebo group (POETYK PSO-1) died of hypertensive cardiovascular disease, 2 patients in the deucravacitinib group (POETYK PSO-2) died of heart failure and sepsis, and hepatocellular carcinoma, and 1 patient in the apremilast group (POETYK PSO-2) died of lung cancer and gastrointestinal hemorrhage.
The proportion of patients who stopped treatment due to adverse events was 2% and 3% for deucravacitinib, 4% for placebo, and 5% and 6% for apremilast during the first 16 weeks of the trials.
During the first 16 weeks of the studies, infections and infestations were reported by 26% to 31% of patients in the deucravacitinib groups, 15% to 26% in the placebo groups, and 18% to 25% in the apremilast groups. Few patients in any groups experienced an infection or infestation that was a serious adverse event, and there were no opportunistic infections or tuberculosis events reported in either study. The proportion of patients with at least a grade 2 increase in creatine kinase (CK) levels was 3% for the deucravacitinib groups, 1% to 4% in the placebo groups, and 0% to 4% in the apremilast groups during weeks 0 to 16. Over the 52-week study period, 6% of patients receiving deucravacitinib and 4% to 5% receiving apremilast reported grade 2 or higher elevated CK levels. None of these events were considered serious adverse events. In both trials, the frequency of other adverse events that may be associated with drugs that work through the Janus kinase pathway (major adverse cardiovascular events, thromboembolic events, malignancy, elevated liver enzymes, lymphopenia, or neutropenia) was generally low.
The POETYK PSO-1 and POETYK PSO-2 studies appear to have a low risk of bias with regards to randomization, allocation concealment, and blinding. In general, the baseline characteristics of patients appeared to be balanced between groups within trials. The efficacy outcomes reported were relevant to patients (i.e., skin clearance, psoriasis symptoms, and HRQoL), had evidence to support their validity, and key patient-reported outcomes were part of the statistical testing procedure to control the type I error rate. However, the coprimary outcome, PASI 75, may be considered the minimum clinically relevant response, whereas in clinical practice a PASI 90 response is generally the expected goal of therapy. Key skin clearance outcomes were analyzed based on the intention-to-treat population and using nonresponder imputation for patients who stopped treatment or with missing data. This composite estimand may be considered a conservative estimate of effects. However, up to 10% of patients were excluded from the DLQI or PSSD response end points (depending on the treatment group). The potential impact of these missing patients on the findings is unclear.
Overall, the clinical expert consulted for this review considered that the patients enrolled would represent patients with moderate to severe psoriasis who may be treated with advanced therapies in Canada, including those who had received prior systemic or biologic therapy. However, the clinical expert identified some issues with apremilast as an active comparator, including that while apremilast is another oral advanced therapy, it is infrequently prescribed in Canada for the treatment of moderate to severe plaque psoriasis. Additionally, the expert stated that the efficacy of apremilast is considered to be low for an advanced therapy, and most dermatologists would select a biologic over apremilast. Thus, based on current practice, apremilast may not be as relevant a comparator as biologics for patients with moderate to severe disease.
The sponsor-submitted ITC conducted a systematic review and used a Bayesian NMA to evaluate the relative efficacy of deucravacitinib to other comparators for the treatment of patients with moderate to severe plaque psoriasis. The NMA was based on a systematic review of the literature and data from up to 84 trials were used to inform the analyses. The main efficacy outcome of interest was PASI response.
