Abstract
Introduction
Moderate-to-severe plaque psoriasis can be difficult to treat; not all patients respond to treatment. POETYK PSO-1 and PSO-2 were 52-week, phase 3, multinational, double-blinded trials in plaque psoriasis. We determined deucravacitinib efficacy in PSO-1/PSO-2 patients who did not respond to apremilast.
Methods
PSO-1/PSO-2 were conducted between July 2018 and November 2020; this analysis includes data from both trials. Adults with moderate-to-severe plaque psoriasis (baseline Psoriasis Area and Severity Index [PASI] ≥ 12, static Physician Global Assessment [sPGA] ≥ 3, body surface area involvement ≥ 10%) were included and randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. Clinical endpoints included ≥ 75%/90% reduction from baseline PASI (PASI 75/90), sPGA score of 0 (clear) or 1 (almost clear) (sPGA 0/1) response rates, and mean percent change from baseline PASI and BSA involvement. Patient-reported outcomes included Dermatology Life Quality Index 0 (no effect) or 1 (little effect) (DLQI 0/1) and mean change from baseline Psoriasis Symptoms and Signs Diary (PSSD) symptom score.
Results
Of 168 (PSO-1) and 254 (PSO-2) patients randomized to apremilast, 54 (32.1% [PSO-1]) and 111 (43.7% [PSO-2]) did not achieve PASI 50 (PSO-1) and PASI 75 (PSO-2) at Week 24 and were switched to deucravacitinib. PASI 75 response rates improved from 0% at Week 24 to 46.3% (PSO-1) and 42.3% (PSO-2) at Week 52. From Weeks 24–52, PASI 90, sPGA 0/1, and DLQI 0/1 response rates increased; mean percent change from baseline PASI decreased by 60% (PSO-1) and 26% (PSO-2); mean change from baseline in PSSD symptom score decreased by ≈20% in both studies; mean percent change from baseline BSA involvement decreased by 65% (PSO-1) and 25% (PSO-2).
Conclusion
Deucravacitinib was efficacious in patients with moderate-to-severe plaque psoriasis who did not respond to apremilast.
Trial Registration
ClinicalTrials.gov identifier, NCT03624127, NCT03611751.
Keywords: Clinical trials, Deucravacitinib, Psoriasis, Psoriasis treatment, Tyrosine kinase 2 inhibitor
Key Summary Points
| Why carry out this study ? |
| In the POETYK PSO-1 and PSO-2 trials, not all patients randomized to apremilast, the active comparator, responded to treatment. |
| This analysis assessed the efficacy of deucravacitinib in patients who did not respond to apremilast. |
| What was learned from the study ? |
| In this analysis of 165 patients from the POETYK PSO-1 and PSO-2 trials who were randomized to apremilast and did not respond over 24 weeks, subsequent deucravacitinib treatment was associated with improvements in clinician- and patient-reported outcomes through 52 weeks. |
| Patients with moderate-to-severe plaque psoriasis who did not respond to apremilast may respond to deucravacitinib. |
Introduction
Tyrosine kinase 2 (TYK2) is an intracellular enzyme that mediates signaling of select proinflammatory cytokines (e.g., interleukin [IL]-23, IL-12, Type I interferons); IL-23 and Type I interferons are involved in psoriasis pathogenesis [1]. Deucravacitinib, an oral, selective TYK2 inhibitor, is approved in multiple countries for treatment of adults with moderate-to-severe plaque psoriasis [2, 3]. Findings from the global, 52-week, phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) trials demonstrated that deucravacitinib was significantly more efficacious than placebo based on the coprimary endpoints of a ≥ 75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) and static Physician Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1) with a ≥ 2-point improvement from baseline at Week 16 [4, 5]. Response rates were significantly greater with deucravacitinib versus placebo at Week 16 for numerous secondary endpoints, including ≥ 90% or 100% reduction from baseline in PASI (PASI 90, PASI 100), sPGA score of 0 (clear), Dermatology Life Quality Index of 0 (no effect) or 1 (little effect) (DLQI 0/1), and mean change from baseline in Psoriasis Symptoms and Signs Diary (PSSD) symptom score. Additional follow-up through Week 52 demonstrated maintenance of clinical efficacy with continued treatment; comparable response rates and improvements were observed by Week 52 in patients who crossed over from placebo to deucravacitinib at Week 16. Rates of adverse events were similar across the 3 treatment groups in both PSO-1 and PSO-2; full safety data have been previously reported [4, 5].
