CADTH Reimbursement Review

Deucravacitinib (Sotyktu)

Sponsor: Bristol Myers Squibb

Therapeutic area: Psoriasis, moderate to severe plaque

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

NOC = Notice of Compliance.

Introduction

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.¹ 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.^1-3 It is estimated that up to 1 million people living in Canada are living with a type of psoriasis, 90% of whom have plaque psoriasis.⁴

Most patients with moderate to severe plaque psoriasis will require systemic therapies to control their symptoms.¹ Traditional systemic drugs include cyclosporine, methotrexate, and acitretin. Advanced therapy, which is usually reserved for patients who fail or are intolerant of traditional systemic therapies, include apremilast and biologic agents (tumour necrosis factor [TNF] alpha inhibitors, interleukin [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.⁵ It was approved by Health Canada for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.⁶ It is available as a 6 mg oral tablet and the recommended dose is 6 mg daily.⁵

The objective of this report is to perform a systematic review of the beneficial and harmful effects of deucravacitinib 6 mg oral tablet for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Stakeholder Perspectives

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 the clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups submitted a joint input: Canadian Psoriasis Network (CPN) and the Canadian Association of Psoriasis Patients (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” commissioned by the CPN that 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. Further, some patients were financially impacted and missed work due to psoriasis.

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.”

Clinician Input

Input From Clinical Expert Consulted by CADTH

According to the clinical expert consulted by CADTH, the goals of treatment are to reduce signs and symptoms of psoriasis and improve quality of life and function. With available treatments, 80% to 90% of patients achieve a 90% reduction in Psoriasis Area and Severity Index score (PASI 90) and approximately 50% to 60% achieve a 100% reduction in Psoriasis Area and Severity Index score (PASI 100). Approximately 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 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 the expert 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 (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 75% reduction in Psoriasis Area and Severity Index score (PASI 75). Like biologics, the expert stated that deucravacitinib should be prescribed by dermatologists.

Clinician Group Input

No input was received from clinician groups.

Drug Program Input

The drug programs identified the following issues that may impact their ability to implement a recommendation: relevant comparators, consideration for initiation of therapy, consideration for continuation or renewal of therapy, consideration for discontinuation of therapy, and consideration for prescribing of therapy. Refer to Table 5.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Two 52-week, double-blind, randomized controlled trials (RCTs) met the inclusion criteria for the systematic review. The POETYK PSO-1 (N = 666) and POETYK PSO-2 (N = 1,020) trials (hereafter referred to as POETYK-1 and POETYK-2) used a parallel study design, with POETYK-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 Psoriasis Area and Severity Index (PASI) score of 12 or higher, with greater than 10% of body surface area (BSA) affected, and with a static Physician’s Global Assessment (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 that did not show an adequate response to therapy (i.e., did not achieve a 50% reduction in Psoriasis Area and Severity Index score [PASI 50] in the POETYK-1 study or PASI 75 in the POETYK-2 study). At week 24 in the POETYK-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 BSA 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, health-related quality of life (HRQoL) and symptoms of psoriasis for deucravacitinib versus placebo or apremilast at week 16, 24, or 52. The POETYK-2 study also evaluated the time to relapse among patients in the deucravacitinib group that 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%), and fewer patients 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%).

Efficacy Results

In the POETYK-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-2 study. The between-group RD 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 (Table 2).

The proportion of patients in the POETYK-1 study 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 RD 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-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 RD 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 (Table 2).

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, in the POETYK-1 and POETYK-2 studies. 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 Dermatology Life Quality Index (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 the POETYK-1 study and 37.6%, 9.8%, and 23.1% for the POETYK-2 study in the deucravacitinib, placebo, and apremilast groups, respectively. The between-group differences favoured deucravacitinib versus placebo (POETYK-1: RD = 30.5%; 95% CI, 23.4% to 37.6%; POETYK-2: RD = 27.9%; 95% CI, 22.2% to 33.7%), with P values less than 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 comparison 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 the POETYK-1 study and 7.5%, 1.3%, and 4.3% in the POETYK-2 study 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-1) and for the subgroup of patients who achieved a PASI 75 response at week 24 (POETYK-2). In the POETYK-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-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).

Harms Results

During the first 16 weeks of the POETYK-1 and POETYK-2 studies (before any treatment switching), the frequency of adverse events (AEs) was generally similar across groups with 53% and 58% of patients in the deucravacitinib groups, 42% and 54% of patients who received placebo, and 55% and 59% who received apremilast reporting 1 or more AEs (Table 3). The most commonly reported events in the deucravacitinib group were nasopharyngitis (6% to 11%), upper respiratory tract infection (5% to 6%), 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 AEs, which appeared to be more common among patients who received apremilast.

The frequency of serious AEs (SAEs) 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 SAE, 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 of the POETYK-1 study died of hypertensive cardiovascular disease, 2 patients in the deucravacitinib group of the POETYK-2 study died of heart failure and sepsis, and hepatocellular carcinoma, and 1 patient in the apremilast group in the POETYK-2 study died of lung cancer and gastrointestinal hemorrhage.

The proportion of patients who stopped treatment due to AEs was 2% and 3% for deucravacitinib, 4% and 4% for placebo, and 6% and 5% for apremilast, in the POETYK-1 and POETYK-2 studies, respectively, 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 SAE, 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 levels was 3% for the deucravacitinib groups, 1% to 4% in the placebo groups, and 0% to 4% in the apremilast groups during week 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 creatinine kinase levels. None of these events were considered SAEs. In both trials, the frequency of other AEs which 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.

Table 2: Summary of Key Efficacy Results From Pivotal and Protocol-Selected Studies

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; NA = not applicable; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PASI 90 = 90% reduction in Psoriasis Area and Severity Index score; PBO = placebo; RD = risk difference; sPGA = static Physician’s Global Assessment; vs. = versus.

^aCochran-Mantel-Haenszel test stratified by geographic region, body weight, and prior biologic use. Nonresponder imputation for missing data.

^bPatients must also have at least a 2-point improvement in their sPGA score vs. baseline.

^cCoprimary end points tested using a 2-sided alpha of 0.05.

^dKey secondary end points tested using a 2-sided alpha of 0.025.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Table 3: Summary of Key Safety Results From Pivotal and Protocol-Selected Studies

AE = adverse event; APREM = apremilast; DEUC = deucravacitinib; PBO = placebo; SAE = serious adverse event.

^aBased on the as-treated population which included all randomized patients who took at least 1 dose of study drug and who were analyzed according to the drug received. Data reported as number of patients with a treatment-emergent AE including events that occurred up to 30 days after the last dose of study drug.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Critical Appraisal

The POETYK-1 and POETYK-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 with prior systemic or biologic therapy. However, the clinical expert identified some issues with apremilast as an active comparator. While apremilast is another oral advanced therapy, it is infrequently prescribed in Canada for the treatment of moderate to severe plaque psoriasis. The expert stated that 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.

Indirect Comparisons

Description of Studies

The sponsor-submitted indirect treatment comparison (ITC) conducted a systematic review and used a Bayesian network meta-analysis (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.

Efficacy Results

The sponsor-submitted ITC reported that in the short-term (at 10 weeks to 16 weeks) with 84 RCTs included, deucravacitinib was favoured over placebo, apremilast, and etanercept in achieving PASI response. Also, no differences were detected between deucravacitinib and tildrakizumab for all PASI levels, or versus tildrakizumab, certolizumab, and ustekinumab on the PASI 100 level, as these comparisons showed 95% credible intervals (CrIs) that overlapped the null. All other comparisons versus deucravacitinib were in favour of the biologic comparator, typically an IL-17 or IL-23 inhibitor.

The ITC reported that in the midterm (at 24 weeks to 28 weeks) with 48 trials included, deucravacitinib was favoured to placebo and apremilast in attaining all levels of PASI responses at weeks 24 to 28. Compared to the rest of the treatments, there was variability in the relative effect of deucravacitinib in attaining different levels of PASI responses. No differences were found for deucravacitinib compared to ustekinumab, secukinumab, and tildrakizumab in attaining PASI 50, tildrakizumab 100 mg and 200 mg attaining PASI 75, and tildrakizumab 100 mg in attaining PASI 100. All other biologic comparators were favoured over deucravacitinib across all PASI response levels.

The sponsor-submitted ITC reported that in the long-term (at 44 weeks to 60 weeks) with 32 trials included, deucravacitinib was favoured to placebo and apremilast in attaining all levels of PASI as found at other time points. No difference was found when comparing deucravacitinib with secukinumab, ustekinumab, and the TNF alpha inhibitors included in the long term analyses, as the 95% CrI included the null. All other treatments were favoured versus deucravacitinib in attaining all levels of PASI score.

Critical Appraisal

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. Nonetheless, the sponsor-submitted ITC had several limitations including heterogeneity present for many patient and study characteristics in the NMA analyses, incorporation of studies that included patients with mild disease, discordance between the sponsor’s assumption of patient treatment adherence and true clinical practice, and lack of data for certain subgroup analyses. Given these limitations, the results from the sponsor-submitted ITC are at some risk of bias for the comparison of deucravacitinib with other treatments in patients with moderate to severe plaque psoriasis. Only 1 measure of efficacy was analyzed, and no harms or quality of life end points were available.

Other Relevant Evidence

Description of Studies

Interim data for a single-arm, open-label extension study, IM011075, was submitted by the sponsor. Patients who completed the POETYK-1 and POETYK-2 studies were eligible to enrol. 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, 48, and 60 weeks, respectively.

Efficacy Results

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.

Harms Results

AEs 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 SAE and 2% stopped treatment due to AEs. 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 SAEs. At the time of the interim analysis, 45 patients (4%) had at least a grade 2 increase in creatinine kinase levels but only 1 patient stopped treatment due to these events. No new safety signals were identified.

