FormalPara Key Summary Points

Why carry out this study?

Moderate to severe psoriasis is a chronic, systemic, immune-mediated disease that is known to have a substantial impact on patients’ physical as well as mental health and quality of life (QoL)

Previous results from this Phase 2 trial in patients with moderate to severe plaque psoriasis demonstrated that treatment with the three highest dosages of the selective tyrosine kinase 2 inhibitor deucravacitinib led to significant improvements in clinical signs and symptoms as well as improvements in QoL measures at 12 weeks compared with placebo

This post hoc analysis from the Phase 2 trial explored temporal response and the relationship between patient-reported outcomes and investigator-assessed clinical measures

What was learned from this study?

This analysis provided additional evidence that deucravacitinib treatment is associated with early improvements in clinical outcomes from baseline through Week 12, as assessed by improvements from baseline in absolute Psoriasis Area and Severity Index, static Physician's Global Assessment, body surface area involvement, and QoL as assessed by Dermatology Life Quality Index

Improvement in QoL followed a pattern of response to treatment similar to that of the clinical outcomes assessed in this analysis

Introduction

Several metrics are utilized to assess the severity of psoriasis, make appropriate treatment decisions, and measure treatment response [1]. The Psoriasis Area and Severity Index (PASI) is a measure of clinical disease severity that is commonly used in clinical trials [2,3,4]. At least 75% reduction from baseline in PASI (PASI 75) is considered a clinically relevant treatment response and was the primary endpoint in a Phase 2 dose-ranging, placebo-controlled, 12-week study of deucravacitinib in adults with moderate to severe psoriasis [3, 5, 6]. Static Physician’s Global Assessment (sPGA) is often used to assess disease severity at a specific time point regardless of baseline disease severity [1, 7]. Another efficacy measure is body surface area (BSA) involvement, which is regarded as a more practical instrument for assessing treatment targets in psoriasis by some dermatologists and other experts [6]. The Dermatology Life Quality Index (DLQI) questionnaire, a patient-reported measurement of health-related quality of life (QoL), is often used in clinical trials to assess measures of bothersome symptoms, such as itch, stinging, and pain, as well as its impact on daily functioning [8, 9].

Deucravacitinib is an oral selective tyrosine kinase 2 (TYK2) inhibitor in development for treatment of moderate to severe plaque psoriasis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, and lupus (NCT03943147) [10]. The mechanism of action of deucravacitinib is distinct from that of other TYK2 or Janus kinase inhibitors in that deucravacitinib selectively binds to a unique pocket in the regulatory domain of TYK2 instead of the highly conserved active site of the catalytic domain [11], allowing high selectivity of action on TYK2 via allosteric inhibition versus related kinases. This leads to targeted inhibition of immune pathways that are central to psoriasis while limiting off-target effects [11]. In the previously published Phase 2 trial in moderate to severe plaque psoriasis, deucravacitinib treatment resulted in 67–75% of patients reaching PASI 75 at 12 weeks with the three highest dosages of 3 mg twice daily (BID), 6 mg BID, and 12 mg once daily (QD) versus 7% of patients receiving placebo. The two lowest dosage groups (3 mg every other day and 3 mg QD) provided limited efficacy compared with placebo [5]. Deucravacitinib treatment also led to improvements versus placebo at 12 weeks in QoL, as assessed by a DLQI score of 0 or 1 (0/1) [5], and was well tolerated overall. Adverse events were reported in 51% of patients in the placebo group and in 55% to 80% of patients in the deucravacitinib groups, with the highest percentage of adverse events occurring in the group receiving deucravacitinib 6 mg BID. Nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection were the most common adverse events. Serious adverse events and adverse events leading to treatment discontinuation were low and balanced across treatment groups. Deucravacitinib-treated patients (at any dose) did not develop laboratory abnormalities characteristic of Janus kinase inhibitors such as neutropenia, liver enzyme or serum creatinine elevations, or dyslipidemia [5].

This analysis of the Phase 2 trial was conducted to further evaluate the efficacy of deucravacitinib at doses ≥ 3 mg BID using a broad range of clinical assessment tools and to further assess the impact on a patient-reported QoL measure (DLQI) for up to 12 weeks in patients with moderate to severe plaque psoriasis.

Methods

Study Design

This was a post hoc analysis of a randomized, double-blind, placebo-controlled, dose-ranging Phase 2 trial of deucravacitinib in adults with moderate to severe plaque psoriasis (NCT02931838) [5]. The study design has been described previously [5]. Adults were eligible for trial participation if they had moderate to severe plaque psoriasis, as defined by affected BSA ≥ 10%, PASI ≥ 12, and sPGA score ≥ 3, and were candidates for phototherapy or systemic therapy. Patients were randomized equally to receive one of five dosages of deucravacitinib (3 mg every other day, 3 mg QD, 3 mg BID, 6 mg BID, or 12 mg QD) or matching oral placebo for 12 weeks.