The sponsor-submitted ITC reported that in the short-term (at 10 to 16 weeks) with 84 RCTs included, deucravacitinib was |||||||| ||||||||||||||||||||||||||||||||||||||||||||||||
The ITC reported that in the midterm (at 24 to 28 weeks) with 48 trials included, deucravacitinib ||||||||||||||||||| ||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||| ||||||||||||||||||||||| |||||||||||||||||||| |||||||||||||||||||| ||||||||||||||||||| ||||| |||||||||||||||||||| ||||||||||| ||||||||||||||||||||||||||||| ||||||||||||||||||| |||||||||| |||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||| |||||||| |||||||||||||||| |||||||||||||| ||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||
The sponsor-submitted ITC reported that in the long-term (at 44 to 60 weeks) with 32 trials included, deucravacitinib was |||||||||||||||||||| ||||||||||||||||||| |||||||||||||| ||| ||||||||||||||||||||||||||||||||||||||||||||||| ||||||||| |||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||| |||||||||||||||||||||||||||| |||||||||||||||||||||||||| ||||||||||||||||||||||||||| ||||||||||||||||||| |||||||||| |||||||||||||
The sponsor-submitted ITC involved a rich evidence base with a large network of RCTs and sample size, which strengthened the robustness of the NMA analyses. |||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||| ||||||||||||||||| ||||||||||||||||||||||||| |||||||||||||||||||| |||||||| |||||||||||||||||||||||||| ||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Interim data for a single-arm, open-label extension study, IM011075, was submitted by the sponsor. Patients who completed the POETYK PSO-1 and POETYK PSO-2 studies were eligible to enroll. A total of 1,221 patients entered the extension study, which represented 72% of the patients randomized in the parent trials. All patients received deucravacitinib 6 mg daily. At the time of interim analysis, 90% of patients were ongoing in the study and receiving treatment, and 95%, 61%, and 20% of patients provided data at 24 weeks, 48 weeks, and 60 weeks, respectively.
In the total extension population, sPGA 0 or 1 response rates were 50.9% (95% CI, 48.1% to 53.8%; N = 1,221) at the start of the extension phase (week 0), and 56.4% (95% CI, 52.7% to 60.0%; N = 745) at week 48. PASI 75 response rates were 65.1% (95% CI, 62.4% to 67.8%) at week 0 and 75.7% (95% CI, 68.7% to 80.6%) at week 48.
Adverse events were reported by 707 of 1,211 patients (58%). The most frequently reported events were COVID-19 (9%) and nasopharyngitis (4%). Seven percent of patients experienced a serious adverse event and 2% stopped treatment due to adverse events. In total, 6 deaths occurred, including 5 due to COVID-19 and 1 due to a ruptured thoracic aortic aneurysm. Infections and infestations were reported by 29% of patients and 4% experienced serious adverse events. At the time of the interim analysis, 45 patients (4%) had at least a grade 2 increase in CK levels but only 1 patient stopped treatment due to these events. No new safety signals were identified.
Limitations of the extension study include selection bias, lack of a control group, and lack of blinding. Reporting of harms and subjective measures (such as those included in the PASI score) may be biased by knowledge of treatment received. As only descriptive statistics were published in this interim report, which were based on observed data with no imputation for missing data, and as there were no comparator groups, the interpretation of the results is limited. Moreover, there is potential for selection bias, as patients who discontinued the parent RCTs due to adverse events, lack of efficacy, or other reasons were excluded.
Table 1: Summary of Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Markov model |
Target population | Adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy, which aligns with the reimbursement request |
Treatmenta | Deucravacitinib |
Dose regimen | 6 mg once daily |
Submitted price | Deucravacitinib, 6 mg tablets: $39.45 |
Treatment cost | $14,409 per patient per year (365.25 days) |
Comparatorsa | Adalimumab, apremilast, bimekizumab, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab, ustekinumab |
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | 10 years |
Key data source | A sponsor-commissioned NMA of 84 clinical trials was used to compare the ability of deucravacitinib to achieve PASI outcomes at 10 to 60 weeks compared to the other biologics. This network included 2 phase III clinical trials for deucravacitinib: POETYK PSO-1 and POETYK PSO-2. |
Key limitations |
|
CADTH reanalysis results | In CADTH reanalyses, deucravacitinib response was assessed at 16 weeks, tildrakizumab was dosed per its Health Canada recommendation, and the basket of biologics representing subsequent therapy was assumed to be the same for all initial comparators. CADTH was unable to address the lack of direct evidence against relevant comparators, as well as uncertainty in discontinuation rates and long-term efficacy.
|
LY = life-year; NMA = network meta-analysis; PASI = psoriasis area severity index; QALY = quality-adjusted life-year.
aAll treatments were sequences that began with the noted comparator, followed by a basket of biologic comparators, followed by best supportive care.