Critical Appraisal

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. Since only descriptive statistics were published in this interim report, which were based on observed data with no imputation for missing data, and since 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 AEs, lack of efficacy, or other reasons were excluded.

Conclusions

In adults with moderate to severe plaque psoriasis who were candidates for systemic therapy or phototherapy, deucravacitinib showed improvement versus placebo in skin and HRQoL in the short-term, with some data showing skin improvements in the intermediate term (up to 52 weeks). For most outcomes, deucravacitinib was also superior to the active comparator apremilast. However, the clinical relevance of these comparator in the Canadian context is limited. AEs were generally similar between deucravacitinib and apremilast, and no new safety signals were identified in longer-term follow-up or an ongoing extension study. Based on ITCs, deucravacitinib is less effective in producing skin improvement than several biologics established in Canada. Collection of data on long-term safety and duration of effect is ongoing. At present, it is unknown whether deucravacitinib could be combined with other treatments or whether it produces immunosuppression or expresses any of the rare AEs associated with medications that affect the Janus kinase pathway. Given that alternative treatments appear generally more effective, deucravacitinib is not expected to alter the overall treatment paradigm for psoriasis. Since response to treatments can be patient specific, patients are concerned about having treatment options and a minority may prefer to avoid injections.

Introduction

Disease Background

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.¹ It is a complex immune-mediated disorder, in which dysregulation of components of the innate and adaptive immune systems, keratinocyte function, and vascular structure contribute to the manifestations of the disease.⁹

In addition to the overt dermatological symptoms, plaque psoriasis is often associated with psychosocial symptoms, including poor self-esteem, and may affect various aspects of social functioning, including interpersonal relationships and performance at school or work. Psoriasis is associated with several comorbid conditions, including depressive symptoms, conditions associated with an increased risk of cardiovascular disease (such as type 2 diabetes, metabolic syndrome, and obesity), and psoriatic arthritis.^1-3

The severity of psoriasis may be classified as mild, moderate, or severe, based on the extent of BSA affected, with 10% or more of BSA affected generally considered more severe disease.³ However, for patients with involvement of the hands, feet, scalp, face, or genital area, or those experiencing significant physical discomfort or emotional impacts from the disease, psoriasis may also be considered severe, regardless of BSA affected.³ For most patients with moderate to severe plaque psoriasis, the disease cannot be adequately controlled with topical treatments or phototherapy alone.³

There are multiple forms of psoriasis, including plaque, guttate, inverse, pustular, and erythrodermic psoriasis, but plaque psoriasis is the most common form and represents approximately 90% of cases.⁴ It is estimated that up to 1 million people living in Canada are living with a type of psoriasis.⁴ In Ontario, the estimated the age- and sex-standardized cumulative prevalence of psoriasis in 2015 was 2.32%.¹⁰ Up to one-third of patients with psoriasis have moderate to severe disease.^11,12

Standards of Therapy

Plaque psoriasis requires lifelong treatment. Measures of treatment success include clearance (absence of signs of disease), control (satisfactory response to therapy as defined by the patient and/or physician), and remission (suppression of signs and symptoms over time). Clearance and symptom control have been identified as treatment outcomes that are important to patients, and treatment decisions depend largely on the patient’s perception of their disease.

In patients with mild psoriasis, topical treatments (such as corticosteroids, vitamin D3 analogues, retinoids, anthralin, and tars) may be sufficient to control the disease; however, for those with moderate to severe psoriasis, systemic therapies are often required.¹ Traditional systemic drugs include cyclosporine, methotrexate, and acitretin. Advanced therapy, which is usually reserved for patients who fail or are intolerant of traditional systemic therapies, includes apremilast and biologic agents. In Canada, there are several biologic drugs approved for the treatment of plaque psoriasis including the TNF alpha inhibitors (infliximab, etanercept, adalimumab, and certolizumab pegol), IL-23 inhibitors (risankizumab, guselkumab, and tildrakizumab), IL-12/23 inhibitor (ustekinumab), and IL-17 inhibitors (bimekizumab, secukinumab, ixekizumab, and brodalumab) (Table 4). According to the clinical expert consulted for this review, IL-17 and IL-23 inhibitors are now chosen more frequently by dermatologists in Canada over TNF alpha inhibitors as the first biologic for the treatment of plaque psoriasis.

Drug

Deucravacitinib is a tyrosine kinase 2 inhibitor that impedes the release of proinflammatory cytokines and chemokines.⁵ It was approved by Health Canada through the standard review process for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.⁶ It is available as a 6 mg oral tablet and the recommended dose is 6 mg daily.⁵

Deucravacitinib has not previously been reviewed by CADTH. The sponsor has requested reimbursement as per the indication.⁶

Table 4: Key Characteristics of Drugs for Moderate to Severe Plaque Psoriasis

IL = interleukin; SC = subcutaneous.

^aHealth Canada indication.

Source: Product monographs.^5,13-25

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input(s) received by CADTH have been included in the stakeholder section at the end of this report.

Two patient groups submitted a joint input. Both the CPN and CAPP are national, not-for-profit organizations that strive to improve lives of people in Canada who live with psoriasis. The CPN provides information on research and treatment options, builds awareness, and advocates about the complexity of psoriatic diseases. The CAPP’s mission is to be a resource and advocate for patients and their families to improve patient care and quality of life. A survey conducted between August and September 2022 in English and French was hosted by the CPN and distributed by both organizations’ communication channels as well as sent to clinics that conducted deucravacitinib trials in Canada. This survey collected a total 22 responses from across Canada except for 1 response, which was from outside Canada. Another survey entitled, “2022 Survey of People with Psoriatic Disease in Canada and their Caregivers” commissioned by the CPN In June 2022, collected responses (N = 809) from patients (n = 502) and their caregivers (n = 307). The patient groups received assistance from 2 medical student volunteers in developing and circulating the survey used to inform the submission.

Approximately one-third of participants from the English survey (33%; n = 3) and June 2022 survey (33%; n = 267) said that they have psoriatic arthritis. From the June 2022 survey, 445 (55%) people responded that they live with plaque psoriasis. Four (33%) and 2 (40%) patients from the English and French survey, respectively, said their severity was “moderate” (between 3% to 10% of BSA). Three (25%) and 2 (40%) patients from the English and French survey, respectively, said that their disease was “severe” (≥ 10% BSA). According to the English survey, symptoms most frequently experienced by patients were flaking and itch (79% each), skin colour change (71%), flares (64%), and pain or burning (50%). French survey respondents said flaking, itch, pain/burning (100% each) were the most frequent symptoms they experienced. The CPN’s June 2022 survey showed the most common symptoms reported by people with psoriatic disease (n = 502) were itching, burning, or painful skin (70%); silvery, scaly plaques (66%); and dry skin that may crack or bleed (58%). The English survey showed that mental health (50%; n = 6) and self-esteem (42%; n = 5) were extremely negatively impacted and social life (58%; n = 7) and finances (42%; n = 7) were moderately negatively impacted. Of the French participants, social life (80%; n = 4), ability to exercise (80%; n = 4), and sleep (80%; n = 4) were the areas of life that were negatively impacted by psoriatic disease. In the June 2022 survey, 63% of participants said their disease made quality of life worse with the most impact felt when choosing clothes to wear (54%) or having to change day-to-day life due to psoriasis (52%). In addition, the participants said they felt less confident in themselves (48%), lost sleep (47%), missed work (26%), and changed career (14%) due to psoriasis and/or psoriatic arthritis.

Regarding patients’ expectations for new medications, all English survey participants (n = 10) said “improved symptoms” and all French survey participants said “better quality of life” and “reduced side effects” (n = 3). Other responses for desirable outcomes included “affordable” (60%; n = 6, and 67%; n = 2, from the English and French surveys, respectively) and “easier to take, e.g., dosing schedule, route of administration” (40%; n = 4, and 67%; n = 2, from English and French surveys, respectively). In the June 2022 survey, participants (n = 502) identified that reducing pain (69%), reducing anxiety (64%), reducing sleep disturbances (59%), addressing side effects (51%), and improving ability to work (44%) were the outcomes most patients wished to improve. Approximately 10% of respondents to the June 2022 survey had concerns about self-injection, and people with severe psoriatic disease were concerned about the availability of treatments and/or treatment modalities that are feasible and accessible to them.

The patient group input also emphasized that management of psoriasis can be complex, partly due to varied patient response to treatments, differences in social determinants of health, lifestyle considerations, and other factors that affect one’s condition. Also, patients are worried about recurrence and resistance to therapies.

Clinician Input

Input From Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of plaque psoriasis.

Unmet Needs

The expert stated that goals of treatment are to reduce signs and symptoms of psoriasis and improve quality of life and function. Although the currently available treatments, especially the biologics, are highly effective, there is no evidence that they modify the disease pathophysiology. With available treatments, 80% to 90% of patients achieve a PASI 90 response and approximately 50% to 60% achieve a PASI 100 response. Approximately 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 are remittive and allow drug discontinuation or 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.

Place in Therapy

According to the clinical expert, deucravacitinib does not address any of the unmet needs in plaque psoriasis and the expert 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. In their opinion, many patients with moderate to severe psoriasis, including those who are needle-phobic, would prefer an injectable biologic (due to its efficacy and infrequent subcutaneous administration), over daily oral medication.

The expert noted that deucravacitinib may replace apremilast; however, apremilast has low efficacy and is infrequently used in Canada for moderate to severe psoriasis. Apremilast is not an immunosuppressant and may have a limited role in patients who need to avoid immunosuppressive medication (e.g., patient with hepatitis B), but deucravacitinib does not have this advantage.