Greater response rates and improvements from baseline in primary and secondary endpoints at Weeks 16 and 24 were observed with deucravacitinib versus the active comparator apremilast, a phosphodiesterase 4 (PDE4) inhibitor [4, 5]. Both PSO-1 and PSO-2 study designs (Fig. 1) stipulated that patients randomized to apremilast who had not achieved PASI 50 (POETYK PSO-1) or PASI 75 (POETYK PSO-2) at Week 24 were to be switched to deucravacitinib through Week 52. This analysis assessed the efficacy of deucravacitinib from Weeks 24 through 52 in patients who did not respond to apremilast.
Fig. 1.
POETYK PSO-1 and PSO-2 study designs. aApremilast was titrated from 10 mg QD to 30 mg BID over the first 5 days of dosing. bUpon relapse (≥ 50% loss of Week 24 PASI percent improvement from baseline), patients were to be switched to deucravacitinib 6 mg QD. The POETYK PSO-1 study design is from Armstrong et al. [4]. https://www.jaad.org/article/S0190-9622(22)02256-3/pdf. This work is licensed under a Creative Commons Attribution License (CC BY-NC-ND 4.0). https://creativecommons.org/licenses/by-nc-nd/4.0/. POETYK PSO-2 study design is from Strober et al. [5]. https://www.jaad.org/article/S0190-9622(22)02643-3/pdf. This work is licensed under a Creative Commons Attribution License (CC BY-NC-ND 4.0). https://creativecommons.org/licenses/by-nc-nd/4.0/. BID twice daily, PASI Psoriasis Area and Severity Index, PASI 50 ≥ 50% reduction from baseline in PASI, PASI 75 ≥ 75% reduction from baseline in PASI, QD once daily, sPGA 0/1 static Physician Global Assessment score of 0 or 1
Methods
Study Design and Patient Population
The POETYK PSO-1 and PSO-2 study designs were described previously (Fig. 1) [4, 5]. Briefly, adults with moderate-to-severe plaque psoriasis (sPGA ≥ 3, PASI ≥ 12, body surface area [BSA] involvement ≥ 10% at baseline) were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. Patients in both trials crossed over from placebo to deucravacitinib at Week 16 in a blinded manner. Patients randomized to apremilast who did not achieve PASI 50 (POETYK PSO-1) or PASI 75 (POETYK PSO-2) at Week 24 were switched in a blinded manner to deucravacitinib through Week 52.
Efficacy outcomes were assessed from Weeks 24 through 52 in patients who switched from apremilast to deucravacitinib. Clinical endpoints included PASI 75, PASI 90, and sPGA 0/1 response rates, mean percent change from baseline PASI, and mean percent change from baseline BSA involvement. Patient-reported outcomes included DLQI 0/1 response rates and mean change from baseline PSSD symptom score.
Nonresponder imputation was used for missing data in binary response endpoints. Data are presented as observed for continuous variables.
Ethical Approval
The PSO-1 and PSO-2 trials were conducted in accordance with Good Clinical Practice, as defined by the International Council for Harmonization and Declaration of Helsinki. Independent institutional review board approvals were obtained, and all participants provided written informed consent.
Results
In total, 168 and 254 patients were randomized to apremilast in POETYK PSO-1 and PSO-2, respectively [4, 5]. In POETYK PSO-1, 54 (32.1%) patients randomized to apremilast did not achieve PASI 50 at Week 24 and were switched to deucravacitinib; in POETYK PSO-2, 111 (43.7%) patients did not achieve PASI 75 at Week 24 and were switched to deucravacitinib. Baseline patient demographics and disease characteristics for the overall study populations have been previously described and were generally comparable across treatment groups and between the two studies [4, 5]. Baseline demographics and disease characteristics of patients who switched from apremilast to deucravacitinib were similar overall to those of the full study population; however, these patients were more likely to have previously received systemic (POETYK PSO-1: 75.9% vs 62.8%; POETYK PSO-2: 61.3% vs 54.2%) and biologic (POETYK PSO-1: 65.9% vs 38.9%; POETYK PSO-2: 66.2% vs 32.1%) treatment compared with the full study population (Table 1) [4, 5].
Table 1.