Study Ethics

The trial was conducted in accordance with Good Clinical Practice guidelines defined by the International Council for Harmonisation, the Declaration of Helsinki, and the laws and regulatory requirements of the countries with participating study centers [5]. The study protocol, consent form, and all other documents given to patients were approved by an institutional review board or independent ethics committee at each site (see Supporting Information). Written informed patient consent was obtained prior to study participation.

Assessments

The assessment tools PASI, sPGA, BSA, and DLQI used in the trial have been previously described [5]. The primary efficacy endpoint for the Phase 2 study was PASI 75 response at Week 12.

Mean percentage changes from baseline in absolute PASI score and in BSA were determined over time through Week 12. PASI 75, ≥ 90% reduction from baseline in PASI (PASI 90), and 100% reduction from baseline in PASI (PASI 100) responses and sPGA score of 0 (clear) or 1 (minimal disease) were previously published [5]. Additional post hoc analyses were the percentages of patients who achieved absolute PASI ≤ 1, absolute PASI ≤ 3, absolute PASI ≤ 5, BSA ≤ 1%, BSA ≤ 3%, and ≥ 75% improvement in the product of sPGA and BSA (sPGA × BSA 75). The sPGA × BSA measurement is a validated composite instrument, which is the product of sPGA (range, 0 [clear] to 5 [severe]) and is based on the average of the severity of induration, erythema, and scaling over all psoriatic plaques at a given time point) and BSA [12,13,14,15]. The DLQI overall score (range, 0 [no impairment of QoL] to 30 [maximum impairment of QoL]) was analyzed over time. The percentages of patients achieving DLQI 0/1 were compared across categories of absolute PASI values and changes from baseline and with BSA involvement.

Statistical Analysis

In analyses of the Phase 2 trial, mean changes in PASI score, as well as PASI 75 and PASI 90 responses, were similar in the highest dosage groups (3 mg BID [n = 45], 6 mg BID [n = 45], 12 mg QD [n = 44]); efficacy was limited in the two lowest deucravacitinib dosage groups (3 mg every other day and 3 mg QD) compared with placebo [5]. These findings provided the rationale for combining data from the three highest dosage groups in subsequent analyses [5, 16]. The placebo group (n = 45) was also included in the analyses for comparative purposes.

Improvement from baseline is presented as percentage change from baseline for absolute PASI and BSA involvement through Week 12. Other outcomes (PASI 90, PASI 100, absolute PASI ≤ 1, absolute PASI ≤ 3, absolute PASI ≤ 5, sPGA, BSA, sPGA × BSA) at Week 12 are expressed as percentages of patients. All missing values were imputed as nonresponse.

Results

A total of 267 patients were randomized and treated, and 224 (84%) completed the 12-week treatment period [5]. The treatment groups were comparable in baseline patient demographics and disease characteristics, as previously reported for absolute PASI score, DLQI score, and BSA involvement [5].

Deucravacitinib treatment groups had a greater mean percentage change from baseline in absolute PASI score than the placebo group at each time point through Week 12, with changes evident as early as the first visit at Week 1; decreases were similar among the three dosage groups (Fig. 1). Mean changes from baseline in BSA percentage were greater in the deucravacitinib groups versus the placebo group at Week 12, − 18.6 (75.9% decrease from baseline), − 17.2 (69.4% decrease), and − 15.2 (73.7% decrease) in the 3 mg BID, 6 mg BID, and 12 mg QD treatment groups, respectively, compared with − 7.7 in the placebo group; Fig. 2). As with the absolute PASI changes, improvement was seen as early as Week 2, with similar improvement among the three deucravacitinib dosage groups (Fig. 2).

Fig. 1
figure 1

Mean percentage change from baseline in PASI scores over time for placebo and the deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD dosage groups. BID twice daily; PASI Psoriasis Area and Severity Index; PBO placebo; QD once daily

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Fig. 2
figure 2

Mean absolute change from baseline in BSA percentage over time for placebo and the deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD dosage groups. BID twice daily; BSA body surface area; PBO placebo; QD once daily

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Responses at Week 12 in patients receiving deucravacitinib compared with placebo for the assessments of PASI 90, PASI 100, absolute PASI ≤ 1, absolute PASI ≤ 3, absolute PASI ≤ 5, and sPGA 0/1 are shown in Fig. 3a–f. The proportions of patients who achieved BSA ≤ 1% (26.7% [3 mg BID], 37.8% [6 mg BID], 38.6% [12 mg QD]) and BSA ≤ 3% (51.1%, 44.4%, and 56.8%, respectively) were higher in the deucravacitinib groups than in the placebo group (0% for BSA ≤ 1% and 2.2% for BSA ≤ 3%; Fig. 3g). The deucravacitinib dosage groups had a higher percentage of patients who achieved sPGA × BSA 75 (≥ 75% improvement from baseline), which has previously been used as an assessment of psoriasis severity and response to therapy [12, 15] versus the placebo group (Fig. 3h).