Patient Population

Advanced therapy, such as deucravacitinib, should be reserved for patients who have failed first-line traditional systemics (methotrexate, acitretin, cyclosporine), according to the clinical expert. Evidence is needed to determine if deucravacitinib is more effective than traditional systematic therapies, such as methotrexate, and if it is effective in patients who have failed traditional systemic or biologic therapies.

The expert noted that there may be interest in using deucravacitinib in patients with mild plaque psoriasis; however, the drug is not approved for this population.

Assessing Response to Treatment

Treatment response for biologics is usually assessed at 12 weeks to 16 weeks (following the induction phase) and then at 1 year. With deucravacitinib, assessment of response may be the same or more frequent for (e.g., every 3 months) because of its efficacy. Physicians are asked to report PASI 75 response and treatment coverage may be discontinued if the patient fails to achieve a PASI 75 response. However, in practice, most physicians would assess response based on gestalt or the Physician’s Global Assessment (PGA) rather than a PASI assessment. In the expert’s experience, once a patient is approved for coverage, few actually discontinue treatment for failing to achieve PASI 75. The expert noted that PASI assessment is subjective and arbitrary, and there is no objective parameter to determine disease severity.

Both patients and physicians expect a PASI 90 response with newer treatment options and may not be satisfied with a PASI 75 response.

Discontinuing Treatment

Deucravacitinib should be discontinued if patients experience a significant adverse effect (e.g., hypersensitivity, serious infection). In addition, the expert stated that deucravacitinib should be discontinued if it fails to provide at least a PASI 75 response. However, the expert noted that once coverage is provided, the drug is often not discontinued even if the response is suboptimal because having some improvement is better than none. Patients who fail deucravacitinib may be treated with biologics that have shown high response rates, but some patients who do not want biologic therapy may elect to stay with deucravacitinib even though the response is suboptimal.

Prescribing Conditions

Advanced treatment such as deucravacitinib should be prescribed by dermatologists, as in the case with the biologics. This is to ensure that the prescriber can diagnose moderate to severe psoriasis and has good knowledge of the treatment paradigm.

Additional Considerations

Deucravacitinib works through the Janus kinase pathway, and it is unclear if it has the same safety concerns as the Janus kinase inhibitors. It has only been studied in patients with psoriasis in the clinical trial setting and the results may not be extrapolated to a wider population that may include vulnerable patients. It is not known if deucravacitinib would induce immunosuppression.

Clinician Group Input

No input was received from clinician groups.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; pCPA = pan-Canadian Pharmaceutical Alliance; RB = restricted benefit.

Clinical Evidence

The clinical evidence included in the review of deucravacitinib is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension (LTE) studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of deucravacitinib 6 mg oral tablet for the treatment of adults with moderate to severe plaque psoriasis who are candidate for systemic therapy or phototherapy.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 6: Inclusion Criteria for the Systematic Review

AE = adverse event; BSA = body surface area; DLQI = Dermatology Life Quality Index; HRQoL = health-related quality of life; MACE = major adverse cardiovascular events; PASI = Psoriasis Area and Severity Index; RCT = randomized controlled trial; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; TNF = tumour necrosis factor; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁶

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was deucravacitinib. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on October 26, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on February 23, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²⁷ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 2 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 7: Details of Included Studies

BSA = body surface area; CV = cardiovascular; DB = double blind; DLQI = Dermatology Life Quality Index; EQ-5D-3L = 3-Level EQ-5D; HADS = Hospital Anxiety and Depression Scale; mNAPSI = modified mail psoriasis severity index; NA = not applicable; PASI = Psoriasis Area and Severity Index score; PASI 50 = 50% reduction in Psoriasis Area and Severity Index score;; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PASI 90 = 90% reduction in Psoriasis Area and Severity Index score; PASI 100 = 100% reduction in Psoriasis Area and Severity Index score; PGA = Physician’s Global Assessment; pp-PASI = palmoplantar Psoriasis Area and Severity Index; PGI-C = Patient’s Global Impression of Change; PSSD = Psoriasis Symptoms and Signs Diary; PSSI = Psoriasis Scalp Severity Index; RCT = randomized controlled trial. SF-36 PCS and MCS = Short Form (36) Health Survey Physical Component Score and Mental Component Score; sPGA = static Physician’s Global Assessment; TB = tuberculosis; VAS = visual analogue scale; WLQ = Work Limitations Questionnaire.

Note: Three additional reports were included (FDA Multidisciplinary Review,³⁰ Armstrong et al. [2022],²⁸ and Strober et al. [2022]²⁹).

^aIf the patients switched to placebo at week 24 experienced a relapse (defined as at least a 50% loss of week 24 PASI percent improvement from baseline at any visit) they were switched to deucravacitinib 6 mg daily.

^bFour-week follow-up period for patients who did not enter the long-term extension study.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2⁸.

Description of Studies

Two 52-week double-blind RCTs met the inclusion criteria for the systematic review. The POETYK-1 study (N = 666) used a parallel study design (Figure 2) and the POETYK-2 study (N = 1,020) used a parallel study design followed by a randomized withdrawal design for responders at week 24 (Figure 3).

The objectives of the pivotal studies were to evaluate the safety and efficacy of deucravacitinib versus placebo and apremilast in adults with moderate to severe plaque psoriasis. Both studies randomized eligible patients (2:1:1) to deucravacitinib 6 mg daily, apremilast 30 mg twice daily, or placebo using a central interactive response technology system and stratified computer-generated randomization schedule. The POETYK-1 study was stratified by geographic region (US, Japan, China, and rest of world), previous biologic use for psoriasis, psoriatic arthritis, or other diseases (yes or no), and body weight (≥ 90 kg and < 90 kg for patients enrolled from all countries except China and Japan). The POETYK-2 study was stratified by geographic region (US and rest of world), previous biologic use for psoriasis, psoriatic arthritis, or other diseases (yes or no), and body weight (≥ 90 kg and < 90 kg).

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 that did not show an adequate response to therapy (i.e., did not achieve a PASI 50 response in the POETYK-1 study or PASI 75 in the POETYK-2 study). At week 24 in the POETYK-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 met the sPGA response and PASI 75 response criteria at week 16 compared with placebo. 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-2 study also evaluated the time to relapse among patients in the deucravacitinib group that achieved a PASI 75 response at week 24.

The trials included sites from Canada (11 sites in POETYK-1; 15 sites in POETYK-2), US, and Europe. The POETYK-1 study also included sites in Asia, and the POETYK-2 study included sites from Israel, New Zealand, and Australia.

At the end of the pivotal studies, patients were eligible to enter the LTE study (IM011075) and receive open-label deucravacitinib.

Populations

Inclusion and Exclusion Criteria

The POETYK-1 and POETYK-2 studies enrolled adults (≥ 18 years) who had moderate to severe plaque psoriasis that was stable (defined as no morphology changes or significant flares) for at least 6 months and who were candidates for systemic psoriasis therapy and/or phototherapy. Patients were required to have a baseline PASI score of 12 or higher, with greater than 10% of BSA affected, and with a sPGA score of at least 3 on a 5-point scale.

Patients with prior exposure to deucravacitinib or apremilast were excluded from the study, but prior exposure to biologic, or nonbiologic systemic or topical therapies for psoriasis were permitted provided the patient had undergone the protocol-specified washout period before enrolment. Other exclusion criteria included patients with nonplaque forms of psoriasis, with active chronic infection, or unstable cardiovascular, neuropsychiatric, or other medical conditions (Table 7).

Figure 2: Study Schematic of POETYK-1

BID = twice daily; OLE = open-label extension; PASI 50 = 50% reduction in Psoriasis Area and Severity Index score; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; QD = daily; sPGA = static Physician’s Global Assessment.

*Apremilast is titrated from 10 mg QD to 30 mg BID over the first 5 days of dosing.

††Patients in the apremilast group who did not achieve PASI 50 response at week 24 were switched in a blinded fashion to deucravacitinib.

Source: Clinical Study Report for POETYK-1.⁷

Figure 3: Study Schematic of POETYK-2

BID = twice daily; OLE = open-label extension; PASI 50 = 50% reduction in Psoriasis Area and Severity Index score; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; QD = daily; sPGA = static Physician’s Global Assessment.

† Upon relapse (at least a 50% loss of week 24 PASI percent improvement from baseline), subjects were switched to deucravacitinib 6 mg QD.

* Apremilast was titrated from 10 mg QD to 30 mg BID over the first 5 days of dosing.

Source: Clinical Study Report for POETYK-2.⁸

Baseline Characteristics

In general, the baseline characteristics of patients enrolled in the POETYK-1 and POETYK-2 studies were similar between groups within trials. The mean age of patients enrolled in the pivotal trials ranged from 44.7 years (SD = 12.1) to 47.9 (SD = 14.0) per treatment group. The majority of patients were men (62% to 71%), and the minority were women (29% to 38% per treatment group). Most patients were white (77% to 93%), with fewer patients who were Asian (3% to 21%) or Black (1% to 4%). 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%). Between 34% and 45% of patients per treatment group had received prior phototherapy (Table 8).

Table 8: Summary of Baseline Characteristics — POETYK-1 and POETYK-2 (FAS)

APREM = apremilast; BMI = body mass index; BSA = body surface area; DEUC = deucravacitinib; DLQI = Dermatology Life Quality Index; FAS = full analysis set; PASI = Psoriasis Area and Severity Index; SD = standard deviation; sPGA = static Physician’s Global Assessment.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Interventions

Patients enrolled in the POETYK-1 and POETYK-2 studies were randomized to deucravacitinib 6 mg daily, apremilast 30 mg twice daily, or placebo. Blinding was maintained using double-dummy methods with placebo tablets that were identical to deucravacitinib and apremilast. Apremilast was titrated up to 30 mg twice daily over 5 days, starting with 10 mg daily on day 1. Patients receiving placebo also received a placebo titration kit to match the apremilast regimen.