Baseline characteristics of patients who did not achieve PASI 50 (POETYK PSO-1) or PASI 75 (POETYK PSO-2) with apremilast at Week 24 and switched to deucravacitinib
| POETYK PSO-1 | POETYK PSO-2 | |
|---|---|---|
| Apremilast to deucravacitinib (n = 54) | Apremilast to deucravacitinib (n = 111) | |
| Age, mean (SD), years | 45.4 (11.3) | 44.2 (12.1) |
| Weight, mean (SD), kg | 87.6 (19.3) | 95.2 (20.7) |
| Body mass index, mean (SD), kg/m2 | 29.3 (6.2) | 31.6 (6.7) |
| Sex, n (%) | ||
| Male | 38 (70.4) | 76 (68.5) |
| Female | 16 (29.6) | 35 (31.5) |
| Race, n (%)* | ||
| White | 42 (77.8) | 101 (91.0) |
| Black or African American | 0 | 1 (0.9) |
| Asian | 12 (22.2) | 7 (6.3) |
| Other | 0 | 2 (1.8) |
| Age at disease onset, mean (SD), years | 28.2 (12.2) | 27.3 (13.8) |
| Duration of disease, mean (SD), years | 18.1 (11.3) | 17.8 (11.0) |
| Psoriasis-related history, n (%) | ||
| Scalp | 48 (88.9) | 102 (91.9) |
| Nails | 25 (46.3) | 56 (50.5) |
| Psoriatic arthritis | 15 (27.8) | 23 (20.7) |
| Prior systemic therapy, n (%) | ||
| Yes | 41 (75.9) | 68 (61.3) |
| Biologic | 27 (65.9) | 45 (66.2) |
| Nonbiologic | 14 (34.1) | 23 (33.8) |
| No | 13 (24.1) | 43 (38.7) |
| sPGA score (0–4), n (%)a | ||
| 3 (moderate) | 45 (83.3) | 80 (72.1) |
| 4 (severe) | 9 (16.7) | 31 (27.9) |
| PASI (0–72), mean (SD)b | 20.5 (7.6) | 22.0 (9.4) |
| BSA involvement, mean (SD), %c | 26.3 (14.9) | 28.5 (17.5) |
| DLQI score (0–30), mean (SD)d | 13.2 (6.2) | 12.6 (6.7) |
| PSSD symptom score (0–100), mean (SD)e | 59.2 (24.5) | 56.0 (25.2) |
| ss-PGA ≥ 3, n (%) | 37 (68.5) | 79 (71.2) |
Baseline eligibility thresholds: asPGA score ≥ 3; bPASI ≥ 12; cBSA involvement ≥ 10%; dDLQI ≥ 2; ePSSD symptom score ≥ 1
BSA body surface area, DLQI Dermatology Life Quality Index, PASI Psoriasis Area and Severity Index, PASI 50/75 ≥ 50%/≥ 70% reduction from baseline in PASI, PSSD Psoriasis Symptoms and Signs Diary, sPGA static Physician Global Assessment, ss-PGA scalp-specific Physician Global Assessment
*The race and ethnicities of the patients in these studies are self-reported and did not include details on specific nationalities
At Week 24, 59.3% of patients who did not meet response criteria on apremilast in POETYK PSO-1 had a 0 to < 25% reduction from baseline in PASI, and 40.7% had a 25% to < 50% reduction (Fig. 2). In POETYK PSO-2, 21.1% had a 0 to < 25% reduction in PASI, 33.0% had a 25% to < 50% reduction, and 45.9% had a 50% to < 75% reduction. Following the switch to deucravacitinib, > 40% of patients in both studies achieved PASI 75 and 29.6% (POETYK PSO-1) and 18.0% (POETYK PSO-2) achieved PASI 90 by Week 52 (Fig. 3a, b). sPGA 0/1 response rates improved from 1.9% at Week 24 to 42.6% at Week 52 in POETYK PSO-1 and from 4.5% to 27.0% in POETYK PSO-2; DLQI 0/1 response rates improved from 5.9% to 25.5% (POETYK PSO-1) and from 9.9% to 24.3% (POETYK PSO-2) (Fig. 3c, d).
Fig. 2.