Fig. 3
figure 3

Response rates at Week 12 for a PASI 90, b PASI 100, c sPGA 0/1, d absolute PASI ≤ 5, e absolute PASI ≤ 3, f absolute PASI ≤ 1, g BSA (≤ 1% and ≤ 3%), and h sPGA × BSA 75 for placebo and the deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD dosage groups. BID twice daily; BSA, body surface area; PASI 75 at least 75% reduction from baseline in Psoriasis Area and Severity Index; PASI 90 at least 90% reduction from baseline in Psoriasis Area and Severity Index; PASI 100 100% reduction from baseline in Psoriasis Area and Severity Index; PBO placebo; QD every day; sPGA × BSA 75 at least 75% improvement from baseline in the product of the static Physician’s Global Assessment and body surface area involvement

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Treatment with deucravacitinib was associated with greater improvement from baseline in QoL versus placebo at each time point, as assessed by the percentage of patients achieving a DLQI overall score of 0/1, which reflects no impact at all on the patient’s life [17] (Fig. 4). The percentage of patients achieving a DLQI 0/1 increased by Week 4 for each of the three deucravacitinib dosage groups versus placebo and continued to increase through Week 12 in the two highest dosage groups; the percentage of patients achieving a DLQI 0/1 in the three deucravacitinib dosage groups combined was 17.9% at Week 4, 41.8% at Week 8, and 55.2% at Week 12 versus the placebo group, which was 6.7%, 4.4%, and 4.4%, respectively (Fig. 4).

Fig. 4
figure 4

Percentage of patients with a DLQI overall score of 0/1, which reflects no impact on patient’s life, for placebo and the deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD dosage groups. BID twice daily; DLQI Dermatology Life Quality Index; QD every day; QoL quality of life

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Improvements in QoL over 12 weeks followed a similar pattern to the improvements observed for clinical outcomes (PASI 75, PASI 90, and sPGA score of 0 or 1 [0/1]; Fig. 5). The DLQI 0/1 responses were concurrent with increases in the percentages of patients from all three deucravacitinib dosage groups combined achieving PASI 75 (0% at Week 1, 70.1% at Week 12), PASI 90 (0% at Week 1, 44.0% at Week 12), and sPGA 0/1 (0% at Week 0, 71.6% at Week 12).

Fig. 5
figure 5

Time course of PASI 75, PASI 90, sPGA 0/1, and DLQI overall score of 0/1 response rates for the combined deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD dosage groups. BID twice daily; DLQI Dermatology Life Quality Index; PASI 75 at least 75% reduction from baseline in Psoriasis Area and Severity Index; PASI 90 at least 90% reduction from baseline in Psoriasis Area and Severity Index; QD every day; sPGA static Physician’s Global Assessment

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Agreement between QoL and PASI improvements were also observed when the achievement of DLQI 0/1 was stratified by absolute PASI bands (≤ 1; ≤ 2; ≤ 3; ≤ 5) at Week 12, suggesting that the percentage of patients achieving DLQI 0/1 was highest in those with absolute PASI ≤ 1 (Fig. 6a) and PASI 100 (Fig. 6b). Similarly, higher rates of achievement of DLQI 0/1 were observed in the BSA ≤ 1% group (78.3%) and the BSA ≤ 3% group (70.6%) compared with the BSA > 3% group (44.8%; Fig. 6c).

Fig. 6
figure 6

DLQI 0/1 at Week 12 by absolute PASI (a), PASI response band (b), and BSA response band (c) for the combined patient groups of deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD dosage groups. BID twice daily; BSA body surface area; DLQI Dermatology Life Quality Index; PASI Psoriasis Area and Severity Index; PASI < 25 < 25% improvement from baseline Psoriasis Area and Severity Index; PASI 25 to < 50 25% to < 50% improvement; PASI 50 to < 75 50% to < 75% improvement; PASI 75 to < 90 75% to < 90% improvement; PASI 90 to < 100 90% to < 100% improvement; PASI 100 100% improvement from baseline Psoriasis Area and Severity Index; QD once daily

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Discussion

This analysis demonstrated that deucravacitinib treatment produced early, clinically meaningful, and similar improvements across several assessments of clinical response (PASI, BSA, sPGA). These improvements were mirrored by QoL improvements, as measured by DLQI. At the three highest dosages tested, a substantial percentage of the deucravacitinib-treated patients met thresholds of clinically meaningful improvement in PASI (PASI 75, PASI 90, PASI 100) as well as treat-to-target BSA values recommended by the National Psoriasis Foundation (BSA ≤ 1% at 12 weeks) [6, 18] and acceptable response (BSA ≤ 3% or BSA improvement ≥ 75% at 12 weeks of treatment).