In both studies, patients in the placebo groups were switched to blinded deucravacitinib 6 mg daily at week 16.

In the POETYK-1 study, patients in the deucravacitinib group remained on this therapy for the full 52 weeks, regardless of treatment response. Patients in the apremilast group who did not achieve at least a PASI 50 response at week 24 were switched to blinded deucravacitinib 6 mg daily and those who met the PASI 50 response criteria remained on apremilast until week 52.

In the POETYK-2 study, patients randomized to deucravacitinib who met the PASI 75 response criteria at week 24 were rerandomized to either remain on deucravacitinib or switch to blinded placebo. Also, patients in the apremilast group who met the PASI 75 response criteria at week 24 were switched to blinded placebo. Any patients in the deucravacitinib or apremilast groups who did not meet the PASI 75 response criteria at week 24 received blinded deucravacitinib 6 mg daily from week 24 to week 52. Among patients switched from active treatment to placebo, those who experienced a relapse received blinded deucravacitinib for the rest of the 52 week period.

There was no protocol provision for dose adjustments of study treatments. Treatment could be resumed after interruption for an AE with consultation with the sponsor.

In both studies, patients were prohibited from receiving any strong cytochrome P450 inducers as per the US apremilast product monograph (e.g., rifampin, phenobarbital, carbamazepine, phenytoin), live vaccines, any drugs that may worsen psoriasis (e.g., lithium, antimalarial drugs, propranolol, indomethacin), opioid analgesics, phototherapy, biologic medications, oral psoriasis medications, oral corticosteroids, or topical medications or medicated shampoos that may affect the evaluation of psoriasis (e.g., corticosteroids, vitamin D derivatives, or salicylic acid). In both studies, patients with an sPGA score or scalp severity Physician’s Global Assessment (ss-PGA) score of 3 or higher at week 24 were eligible to start restricted topical therapies or shampoos at the investigator’s discretion. These topical treatments included high potency corticosteroids (Classes I to V), greater than 3% salicylic acid, urea, alpha- or beta-hydroxy acids, anthralin, calcipotriene, vitamin D derivatives, retinoids, or tazarotene.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are further summarized in the following. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

DLQI = Dermatology Life Quality Index; EQ-5D-3L = 3-Level EQ-5D; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PASI 90 = 90% reduction in Psoriasis Area and Severity Index score; PASI 100 = 100% reduction in Psoriasis Area and Severity Index score; PGA-F = Physician’s Global Assessment–Fingernail; PSSD = Psoriasis Symptoms and Signs Diary; SF-36 PCS and MCS = Short Form (36) Health Survey Physical Component Score and Mental Component Score; sPGA = static Physician’s Global Assessment; ss-PGA = scalp severity Physician’s Global Assessment; VAS = visual analogue scale.

^aWith at least a 2-point improvement from baseline.

^bIn the subgroup of patients with a baseline ss-PGA or PGA-F score of at least 3.

^cIn the subgroup of patients with a baseline PSSD score of at least 1.

^dAnalyzed in patients with a baseline DLQI score of at least 2.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Efficacy assessments were conducted by dermatologists or trained investigators who were experienced in the assessment of patients with psoriasis. Where possible, the same investigator conducted all assessments for a given patient. Outcome assessors underwent training provided by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

Both trials were conducted during the COVID-19 pandemic, which disrupted some study visits and assessments due to site closures and concerns for risk of COVID-19. In the POETYK-1 study, 30 patients had 50 visits impacted, including 25 patients with visits not performed and 5 patients with visits performed virtually. All disruptions occurred after week 24 and only 1 patient had missing data due to COVID-19 at week 52. In the POETYK-2 study, disruptions occurred at the week 20 visit or later and affected 51 patients and 88 visits (45 patients with missed visits and 6 with remote visits). Ten patients missed the week 24 visit (including 2 who had stopped study drug) and 6 patients missed the week 52 visit. The Clinical Study Reports state the disruptions did not affect efficacy outcomes up to week 16 and had a minor impact for outcomes assessed at subsequent time points.

Psoriasis Area and Severity Index

The PASI is widely used in psoriasis trials to grade the extent and severity of psoriatic lesions. It combines an assessment of the BSA affected in 4 anatomic regions (head, trunk, arms, and legs) and the severity of desquamation, erythema, and plaque induration or infiltration (thickness) in each region. Scores range from 0 to 72 points. The percent improvement in PASI score is calculated as the baseline PASI score minus postbaseline PASI score, divided by baseline PASI score, multiplied by 100. Patients with a 50%, 75%, 90%, or 100% improvement are categorized as achieving a PASI 50, PASI 75, PASI 90, or PASI 100 response. PASI scores have shown weak to moderate correlation with DLQI scores and good interrater and moderate intrarater reliability.^31,32 Responsiveness may be weak, especially when the BSA affected is less than 10%.^33,34

A reduction of PASI score by 75% (PASI 75) is a benchmark in psoriasis clinical trials,³⁵ while more aggressive treatment goals such as reduction of PASI scores by 90% or 100% (total clearance) are also used as end points in psoriasis clinical trials.^36,37

Static Physician’s Global Assessment

The sPGA is a composite score of the physician’s assessment of the overall severity of the patient’s psoriatic lesions at a given point of time. The investigator assessed the overall severity of psoriasis based on erythema, scaling, and induration, using a 5-point scale, described as clear (0), almost clear (1), mild (2), moderate (3), or severe (4). The scores are then averaged, with equal weights for each item, to obtain a single score. The sPGA has shown moderate correlation with DLQI, and strong correlation with PASI scores.^38,39 The sPGA has shown acceptable test-retest reliability,³⁸ but no information on responsiveness was found.

In both studies, the coprimary outcome of sPGA response was defined as a sPGA score of “clear” or “almost clear” (i.e., 0 or 1), with at least a 2-category improvement from baseline, which is generally accepted as a clinically meaningful score.^40,41

The same scale and responder definition was used for separate analyses in the subgroup of patients with fingernail psoriasis who had a baseline Physician’s Global Assessment–Fingernail score of at least 3.⁷ In patients with scalp psoriasis at baseline, ss-PGA was rated on a 5-point scale; absence of disease (0), very mild (1), mild (2), moderate (3), and severe disease (4). The same responder definition was applied to patients with scalp psoriasis.⁷

Time to Relapse

In the POETYK-2 study, disease relapse was defined as at least a 50% loss of week 24 PASI percent improvement from baseline among patients who had achieved at least a PASI 75 response at week 24.

Psoriasis Symptoms and Signs Diary

The PSSD is a patient-reported 11-item instrument used to assess the severity of symptoms and signs associated with plaque psoriasis. It includes 5 symptoms (itch, pain stinging, burning, and skin tightness) and 6 signs (skin dryness, cracking, scaling, shedding or flaking, redness, and bleeding) which are assessed on a 0 (absent) to 10 (worst imaginable) scale over the past 24 hours. The symptom score, the signs score, and the total score are the average of the relevant item scores multiplied by 10 and range from 0 (absence of symptoms or signs) to 100 (most severe). In both studies, patients completed the PSSD each day using and eDiary and scores were averaged over at least 4 of the past 7 days. The PSSD has shown acceptable convergent validity, internal consistency, and test-retest reliability.^42,43 Estimates for the minimal important difference (MID) of the PSSD total score range from 9 to 12 using anchor-based methods and 5.7 to 13.1 using distribution-based methods.⁴³ No MID was identified for the PSSD symptom score based on the 24-hour recall version, but a 9.1 point MID was reported for the 7-day recall version of the questionnaire.⁴³

Health-Related Quality of Life

The DLQI is a dermatology-specific questionnaire that has been used to assess the impact of the disease on a patient’s 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. Each item is scored on a 4-point Likert scale: 0 (not at all affected or not relevant), 1 (a little affected), 2 (a lot affected), and 3 (very much affected). The overall DLQI score is a numeric score between 0 to 30, with lower scores indicating better quality of life. The final numeric score translates to the effect of the patient’s disease on their quality of life, where 0 to 1 = no effect, 2 to 5 = small effect, 6 to 10 = moderate effect, 11 to 20 = very large effect, and 21 to 30 = extremely large effect.⁴⁴ The DLQI has shown strong correlation with the EQ-5D index score and the bodily pain and social functioning domains of the Short Form (36) Health Survey (SF-36).⁴⁵ It may, however, lack conceptual validity for the psychological impact of psoriasis. There is evidence of responsiveness and test-retest reliability.^45,46 Estimates of the MID range from 2.2 to 6.9.^45,47,48

The 3-Level EQ-5D questionnaire is a generic, preference-based, HRQoL measure. It includes 5 dimensions: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Each dimension is divided into 3 levels representing “no problems,” “some problems,” and “extreme problems” (1, 2, and 3, respectively). The 5 questions are scored and together contribute to the EQ-5D index (utility) score between 0 and 1, where 0 represents death, and 1 represents perfect health. Different utility functions are available that reflect the preferences of specific populations (e.g., US, UK). The EQ-5D also includes a visual analogue scale (VAS) of the patient’s self-rated health status on a vertical 20 cm scale that ranges from 0 (worst imaginable health status) to 100 (best imaginable health status). In patients with psoriasis, MID estimates for the VAS range from 3.82 to 8.43 based on PASI improvement and PGA score and was 10.34 based on distributional methods.⁴⁵

The SF-36 is a 36-item, general health status instrument that consists of 8 health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The SF-36 also provides 2 component summaries, the Physical Component Score (PCS) and the Mental Component Score (MCS), derived from aggregating the 8 domains according to a scoring algorithm. All domain and component scores are based on a scale of 0 to 100, with higher scores indicating higher health status. An MID of at least 3 points for the SF-36 PCS or MCS has been reported in the literature.^49,50

Harms

Data were collected on treatment-emergent AEs, SAEs, AEs leading to treatment discontinuation, and deaths, including events that occurred up to 30 days after the last dose of study drug. Safety data beyond the 16-week placebo-controlled period were reported using exposure-adjusted incidence rates (IR) per 100 patient-years (PYs) that took into consideration switches between treatments. In addition, the studies’ protocols identified specific AEs of special interest (infection, malignancy, skin-related AEs, and creatine kinase elevation) as well as specific events that were adjudicated by independent external blinded evaluators (cardiovascular events, infections, and suicidal ideation or behaviour). The infections of interest were selected based on the immunomodulatory mechanism of action of deucravacitinib and included herpes zoster, influenza, opportunistic infections, and tuberculosis.