PASI response thresholds at Week 24 in patients randomized to apremilast who did not achieve PASI 50 (POETYK PSO-1) or PASI 75 (POETYK PSO-2) (as observed). For PSO-2, patients who had any visit impacted by COVID-19 were excluded from that visit. aIn PSO-1, patients who did not achieve PASI 50 at Week 24 switched to deucravacitinib, while patients who did achieve PASI 50 continued to receive apremilast. Therefore, there are no nonresponders in the PASI 50 to < 75 category for PSO-1. CI confidence interval, PASI Psoriasis Activity and Severity Index
Fig. 3.
a PASI 75, b PASI 90, c sPGA 0/1, and d DLQI 0/1 response rates from Weeks 24 through 52 in patients who did not achieve PASI 50 (POETYK PSO-1) or PASI 75 (POETYK PSO-2) with apremilast at Week 24 (NRI). For PSO-2, patients who had any visit impacted by COVID-19 were excluded from that visit. DLQI 0/1 Dermatology Life Quality Index score of 0 (clear) or 1 (almost clear) with a ≥ 2-point reduction from baseline, NRI nonresponder imputation, PASI 50/75/90 ≥ 50%/75%/90% reduction from baseline in Psoriasis Activity and Severity Index, sPGA 0/1 static Physician Global Assessment score of 0 (clear) or 1 (almost clear) with a ≥ 2-point reduction from baseline
Among patients who switched from apremilast to deucravacitinib at Week 24, mean percent change from baseline PASI decreased by 60% from Weeks 24 through 52 (− 12.7% to − 73.1%) in POETYK PSO-1 and by 26% (− 41.4% to − 67.0%) in POETYK PSO-2 (Fig. 4a). Mean percent change from baseline in PSSD symptom score also decreased by approximately 20% in both studies from Weeks 24 through 52 (Fig. 4b). BSA involvement improved from Weeks 24 through 52, with a 65% mean percent decrease from baseline in POETYK PSO-1 and a 25% decrease in POETYK PSO-2 (Fig. 4c).
Fig. 4.
a Mean percent change from baseline PASI, b mean change from baseline PSSD symptom score, and c mean percent change from baseline BSA involvement over Weeks 0–52 for patients who did not achieve PASI 50 (POETYK PSO-1) or PASI 75 (POETYK PSO-2) with apremilast at Week 24 (as observed). BSA body surface area, CI confidence interval, PASI Psoriasis Area and Severity Index, PASI 50/75 ≥ 50%/75% reduction from baseline in PASI, PSSD Psoriasis Symptoms and Signs Diary
Discussion
The results of this analysis underscore the greater potency of deucravacitinib compared with apremilast in patients with moderate-to-severe plaque psoriasis and are consistent with the superior efficacy of deucravacitinib previously demonstrated in POETYK PSO-1 and PSO-2 [4, 5]. Patients who switched to deucravacitinib at Week 24 after not meeting predefined response criteria with apremilast experienced substantial improvements through Week 52 across several clinician- and patient-reported outcomes. Efficacy outcomes in patients who switched from apremilast to deucravacitinib followed a similar pattern of improvement to those previously reported in patients who received continuous deucravacitinib treatment from baseline [4, 5].
Differences in the mechanisms of action between deucravacitinib and apremilast may account for these observations. Although apremilast and deucravacitinib both inhibit inflammatory cytokines, they target different steps along the immune pathway. Apremilast is a PDE4 inhibitor; inhibition of PDE4 increases intracellular cyclic adenosine monophosphate, which in turn decreases production of Type I interferons, IL-23, IL-12, and IL-17A [6, 7]. Deucravacitinib targets TYK2, a nonreceptor tyrosine kinase essential for regulating signal transduction downstream of the receptors for IL-23, IL-12, and Type I interferons [1, 8]. This targeted downstream mechanism may lead to increased inhibition of IL-23 and other key cytokines involved in psoriasis pathogenesis compared with the upstream effects of apremilast.
Limitations
A limitation of this analysis is the short observation period. POETYK PSO-1 and PSO-2 were 52-week trials, and patients who switched from apremilast received deucravacitinib for 28 weeks. Longer treatment periods are needed.
Conclusion
Deucravacitinib was efficacious at Week 52 in patients who did not meet response criteria with apremilast, based on physician-assessed endpoints (PASI 75/90, sPGA 0/1, percent change from baseline in PASI and BSA) and patient-reported outcomes (DLQI 0/1, change from baseline in PSSD symptom score). These results provide clinical evidence that patients with moderate-to-severe plaque psoriasis who do not respond to apremilast may achieve substantial benefits with deucravacitinib, a once-daily oral treatment.