CADTH identified the following key limitations with the sponsor’s analysis: the eligible patient population was inappropriately estimated by including the pediatric population of Canada, the Non-Insured Health Benefits population was included in an inappropriate manner, and biologic therapy was assumed to be publicly funded for all patients; the model was poorly conceptualized and results did not meet face validity, which substantially overestimated the costs associated with the treatment of plaque psoriasis in Canada; response rates and discontinuation assumptions had the same limitations as outlined in the pharmacoeconomic analysis; the use of the health care payer perspective was inappropriate; the market uptake of deucravacitinib and its displacement of other comparators is uncertain; biosimilar use was underestimated; there was uncertainty in the modelling of the basket of biologics used to represent subsequent therapies; and the analysis assumes only patients who would otherwise receive a biologic will access deucravacitinib.
CADTH was unable to fully mitigate the conceptual limitations associated with the model due to structural inflexibility and nonintuitive programming. As deucravacitinib is less expensive per treatment year than most biologic therapies currently being reimbursed, its use is likely to result in cost savings to jurisdictional drug plans over the short-term (i.e., within a 3-year time horizon) as more expensive therapies would be displaced. However, due to its lower efficacy (as suggested in the sponsor’s NMA), it is likely that the use of deucravacitinib will delay rather than prevent the use of more expensive and more effective therapies, thus reimbursement may result in an overall increase in costs over the course of each patient’s life.
CADTH conducted reanalyses to adjust the eligible patient population to include only adults with plaque psoriasis, to mitigate overcounting the number of patients initiating a new therapy each year, to assume that deucravacitinib response would be assessed at 16 weeks, to exclude costs not within drug plan program budgets, to decrease the assumed uptake of deucravacitinib, to assume 100% biosimilar use where available, to equalize subsequent therapies between comparators, and to dose tildrakizumab according to its Health Canada recommendation.
CADTH exploratory analyses suggest that if deucravacitinib is reimbursed in a similar manner to the biologics available for the treatment of moderate to severe plaque psoriasis, its reimbursement might be associated with budgetary savings of $2,469,191 in year 1, $9,227,095 in year 2, and $12,766,452 in year 3, for a 3-year incremental savings of $24,462,738.
The sponsor filed a Request for Reconsideration of the draft recommendation for deucravacitinib for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. In their request, the sponsor identified the following issues:
The decision did not fully consider that there is an unmet need for a new oral therapy and individualized treatment options.
Deucravacitinib has a therapeutic benefit compared with biologics currently used in clinical practice.
Apremilast is a relevant comparator in Canadian clinical practice and demonstrates the need for oral therapies.
The PASI response data submitted for deucravacitinib are clinically relevant within the Canadian treatment landscape.
The CDEC decision to not reimburse is inconsistent with prior CADTH recommendations. A new route of administration and new mechanism of action have previously been recognized as addressing an unmet need in previous CADTH reviews.
The CDEC decision not to reimburse is inconsistent with recent applications of the recommendation framework in moderate to severe psoriasis for drugs that had similar efficacy and safety as relevant comparators. A “reimburse with clinical criteria and/or conditions” recommendation has been applied in the past 3 years according to the framework for products with at least comparable clinical benefit to 1 or more appropriate comparators.
In the meeting to discuss the sponsor’s Request for Reconsideration, CDEC considered the following information:
feedback from the sponsor
information from the initial submission relating to the issues identified by the sponsor
feedback from 1 clinical specialist with expertise in the diagnosis and management of plaque psoriasis
feedback from the public drug plans
feedback from 3 clinician groups: the Atlantic Provinces Dermatology group, the Fraser Health Dermatology Group, and the Canadian Dermatology Association
feedback from 3 patient groups: CPN, CAPP, Canadian Skin Patient Alliance.
All stakeholder feedback received in response to the draft recommendation from patient and clinician groups and the public drug programs is available on the CADTH website.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Initial meeting date: February 22, 2023
Regrets: One expert committee member did not attend.
Conflicts of interest: None
Reconsideration meeting date: July 26, 2023
Regrets: Two expert committee members did not attend.
Conflicts of interest: None
ISSN: 2563-6596
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for noncommercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
Redactions: Confidential information in this document may be redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.