Statistical Analysis

Statistical Models

In both studies, the coprimary outcomes (proportion of patients with sPGA score of 0 or 1, and PASI 75 response at week 16 versus placebo) were tested using a stratified Cochran-Mantel-Haenszel test, which was stratified by the factors used a randomization (geographic region, prior biologic use, and body weight). If expected cell counts were insufficient for each strata, then strata levels were combined. Nonresponder imputation was used for patients who prematurely discontinued the study or the study drug, or those with missing outcome data at that time point (i.e., analyzed as not having met the response criteria). The Clinical Study Report states that this represents an implicit composite estimand analysis strategy. Sensitivity analyses for the coprimary outcomes are listed in Table 10.

Other binary end points were analyzed using the same methods as the primary end points. Continuous end points were analyzed using an analysis of covariance model that included the baseline value and stratification factors. Baseline observation carried forward was used for patients who discontinued the study treatment due to lack of efficacy or AEs, otherwise the last observation was carried forward for other missing data. In the POETYK-1 study, patients in the apremilast group who did not achieve a PASI 50 response at week 24 were considered to be nonresponders for binary end points or had baseline observation carried forward for continuous end points that were analyzed for later time points.

The time to relapse between week 24 and week 52 was reported in the POETYK-2 study for the patients in the deucravacitinib group (who were rerandomized to placebo or deucravacitinib) and patients in the apremilast group (who remained on apremilast) that achieved a PASI 75 response at week 24. The Kaplan-Meier product limit method was used to generate the survival curves, with the difference between deucravacitinib and placebo tested using a stratified log-rank test. Patients who discontinued the study or treatment, had missing data, and did not have relapse by week 52 were censored and the date they experienced these criteria.

Table 10: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; BOCF = baseline observation carried forward; FAS = full analysis set; GEE = general estimating equation; LOCF = last observation carried forward; MMRM = mixed effect model with repeated measures; NRI = nonresponder imputation; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; sPGA = static Physician’s Global Assessment.

^aNonresponder imputation for patients who discontinued the treatment or the study before that time point or had missing data for any reason at that time point.

^bThe baseline value was carried forward for patients who discontinued study treatment for all time points after discontinuation due to lack of efficacy or adverse events. Patients who stopped study drug for other reasons or had missing data at the time point of comparison had the last valid observation carried forward. Patients with missing baseline values were excluded from the change from baseline analyses.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Statistical Power

Both studies were estimated to have greater than 99% power to detect superiority (2-sided significance level of 0.05) of deucravacitinib versus placebo for each of the coprimary outcomes, based on a planned enrolment of 600 patients (300 to deucravacitinib and 150 each to placebo and apremilast groups) for the POETYK-1 study and 1,000 patients (500 to deucravacitinib, and 250 each to placebo and apremilast) for the POETYK-2 study. These calculations assumed response rates for PASI 75 and sPGA response at week 16 of 60% for deucravacitinib, 35% for apremilast, and 10% for placebo, based on deucravacitinib data from a phase II study (Bristol Myers Squibb study IM011011), and published response rates for placebo and apremilast. Based on a 2-sided chi-square test with an alpha of 0.025, the trials also had greater than 99% power to detect superiority versus apremilast for both coprimary end points at week 16.

Control of Type I Error Rate

The trials used a similar hierarchical testing procedure to control for the family-wise type I error rate. The coprimary outcomes were tested first at an alpha of 0.05 and if both achieved statistical significance, then the key secondary outcomes were tested in the order listed in Table 11. Two independent fixed-sequence testing branches that compared deucravacitinib to placebo, and to apremilast, proceeded with a 2-sided alpha of 0.025 for each branch. The testing of each branch could proceed only if the prior outcome in the sequence achieved statistical significance. If an outcome failed, then any subsequent outcomes were considered descriptive. Of note, there were 2 testing hierarchies, 1 for the US submission and 1 for submissions to other regulators. For the POETYK-1 study, the DLQI responder outcome was included the global testing procedure but not the US, and in the POETYK-2 study the DLQI responder and time to relapse outcomes were included the global procedure only. For any other outcomes not listed in Table 11, the P values reported are nominal.

Table 11: Statistical Testing Order

DLQI = Dermatology Life Quality Index; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PASI 90 = 90% reduction in Psoriasis Area and Severity Index score; PASI 100 = 100% reduction in Psoriasis Area and Severity Index score; PGA-F = Physician’s Global Assessment–Fingernail; PSSD = Psoriasis Symptoms and Signs Diary; sPGA = static Physician’s Global Assessment; ss-PGA = scalp severity Physician’s Global Assessment.

^aAmong patients with baseline score ≥ 3 points.

^bAmong patients with baseline PSSD symptom score ≥ 1.

^cAmong patients with baseline DLQI score ≥ 2 points.

^dThis outcome was controlled for type I error rate in the global testing hierarchy, but not in the US-based testing procedure.

^eAmong patients who initially randomized to deucravacitinib who achieved PASI 75 response at week 24.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Adverse Events

AE data were presented as the number and percentage of patients with an event, with events counted only once per patient for recurring AEs within each system organ class (SOC) or preferred term, starting with the first dispensation date within a period in the as-treated population. Due to the treatment switches that occurred after week 16, AEs for the total study period were reporting using the exposure-adjusted IR. The exposure-adjusted IR was calculated by multiplying the total number of patients with an AE divided by the sum of exposure time for that AE under each treatment that patients were exposed to, multiplied by 100 and 365. Individual patient’s exposure time was calculated separately for each treatment a patient received (if the patient switched therapy) based on that treatment’s start date until the first occurrence of that AE (for patients with an event) or until the treatment stop date (for patients with no events and who continued into the extension study), or the treatment stop date plus 30 days (for patients with no events who completed the safety follow-up period).

Subgroup Analyses

Both studies conducted several preplanned subgroup analyses for the coprimary outcomes. Of these, the analyses based on prior biologic use (yes or no) were of interest to this systematic review. Other planned subgroups included gender, age category, race, body weight categories, and geographic region. These subgroup analyses were conducted using the same methods as the primary end point analyses.

Analysis Populations

In the POETYK-1 and POETYK-2 studies, efficacy analyses were based on the full analysis set that included all patients randomized, who were analyzed according to the treatment groups assigned at randomization. The as-treated (i.e., safety) population included all randomized patients who took at least 1 dose of study drug and who were analyzed according to the drug received.

Of note, patients with missing data due to COVID-19 at week 24 or 52 were excluded from the analyses.

Protocol Amendments

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Results

Patient Disposition

A total of 965 patients were screened for inclusion in the POETYK-1 study, of which 666 patients (69%) were randomized (Table 12). During the first 16 weeks of the trial, 8%, 12%, and 14% of patients in the deucravacitinib, placebo, and apremilast groups, respectively, discontinued study treatment. Between week 16 and 24, 2% to 3% of patients per group stopped treatment (Table 13). From week 24 to 52, another 11% of patients randomized to deucravacitinib stopped treatment, as did 8% of the patients switched from placebo to deucravacitinib, 5% of the responders who continued apremilast, and 13% of nonresponders who switched from apremilast to deucravacitinib (Table 14).

In the POETYK-2 study, 1,519 patients were screened, and 1,020 patients were randomized (67%). The proportion of patients who stopped treatment during the first 16 weeks was 11%, 17%, and 15% in the deucravacitinib, placebo, and apremilast groups, respectively (Table 15). Between week 16 and 24, 4% of patients per group stopped treatment (Table 16). Among PASI 75 responders who had received deucravacitinib throughout the study, 7% stopped treatment between week 24 and 52, compared with 11% of responders who switched from deucravacitinib to placebo, and 16% of responders to apremilast who were switched to placebo (Table 17). Among PASI nonresponders at week 24, 12% of those who remained on deucravacitinib and 18% who were switched from apremilast to deucravacitinib, stopped treatment between week 24 and 52, as did 11% of patients who initially received placebo and were switched to deucravacitinib at week 16. The reasons for discontinuation as well as the number of patients switched between treatments at week 16 and 24 are listed in Table 16 and Table 17.

|| ||| |||||||| |||||| | |||||||| |||||||||||| ||||| ||||||||| ||| || |||||||||||||||| ||||||| || |||| |||||||||||||||| | |||| |||||||| ||| | |||| |||||||||| |||||||| ||| || ||||| |||||||| ||||||| |||| || ||| ||| || |||||||| |||||||||||| ||||| ||||||||| ||| || || ||||||| ||||| || ||||||||| || ||||||||| | ||||| ||| || |||||||| |||||||||||| ||| ||||| |||| ||| || |||||||| |||||||||||||||| || ||||||||| ||||||| | ||||||||| ||| |||||||||| | |||||||| ||| |||| |||||| || |||||| ||||| |||||| ||| |||||||||| |||||||||| || ||||||| || |||||||||| || ||||||| ||||| || |||||||| || |||||||||| ||||| || ||| |||||||| |||||||||||| ||||||| |||| || ||| ||| ||| || |||||||| |||||||||||| ||||||| |||| || ||| |||.