At Week 12, the percentages of patients with PASI 75, PASI 90, PASI 100, and sPGA 0/1 were substantially higher in the deucravacitinib dosage groups than in the placebo group. In the main analysis of this Phase 2 trial, an sPGA score of 0/1 was achieved in 7% of the placebo group and in 76% of the deucravacitinib 3 mg BID group, 75% of the 12 mg QD group, and 64% of the 6 mg BID group at Week 12 [5]. Additionally, up to 38.6% and 56.8% of patients combined across the three deucravacitinib dosage groups achieved BSA ≤ 1% and ≤ 3%, respectively. As would be expected in this patient population, at Week 12 a similar proportion of patients in the combined deucravacitinib dosage group achieved sPGA × BSA 75 and PASI 75. Comparable findings from other studies that also used a composite assessment with BSA suggest sPGA × BSA may be a viable alternative to PASI that may be used in both clinical trials and clinical practice settings to assess severity of psoriasis [12, 19,20,21]. Treatment with deucravacitinib resulted in greater improvements in QoL (as assessed by DLQI) versus placebo, which occurred by Week 4. The improvements in QoL paralleled increases in the rates of PASI 75, PASI 90, PASI 100, and sPGA 0/1 and were commensurate with improvements in absolute PASI and BSA scores over time through Week 12.

Consistency between clinical and QoL outcomes is not unexpected, given the association between disease severity and QoL and the volume of literature reporting a substantial negative impact of psoriasis on QoL and, conversely, greater improvement in QoL mirroring an increase in skin clearance [3, 9, 22,23,24,25,26,27]. Previous studies have demonstrated consistency between physician-reported clinical outcomes and patient-reported outcomes such as QoL [25, 28,29,30,31,32,33]. In addition to the similar pattern of responses for clinical and QoL outcomes reported here, the current analysis also showed that a large percentage of patients achieved DLQI 0/1 despite absence of complete skin clearance (see Fig. 6) and despite having BSA involvement > 3% [6]. Awareness has increased over the last decade that patients with psoriasis experience effects on QoL beyond their level of skin involvement [25, 34]. Furthermore, the association between objective clinical response and QoL may vary depending on BSA affected [23], QoL domain (e.g., mental vs. physical) [35], QoL assessment tool (e.g., the dermatology-specific measure DLQI vs generic health status measures) [26], ethnicity [36, 37], sex [38], culture [36], and socioeconomic status [36, 38]. The current analysis and other studies in psoriasis highlight the importance of patient-reported outcomes, in addition to clinician-reported outcomes and other traditional clinical severity tools, when assessing treatment efficacy and the impact of psoriasis on daily life with effective agents [6, 25,26,27, 31, 39,40,41,42,43].

The limitations of this post hoc analysis must be considered. Differences between deucravacitinib and placebo in clinical and patient-reported outcomes were not multiplicity-adjusted for statistical significance. Analysis of the rate of achievement of DLQI 0/1 by PASI response bands was limited by the relatively small number of patients in individual PASI categories [5]. It should also be noted that all of the instruments available for assessing clinical outcomes or QoL have limited precision and truncation associated with the limitations of data capture. Finally, the relatively short 12-week treatment period and small sample size in the Phase 2 trial presented another limitation for this analysis. Larger, longer-term Phase 3 trials of deucravacitinib in psoriasis are ongoing or have been completed (POETYK PSO-1 [NCT03624127] [44]; POETYK PSO-2 [NCT03611751]; POETYK PSO-3 [NCT04167462]; POETYK PSO-4 [NCT03924427]; POETYK PSO-LTE [NCT04036435]) and will provide important data regarding consistency between clinical outcomes and QoL in a larger population of psoriasis patients over longer follow-up periods.

Conclusion

This post hoc analysis of the Phase 2 trial demonstrated that deucravacitinib at doses of ≥ 3 mg BID provided early improvements across multiple assessments of clinical efficacy as well as QoL in patients with moderate to severe plaque psoriasis, suggesting that deucravacitinib may be a promising therapy for this population. Early concurrent trends in improvement occurred over the 12-week trial across different assessments, with no impact on life (DLQI 0/1) observed in many patients who did not achieve complete skin clearance.