Acknowledgements
The authors thank the patients and investigators for the POETYK studies.
Medical Writing/Editorial Assistance
Writing and editorial assistance was provided by Kimberly MacKenzie, PhD, of Peloton Advantage, LLC, an OPEN Health company, funded by Bristol Myers Squibb.
Author Contributions
April W. Armstrong had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Misti Linaberry, Carolin Daamen. Acquisition, analysis, or interpretation of data: All authors (April W. Armstrong, Richard B. Warren, Howard Sofen, Lynda Spelman, Misti Linaberry, Brandon Becker, Ying-Ming Jou, Carolin Daamen and Alexa B. Kimball). Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Misti Linaberry, Ying-Ming Jou, Carolin Daamen.
Funding
This study and the funding of the journal’s Rapid Service Fees were sponsored by Bristol Myers Squibb and supported by the Manchester NIHR Biomedical Research Centre (NIHR203308).
Data Availability
The Bristol Myers Squibb policy on data sharing may be found at: https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
Declarations
Conflict of Interest
April W. Armstrong has served as a research investigator, scientific advisor, and/or speaker for AbbVie, Almirall, Arcutis, Aslan, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, EPI Health, Incyte, Janssen, LEO Pharma, Lilly, Mindera Health, Nimbus, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Richard B. Warren is an Editor-in-Chief of Dermatology and Therapy and was not involved in the selection of peer reviewers for this manuscript nor any of the subsequent editorial decisions. Professor Warren has received research grants from AbbVie, Almirall, Amgen, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, and UCB and consulting fees from AbbVie, Almirall, Amgen, Astellas, Boehringer Ingelheim, Celgene, DICE Therapeutics, GSK, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi, UCB, and Union Therapeutics. Howard Sofen has served as a clinical investigator for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, LEO Pharma, Lilly, Novartis, and Sun Pharma. Lynda Spelman has served as a consultant, paid investigator, clinical advisory board member and/or speaker for AbbVie, Amgen, Anacor, AnaptysBio, Ascend, Astellas, AstraZeneca, Blaze Bioscience, Boehringer Ingelheim, Botanix, Bristol Myers Squibb, Celgene, ConnectBiopharma, Genesis Care, Dermira, Eli Lilly, Enkang Pharmaceuticals, Equillium, Evelo Biosciences, Genesis Care, Galderma, Genentech, GlaxoSmithKline, Hexima, Incyte, InflaRx GmbH, Invion, Janssen, Kiniksa Pharmaceuticals, Kobio Labs, LG Chem, Lipidio Pharma, LEO Pharma, Mayne, Medimmune, Merck, Merck-Serono, Novartis, Nektar Therapeutics, Olix Pharmaceuticals, Otsuka, Pfizer, Phosphagenics, Photon MD, Principia, Regeneron, Ribon, Samumed, Sanofi Genzyme, SHR, Sun Pharma, Takeda, UCB, and Zai Lab. Misti Linaberry, Brandon Becker, and Ying-Ming Jou are employees of and shareholders in Bristol Myers Squibb. Carolin Daamen was an employee of and shareholder in Bristol Myers Squibb at the time of study conduct. Alexa B. Kimball’s institution received grants from AbbVie, AnaptysBio, Bristol Myers Squibb, Eli Lilly, Incyte, Janssen, MoonLake Immunotherapeutics, Novartis, Pfizer, Prometheus, Sanofi, Sonoma Biotherapeutics, and UCB; she received consulting fees from AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, MoonLake Immunotherapeutics, Novartis, Takeda, Target RWE, UCB, Union Therapeutics, and Ventyx; and serves on the board of directors of Almirall.
Ethical Approval
The POETYK PSO-1 and PSO-2 trials were conducted in accordance with Good Clinical Practice, as defined by the International Council for Harmonization and Declaration of Helsinki. Independent institutional review board approvals were obtained and all participants provided written informed consent.
Footnotes
Prior Presentation
This work was presented at the American Academy of Dermatology (AAD) Annual Meeting, March 25–29, 2022; Boston, MA. Poster 34658.
Publisher's Note
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Associated Data
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Data Availability Statement
The Bristol Myers Squibb policy on data sharing may be found at: https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.