Table 12: Patient Disposition — POETYK-1 (Screening to Week 16)

APREM = apremilast; DEUC = deucravacitinib; FAS = full analysis set; PBO = placebo.

||||| |||||| ||||||| ||| ||||||||| ||||||| |||| ||| |||||||| ||| ||| |||| ||||||| |||||||| ||||||||| |||||||| |||||| |||| || ||||| || ||| ||||||||| |||||||| || |||||||| |||| |||| || ||||||||||||||||||| ||||||| ||||||| || ||| ||||||||| |||||| |.

^bOne patient in the placebo group was not treated. ||| ||||||| |||||||||||| ||| ||||| |||||| ||| ||||| || ||||||||| ||| || ||||||||| ||||||||||||| |||||| ||| ||| |||| ||||||||| |||||||| ||| |||| ||| |||| ||||||||.

Source: Clinical Study Report for POETYK-1.⁷

Table 13: Patient Disposition — POETYK-1 (Week 16 to Week 24)

APREM = apremilast; DEUC = deucravacitinib; PBO = placebo.

^aAt week 16, all patients in the placebo group switched to deucravacitinib 6 mg daily until week 52.

Source: Clinical Study Report for POETYK-1.⁷

Table 14: Patient Disposition — POETYK-1 (Week 24 to Week 52)

APREM = apremilast; DEUC = deucravacitinib; PASI 50 = 50% reduction in Psoriasis Area Activity Index score; PBO = placebo.

^aAt week 16 all patients randomized to the placebo group switched to deucravacitinib 6 mg daily until week 52.

^bAt week 24, patients randomized to the apremilast group who met the PASI 50 response criteria continued to receive apremilast until week 52. Those who did not achieve a PASI 50 response were switched to deucravacitinib 6 mg daily.

Source: Clinical Study Report for POETYK-1.⁷

Table 15: Patient Disposition — POETYK-2 (Screening to Week 16)

APREM = apremilast; DEUC = deucravacitinib; FAS = full analysis set; PBO = placebo; PP = per protocol.

||||| |||||| |||||| ||| ||||||||| ||||||| |||| ||| |||||||| ||| ||| |||| ||||||| |||||||| ||||||||| |||||||| |||||| |||| || ||||| || ||| ||||||||| |||||||| || |||||||| |||| |||| || ||||||||| || |||||| |||| |||||||||||| ||| |||||||||| |||||||||| || ||||||||||| |.

^bOne patient was not treated.

Source: Clinical Study Report for POETYK-2.⁸

Table 16: Patient Disposition — POETYK-2 (Week 16 to Week 24)

APREM = apremilast; DEUC = deucravacitinib; PBO = placebo.

^aAt week 16, all patients in the placebo group switched to deucravacitinib 6 mg daily until week 52.

Source: Clinical Study Report for POETYK-2.⁸

Table 17: Patient Disposition — POETYK-2 (Week 24 to Week 52)

APREM = apremilast; DEUC = deucravacitinib; PASI 75 = 75% reduction in Psoriasis Area Activity Index score; PBO = placebo.

^aAt week 24, patients randomized to the deucravacitinib group who achieved a PASI 75 response were rerandomized to deucravacitinib or placebo. Patients who did not achieve PASI 75 response remained on deucravacitinib 6 mg daily until week 52.

^bAt week 16 all patients in the placebo group switched to deucravacitinib 6 mg daily until week 52.

^cAt week 24, patients randomized to the apremilast group who met the PASI 75 response criteria were switched to placebo. Patients who did not achieve PASI 75 response were switched to deucravacitinib 6 mg daily until week 52.

Source: Clinical Study Report for POETYK-2.⁸

Exposure to Study Treatments

|||||| ||| ||||| || ||||| || ||| ||||||| ||||||| ||| |||||| |||||||| || |||||||| ||| ||| |||| ||| ||| ||||||||| ||||||| |||| || ||||||| ||||||||| |||||||| ||||||| |||| | ||| || | ||||||| || ||| |||| | ||. Across the 52-week study period and including treatment switches, the total PYs of exposure was 419.1 and 549.9 PYs for deucravacitinib, 46.9 and 194.0 PYs for placebo, and 115.8 and 105.3 PY for apremilast in the POETYK-1 and POETYK-2 studies, respectively.

|| ||| |||||||| |||||| || |||||||| ||| ||||||||| ||||||||||| ||||||| |||| || ||| || ||| || ||||||||| |||| ||||||||||||| ||||||| ||||||| | ||| || ||||| || ||||||||| || |||||||| ||| ||||||||| ||||||||||| ||| || ||||||||| ||| ||||||||||||| |||||||| ||||| |||| ||| |||| |||| ||||||| |||| || ||| ||| ||| |||||||| || |||||||||||| |||||| |||| | |||| || || |||||.

Table 18: Duration of Exposure to Study Drug — POETYK-1 and POETYK-2 (Safety Population)

APREM = apremilast; DEUC = deucravacitinib; PBO = placebo; SD = standard deviation.

^aIncludes all patients who received DEUC at any time during the 52 week study period.

^bIncludes patients initially randomized to PBO and those switched from active treatment to PBO at week 24.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the following. Refer to Appendix 3 for detailed efficacy data.

Skin Clearance and Psoriasis Scores

Induction Therapy

In the POETYK-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 (with at least a 2-point decrease from baseline) at week 16. The between-group differences favoured deucravacitinib versus placebo (RD = 46.7%; 95% 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) (Table 19).

The proportion of patients who met sPGA 0 or 1 response criteria at week 16 was 49.5%, 8.6%, and 33.9% in the deucravacitinib, placebo, and apremilast groups, respectively, in the POETYK-2 study. The between-group RD 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.

For both studies, the results for the proportion of patients with an sPGA score of 0 at week 16 also favoured deucravacitinib versus placebo and versus apremilast, with P values below the testing boundary (Table 19).

Data on the PASI response at week 16 are reported in Table 20. In the POETYK-1 study, 58.4%, 12.7%, and 35.1% of patients achieved PASI 75 response at week 16 in the deucravacitinib, placebo, and apremilast groups, respectively, with a RD 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-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 RD 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 responders was higher for deucravacitinib versus apremilast, this comparison was not controlled for type I error rate.

In both studies the results of the sensitivity analyses for the coprimary end points showed results that were supportive of the primary efficacy analyses. The subgroup analyses also reported sPGA 0 or 1 and PASI 75 response results that were consistent for patients based on prior biologic therapy (yes or no), prior systemic therapy (yes or no), baseline sPGA score (moderate or severe), and baseline PASI score (≤ 20 or > 20) (Appendix 3, Table 39, and Table 40).

Both studies reported 16-week response data for the subgroup of patients that had moderate to severe scalp or fingernail psoriasis at baseline. Approximately two-thirds of patients enrolled had scalp psoriasis at baseline (60% to 73% per treatment group), with only 10% to 20% of patients reporting fingernail psoriasis at the start of the trials. Among those with scalp psoriasis, the proportion of responders who achieved an ss-PGA score of 0 or 1 at week 16 favoured deucravacitinib versus placebo in the POETYK-1 study (RD = 52.8%; 95% CI, 43.7% to 62.0%) and the POETYK-2 study (RD = 42.3%; 95% CI, 34.3% to 50.3%), both with P values of less than 0.0001. The 16-week differences also favoured deucravacitinib versus apremilast in both studies with a P value of less than 0.0001 (POETYK-1: RD = 29.6%; 95% CI, 18.7% to 40.6%; POETYK-2: RD = 23.5%; 95% CI, 14.3% to 32.6%) (Appendix 3, Table 41). Neither study detected a difference between deucravacitinib and placebo or apremilast in the proportion of patients who achieved a Physician’s Global Assessment–Fingernail score of 0 or 1 at week 16.

The POETYK-1 and POETYK-2 studies reported the proportion of patients who achieved a sPGA 0 or 1, PASI 75, or PASI 90 response at week 24 in the deucravacitinib versus apremilast groups. All comparisons favoured deucravacitinib versus apremilast with absolute differences of 20.4% to 27.5% for an sPGA 0 or 1 response, 21.1% to 31.0% for PASI 75, and 13.0% to 20.0% for PASI 90 response at week 24, (all comparisons with a P value of less than 0.0001). Full details are shown in Appendix 3, Table 42.

Table 19: sPGA Response at Week 16 — POETYK-1 and POETYK-2 (FAS)

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; NA = not applicable; OR = odds ratio; PBO = placebo; RD = risk difference; sPGA = static Physician’s Global Assessment; vs. = versus.

Note: For the coprimary end point (sPGA 0 or 1) in the POETYK-1 study, 8%, 13%, and 13% of patients in the DEUC, PBO, and APREM groups, respectively, had stopped treatment or had missing data at week 16 and had data imputed as nonresponders. In POETYK-2 study, 11%, 16%, and 14% of patients in the DEUC, PBO, and APREM groups, respectively, had data imputed.

^aCochran-Mantel-Haenszel test stratified by geographic region, body weight, and prior biologic use. Nonresponder imputation for missing data.

^bPatients must also have at least a 2-point improvement in their sPGA score vs. baseline.

^cTested using a 2-sided alpha of 0.025.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Table 20: PASI Response at Week 16 — POETYK-1 and POETYK-2 (FAS)

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; NA = not applicable; OR = odds ratio; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PASI 90 = 90% reduction in Psoriasis Area and Severity Index score; PASI 100 = 100% reduction in Psoriasis Area and Severity Index score; PBO = placebo; RD = risk difference; vs. = versus.

Note: For the coprimary end point (PASI 75) in the POETYK-1 study, 8%, 13%, and 13% of patients in the DEUC, PBO, and APREM groups, respectively, had stopped treatment or had missing data at week 16 and had data imputed as nonresponders. In POETYK-2 study, 11%, 16%, and 14% of patients in the DEUC, PBO, and APREM groups, respectively, had data imputed.

^aCochran-Mantel-Haenszel test stratified by geographic region, body weight, and prior biologic use. Nonresponder imputation for missing data.

^bTested using a 2-sided alpha of 0.025.

^cP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Maintenance Therapy

In the POETYK-1 study, patients in the apremilast group who achieved at least a PASI 50 response at week 24 continued to receive apremilast until week 52, whereas patients randomized to deucravacitinib remained on this therapy until week 52, regardless of the 24-week treatment response. Maintenance of treatment response was analyzed based on the proportion of patients who achieved an sPGA 0 or 1 response, PASI 75, or PASI 90 response at week 24 and week 52 in the full analysis set (i.e., intention-to-treat population with nonresponder imputation for patients with missing data or who had stopped the study drug) (Table 21). The proportion of patients who maintained sPGA 0 or 1 response favoured deucravacitinib (45.5%) versus apremilast (22.2%) with an absolute difference of 23.0% (95% CI, 14.9% to 31.1%; P < 0.0001). PASI response rates also favoured deucravacitinib versus apremilast. PASI 75 response at week 24 and week 52 was achieved by 56.3% and 30.5% of patients in the deucravacitinib and apremilast groups, respectively, and the absolute difference was 25.5% (95% CI, 16.9% to 34.0%; P < 0.0001). PASI 90 response was reported in 31.0% and 15.6% of patients in the deucravacitinib and apremilast groups, respectively, and the absolute difference was 15.2% (95% CI, 8.0% to 22.4%; P = 0.0002).

In the POETYK-2 study, maintenance of treatment response (at week 24 and week 52) was reported for patients in the deucravacitinib group who achieved at least a PASI 75 response at week 24 and were rerandomized to receive deucravacitinib or placebo during the maintenance phases of the trial. Among patients who continued on deucravacitinib, 72% achieved an sPGA 0 or 1 response at week 24 and week 52, compared with 23.5% of patients switched to placebo (absolute difference 47.8%; 95% CI, 36.6% to 59.0%) (Table 22). PASI 75 response at week 24 and week 52 was achieved by 82.1% versus 31.3% among patients who received maintenance deucravacitinib versus placebo, with an absolute difference of 50.6% (95% CI, 40.9% to 60.4%). These data were reported descriptively, with no statistical testing performed.

Table 21: Maintenance of sPGA and PASI Response at Week 52 — POETYK-1 (FAS)

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; NA = not applicable; OR = odds ratio; PASI = Psoriasis Area and Severity Index; PASI 50 = 50% reduction in Psoriasis Area and Severity Index score; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PASI 90 = 90% reduction in Psoriasis Area and Severity Index score; PBO = placebo; RD = risk difference; sPGA = static Physician’s Global Assessment.

^aPatients in the APREM group who did not achieve a PASI 50 response at week 24 were switched to DEUC. Patients with at least a PASI 50 response, continued on APREM.

^bCochran-Mantel-Haenszel test stratified by geographic region, body weight, and prior biologic use. Nonresponder imputation for missing data.

^cPatients must also have at least a 2-point improvement in their sPGA score versus baseline.

^dTested using a 2-sided alpha of 0.025.

Source: Clinical Study Report for POETYK-1.⁷

Table 22: Maintenance of sPGA and PASI Response at Week 52 — POETYK-2 (FAS)

CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PBO = placebo; RD = risk difference; sPGA = static Physician’s Global Assessment.

^aAmong patients initially randomized to DEUC who achieved at least a PASI 75 response at week 24 and who were rerandomized to DEUC or PBO.

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Relapse

In the POETYK-2 study, time to relapse was tested for patients in the deucravacitinib group who achieved a PASI 75 response at week 24 and were rerandomized to deucravacitinib or placebo. Among responders, |||| of patients who remained on deucravacitinib experienced a relapse, compared with ||||| who were switched to placebo |||||||||| (Table 23). Of note, this outcome was controlled for multiple testing based on the global statistical testing procedure but not the US statistical hierarchy.

Relapse was reported by ||||| of patients who achieved a PASI 75 response with apremilast and were then switched to placebo, with a median time to relapse of ||| |||| |||| || ||| |||| || ||| |||||||||||.

Table 23: Time to Relapse Among Patients With PASI 75 Response at Week 24 — POETYK-2 (FAS)

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; NA = not applicable; NE = not estimable; PASI = Psoriasis Area and Severity Index; PASI 75 = 75% reduction in Psoriasis Area and Severity Index score; PBO = placebo.

^aRelapse was defined as at least a 50% loss of week 24 PASI percent improvement from baseline in the 224 day period after the week 24 visit. The analyses included patients who achieved PASI 75 response at week 24. The time to relapse was based on the Kaplan-Meier product limit method, with P value based on a log-rank test that was stratified by geographic region, body weight, and prior biologic use. Patients who had a relapse after the 224 day follow-up period were censored at day 224.

^bTested at the alpha 0.025 level in the global testing hierarchy. This end point was not controlled for type I error rate according to the US testing hierarchy.

Source: Clinical Study Report for POETYK-2.⁸

Health-Related Quality of Life

HRQoL was measured using the disease-specific DLQI questionnaire, as well as the generic instruments, EQ-5D VAS and SF-36. The analyses of the change from baseline in the SF-36 and EQ-5D VAS scores were not controlled for type I error rate. A MID of at least 3 points for the SF-36 PCS or MCS has been reported in the literature.^49,50 In patients with psoriasis, MID estimates for the EQ-5D VAS range from 3.82 to 8.43 using anchor-based methods and was 10.34 based on distributional methods.⁴⁵ Not all randomized patients were included in these analyses. At week 16, the DLQI response analyses were missing 3% to 4%, ||| ||||| ||||| |||||||| |||| ||||||| || || || || |||||||| ||| ||||||||| ||||||.

The proportion of patients who achieved a DLQI score of 0 or 1 at week 16 (classified as no impact of disease on HRQoL) was 41.0%, 10.6%, and 28.6% for the POETYK-1 study and 37.6%, 9.8%, and 23.1% for the POETYK-2 study in the deucravacitinib, placebo, and apremilast groups, respectively. The between-group differences favoured deucravacitinib versus placebo, with P values less than 0.0001. Although numerically more patients reported a DLQI response in the deucravacitinib group than in the apremilast group, this comparison was not controlled for type I error rate (Table 24).

||| ||||||| ||||| |||||||||| || ||| |||||| |||| |||||||| || ||| ||||| ||| ||| ||| || |||| || |||||| |||||| ||| || |||| |||||||| ||| ||||| || ||| |||||| ||| ||||||| ||||| |||||| |||| |||||||| ||| ||| |||||| ||| ||||||| ||| |||||||| || ||| |||||||||| | ||||| ||| ||| |||||| |||| |||||||| || |||| || || ||| ||||| |||| ||| ||||| |||||| |||| |||| |||||| || ||| ||||||||||||||| ||||| ||| ||||||||| ||||||| || ||| ||||||||||||||| |||||| |||||| ||||||| ||||||| ||| |||| ||| |||||||| ||||| |||||| ||||||| ||||| ||||||||||| |||| |||||||| ||| |||||| ||| |||||||| ||||| ||||||| |||||||| || ||| ||||||||||| || |||||||| || ||||||||||||| ||||||||||| |||||||||| ||| |||||||| ||||||| ||||||||||||||| |||||| |||||||||| || ||| |||||| || ||| |||||| ||| ||| ||||||| ||||| |||||||||| || |||||||| ||| ||| |||||| ||| |||||| ||| ||||| | ||.

Table 24: DLQI Score 0 or 1 at Week 16 — POETYK-1 and POETYK-2 (FAS)

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; DLQI = Dermatology Life Quality Index; FAS = full analysis set; NA = not applicable; OR = odds ratio; PBO = placebo; RD = risk difference; vs. = versus.

^aCochran-Mantel-Haenszel test stratified by geographic region, body weight, and prior biologic use. Nonresponder imputation for missing data.

^bAnalyzed in patients with a baseline DLQI score of at least 2.

^cTested at the alpha 0.025 level in the global testing hierarchy. This end point was not controlled for type I error rate according to the US testing hierarchy.

^dP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Table 25: Change in EQ-5D and SF-36 at Week 16 — POETYK-1 and POETYK-2 (FAS)

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; LS = least squares; MCS = Mental Component Score; PBO = placebo; PCS = Physical Component Score; RD = risk difference; SD = standard deviation; SE = standard error; SF-36 = Short Form (36) Health Survey; VAS = visual analogue scale; vs. = versus.

^aAnalysis of covariance model with factors for geographic region, body weight, and prior biologic use, and baseline value as covariate (modified baseline observation carried forward for missing data).

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Symptoms

The patient-reported PSSD symptom questionnaire 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. A 9.1-point MID has been reported for the 7-day version of the PSSD symptoms score.⁴³ Of note, 6% to 10% of patients per treatment group were missing from these analyses.

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 the POETYK-1 study and 7.5%, 1.3%, and 4.3% in the POETYK-2 study in the deucravacitinib, placebo, and apremilast groups, respectively (Table 26). The differences favoured deucravacitinib versus placebo, but with no statistically significant difference detected versus apremilast in both studies.

The LS mean difference the change from baseline in the PSSD symptom score was ||||| ||| ||||| for deucravacitinib versus placebo, and −8.8 and −7.2 for deucravacitinib versus apremilast, respectively in the POETYK-1 and POETYK-2 studies. While the comparisons with apremilast were part of the statistical testing hierarchy and were controlled for multiplicity, the between-group difference did not exceed MID estimates. There was no control of the type I error rate for the comparison with placebo.

Table 26: PSSD Symptoms Score 0 at Week 16 — POETYK-1 and POETYK-2 (FAS)

APREM = apremilast; CI = confidence interval; DEUC = deucravacitinib; FAS = full analysis set; LS = least squares; NA = not applicable; OR = odds ratio; PBO = placebo; PSSD = Psoriasis Symptoms and Signs Diary; RD = risk difference; SD = standard deviation; SE = standard error; vs. = versus.

^aCochran-Mantel-Haenszel test stratified by geographic region, body weight, and prior biologic use. Nonresponder imputation for missing data.

^bIn the subgroup of patients with a baseline PSSD score of at least 1.

^cTested using a 2-sided alpha of 0.025.

^dAnalysis of covariance model with factors for geographic region, body weight, and prior biologic use, and baseline value as covariate (modified best observation carried forward for missing data).

^eP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Reports for POETYK-1⁷ and POETYK-2.⁸

Harms

Only those harms identified in the review protocol are reported in the following. Refer to Table 27 and Table 28 for detailed harms data.

Adverse Events

During the first 16 weeks of the POETYK-1 and POETYK-2 studies, 53% and 58% of patients in the deucravacitinib groups reported an AE compared with 42% and 54% of patients who received placebo, and 55% and 59% who received apremilast. The most commonly reported events in the deucravacitinib group were nasopharyngitis (6% to 11%), upper respiratory tract infection (5% to 6%), diarrhea and headache (each reported in 4% to 5%), and in the apremilast groups, nausea and diarrhea (9% to 13%), headache (10% to 11%), and nasopharyngitis (8% to 9%) were most common. In the placebo group, 4% to 11% of patients reported nasopharyngitis, 4% reported upper respiratory tract infection, 4% to 8% reported diarrhea and 3% to 6% reported headache.

For the 52-week study period, the AE IR was similar in the deucravacitinib (212 events per 100 PY) and apremilast groups (234 per 100 PY) in the POETYK-1 study, and for the deucravacitinib (242 per 100 PY) and placebo groups (222 per 100 PY) in the POETYK-2 study, but higher in the apremilast group (330 per 100 PY) in the POETYK-2 study.

Serious Adverse Events

In the first 16 weeks of the POETYK-1 study, 7 patients (2%), 9 patients (5%), and 4 patients (2%) reported a SAE in the deucravacitinib, placebo, and apremilast groups, respectively. In the POETYK-2 study, 8 patients (2%), 3 patients (1%), and 1 patient (0.4%) in the deucravacitinib, placebo, and apremilast groups, respectively, experienced a SAE. No specific events were reported in 2 patients or more up to week 16.

Over the entire POETYK-1 study duration, the exposure-adjusted IR for SAEs was 7.5 and 5.2 events per 100 PYs in the deucravacitinib and apremilast groups, respectively. The exposure-adjusted IR in the POETYK-2 study was 4.3 per 100 PYs in the deucravacitinib group compared with 2.5 and 2.8 per 100 PYs in the placebo and apremilast groups. Events that were reported in 2 or more patients in the deucravacitinib groups included pericarditis (2 patients in the POETYK-1 study), cholecystitis acute (2 patients in the POETYK-1 study), and pneumonia (3 patients the POETYK-2 study). No other SAEs were reported in 2 or more patients per group.

Withdrawals Due to AEs

The proportion of patients who stopped treatment due to AEs was 2% and 3% for deucravacitinib, 4% for placebo, and 5% and 6% for apremilast during the first 16 weeks in the POETYK-1 and POETYK-2 studies. In the POETYK-1 study, no events were reported in more than 1 patient in the deucravacitinib or placebo groups | || ||||||||| |||||||||| |||||||||| |||| |||||||||| ||||||||| |||||||| ||| ||||||| ||| || ||||||||||||||| || ||||||||||||||| || | || |||| ||||||||. In the placebo group of the POETYK-2 study, 3 patients stopped therapy due to psoriasis. In both studies gastrointestinal AEs were the most common reason for stopping therapy in the apremilast groups.

The 52-week IR for withdrawals due to AEs was 3.3 and 10.3 per 100 PYs in the deucravacitinib and apremilast groups, respectively, in the POETYK-1 study, and 5.2, 8.0, 13.1 per 100 PYs in the deucravacitinib, placebo, and apremilast groups in the POETYK-2 study. Two patients in the deucravacitinib group,1 patient in the apremilast group, and no patients in the placebo group stopped treatment due to increased creatinine kinase levels in the POETYK-2 study. No patients in the POETYK-1 study stopped therapy due to increase creatinine kinase levels.

Mortality

In the POETYK-1 study, 1 patient in the placebo group died of hypertensive cardiovascular disease. No deaths were reported in the deucravacitinib and apremilast groups.

There were 3 deaths during the 52 week POETYK-2 study, including 1 patient of heart failure and sepsis, and 1 patient due to hepatocellular carcinoma, both in the deucravacitinib group, and 1 patient in the apremilast group due to lung cancer and gastrointestinal hemorrhage.

Notable Harms

During the first 16 weeks of the studies, infections and infestations SOC were reported || ||| || ||| || |||||||| || ||| ||||||||||||||| ||||||| ||| || ||| || ||| ||||||| |||||| ||| ||| || ||| || ||| |||||||||| |||||||. Overall, the IR of infections and infestations SOC was |||| ||| ||||| |||||| ||| ||| || ||| |||||||| ||||||||| |||||||||||||||| ||| |||| ||| |||| ||| ||| || ||| ||||| ||||||||| ||||||||||| ||| |||||||| || ||| |||||| ||||||||||| || ||||||||| || ||||||||||| |||| ||| | ||||||| ||||||| |||||| ||| ||||| |||| || ||||||||||||| |||||||||| || |||||||||||| |||||| |||||||| || |||||| |||||||. With regards to adjudicated major adverse cardiovascular events, a total of | |||||| ||||||||||| ||||||||||| |||||||| ||||||| ||||||| ||||||| ||| ||||||||||||||| ||||||||| |||| |||||||| ||||| |||||||| ||| |||||||| ||||||||||||||| || |||||| |||||| ||||| |||||||| || ||| ||||||| |||||| |||||||| |||| |||||| || ||||| |||||||||| ||||||||||| |||||||||||| ||||| ||||||| ||| |||||||| ||||||| ||| | |||||||| || ||| |||||||||| |||||| |||||||| |||||||| |||||| || ||||||||| ||| |||||||||| |||||||||||. No adjudicated thromboembolic SAEs occurred in the POETYK-2 study, and 1 patient experienced a pulmonary embolism in the deucravacitinib group in the POETYK-1 study. Other thromboembolic events reported included ischemic clot of right leg, and thrombosis of right radial vein in 2 patients receiving deucravacitinib, and thrombosis of superficial vein of lower limb in a patient receiving apremilast in the POETYK-2 study.

||| | |||||||||||| || |||||||| ||||| |||| |||||||| || ||| ||||||||||||||| |||||| |||||| |||||||| |||||||| |||||| ||||||| ||||||||| |||||||| ||||||||| ||||| ||||| |||||||| ||| ||||| |||| |||||||||| || |||||||| ||||| | ||||| || | |||||||| |||||||| | ||||||||||| | || ||| ||||||||||||||| ||||| ||| | || ||| |||||||||| |||||| ||| ||||||| |||| |||||||||||| |||| ||||||| ||| | |||| ||||| |||||| ||||||||||||||| ||||||||| || ||| ||||||||||||||| ||||| ||| |||| |||||||||||||| || ||| |||||||||| |||||||.

In both studies, the proportion of patients that reported a grade 2 or higher increase in aspartate aminotransferase, alanine aminotransferase, or bilirubin levels ranged from 0% to 2% across all treatment groups during week 0 to 16. In the overall study period of the POETYK-1 study, 1 patient who received deucravacitinib had elevated alanine aminotransferase and aspartate aminotransferase levels greater than 3 times the upper limit of normal and total bilirubin 2 or more times the upper limit of normal; however, this patient also had a history of alcohol dependence and fatty liver, thus did not meet the criteria for drug-induced liver disease. Liver function tests returned to the patient’s normal after the drug was discontinued. The proportion of patients with a grade 2 or higher decrease in the neutrophil or lymphocyte count during week 0 to week 16 was generally similar between groups and did not exceed 3% in the deucravacitinib groups.

The proportion of patients with at least a grade 2 increase in creatinine kinase levels was 3% for the deucravacitinib groups, 1% to 4% in the placebo groups, and 0% to 4% in the apremilast groups during week 0 to 16. Over the 52-week study period, 6% of patients receiving deucravacitinib and 4% to 5% receiving apremilast reported grade 2 or greater elevated creatinine kinase levels. None of these events were considered SAEs.

Table 27: Summary of Harms — POETYK-1 (Safety Population)

ALT = alanine aminotransferase; APREM = apremilast; AST = aspartate aminotransferase; CK = creatine kinase; DEUC = deucravacitinib; IR = incidence rate; MACE = major adverse cardiovascular events; NR = not reported; PBO = placebo; PY = patient-years; SAE = serious adverse event; SOC = system organ class; URTI = upper respiratory tract infection.

^aFrequency > 5% per group in either pivotal trial.

^bReported in 2 or more patients per group.

^cIncludes herpes zoster, influenza, opportunistic infections, and tuberculosis. Events were adjudicated by a blinded independent committee.

^dIncludes nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and unstable angina requiring hospitalization.

Source: Clinical Study Report for POETYK-1.⁷

Table 28: Summary of Harms — POETYK-2 (Safety Population)