Deucravacitinib: Adverse Events of Interest Across Phase 3 Plaque Psoriasis Trials

Abstract

Introduction

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in multiple countries for adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. The safety and efficacy of deucravacitinib in psoriasis has been demonstrated through 3 years in the phase 3 POETYK PSO-1, PSO-2, and long-term extension (LTE) trials enrolling adults with moderate to severe plaque psoriasis.

Methods

To review the effect of deucravacitinib treatment on adverse events of interest (AEIs) over 3 years in POETYK PSO-1, PSO-2, and LTE, cumulative exposure-adjusted incidence rates (EAIRs) of AEIs were recorded through 3 years.

Results

AEIs and 3-year EAIRs of select infections included serious infections (2.5/100 person-years [PY]), COVID-19 (1.6/100 PY), and herpes zoster (0.6/100 PY). Excluding COVID-19, the serious infections EAIR was 0.9/100 PY. Major adverse cardiovascular event (MACE) and venous thromboembolism EAIRs were 0.3/100 PY and 0.1/100 PY, respectively. The EAIRs for malignancies were 0.9/100 PY overall and 0.5/100 PY, excluding nonmelanoma skin cancer (NMSC). Cutaneous events included acne (EAIR, 1.3/100 PY) and folliculitis (EAIR, 1.1/100 PY). Three-year cumulative EAIRs generally remained stable or decreased relative to 1-year rates. EAIRs of non-COVID-19 serious infections, malignancies excluding NMSC, and MACE through 3 years were consistent with rates for other antipsoriatic agents from clinical trials, disease registries, and real-world claims data.

Conclusion

In adults with plaque psoriasis treated with deucravacitinib, the cumulative incidence of AEIs remained comparable or decreased over 3 years of follow-up and aligned with comparison data for other antipsoriatic therapies.

Key Summary Points

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in multiple countries for adults with moderate to severe plaque psoriasis who are candidates for systemic therapy.

Here, we reviewed the effect of deucravacitinib treatment on adverse events of interest over 3 years in the POETYK PSO-1, PSO-2, and long-term extension trials.

Rates of adverse events of interest were low (range 0.1–1.3/100 person-years, excluding COVID-19 infection), generally remaining stable or decreasing at 3-year versus 1-year clinical trial follow-up.

The cumulative incidence of adverse events of interest aligned with comparison data for other antipsoriatic therapies.

Introduction

The intracellular enzyme tyrosine kinase 2 (TYK2) is known to mediate signaling of select inflammatory cytokines, such as interleukin (IL)-23, IL-12, and type I interferons, while IL-23 and type I interferons are involved in psoriasis pathogenesis [1]. The oral, selective, allosteric TYK2 inhibitor deucravacitinib is approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy [2, 3, 4, 5–6]. Deucravacitinib represents the first in a new class of oral drugs, as it uniquely binds to the regulatory domain of TYK2 rather than to the catalytic domain where Janus kinase (JAK) 1,2,3 inhibitors bind; selectivity for TYK2 is driven through allosteric inhibition [1, 7].

POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) were global, 52-week, phase 3, double-blind trials that randomized patients with moderate to severe plaque psoriasis 1:2:1 to placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily (active comparator) [8]. In POETYK PSO-1 and PSO-2, deucravacitinib was more efficacious than placebo (week 16) and apremilast (weeks 16 and 24) in patients with moderate to severe plaque psoriasis [9, 10]. At week 52, patients who completed the POETYK PSO-1 and PSO-2 parent trials could enroll in the ongoing POETYK long-term extension (LTE) trial (NCT04036435) and receive open-label deucravacitinib [11]. Baseline patient demographics and clinical characteristics of the POETYK LTE population have been described previously and were typical of patients with moderate to severe plaque psoriasis [8].

Clinical efficacy was maintained well through 3 years in patients continuously treated with deucravacitinib. The safety profile at 3 years with continued deucravacitinib treatment was consistent with results at 1 year, with no new safety signals identified [8].

Methods

In the POETYK trials, adverse events of interest (AEIs) were selected on the basis of the following: the mechanism of action of deucravacitinib; adverse events observed in phase 2 deucravacitinib trials in psoriasis and psoriatic arthritis; adverse events observed in trials of JAK1,2,3 inhibitors; and comorbidities known to be associated with psoriasis, such as cardiovascular disease [9]. The AEIs considered included select infections (e.g., serious infections, COVID-19, herpes zoster), major adverse cardiovascular events (MACE) (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), venous thromboembolism (VTE) events, malignancies, and cutaneous events. Here, we review the AEIs in patients with moderate to severe plaque psoriasis receiving deucravacitinib for over 3 years.

The POETYK PSO-1, PSO-2, and LTE studies were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines of the International Council for Harmonisation and in accordance with the European Union Directive 2001/20/EC and the US Code of Federal Regulations, Title 21, Part 50 (21CFR50), as well as applicable local requirements. The study protocols and amendments were approved by an institutional review board or independent ethics committee before initiation of the study at each site. All patients or their legal representatives provided written informed consent prior to study participation.

Results

Across the POETYK PSO-1, PSO-2, and LTE trials, 1519 patients received at least one dose of deucravacitinib, representing a total exposure of 3294.3 person-years (PY) over the 3-year period [8]. Table 1 shows the cumulative exposure-adjusted incidence rates (EAIRs) of AEIs through 1 year (POETYK PSO-1 and PSO-2) and through 3 years (POETYK PSO-1, PSO-2, and LTE).

Table 1. Adverse events of interest through 1 year and 3 years

	Cumulative through 1 yeara (POETYK PSO-1 + PSO-2)			Cumulative through 3 yearsb (POETYK PSO-1 + PSO-2 + LTE)
	Placebo (n = 666) Total PY = 240.9c	Apremilast 30 mg BID (n = 422) Total PY = 221.1	Deucravacitinib 6 mg QD (n = 1364) Total PYc = 969.0	Deucravacitinib 6 mg QD (N = 1519) Total PYc = 3294.3
	EAIR/100 PY (95% CI)	EAIR/100 PY (95% CI)	EAIR/100 PY (95% CI)	EAIR/100 PY (95% CI)
Deaths	0.4 (0.1–2.8)	0.4 (0.1–3.1)	0.2 (0.1–0.8)	0.3 (0.2–0.6)
Serious infectionsd	0.8 (0.2–3.2)	1.8 (0.7–4.7)	1.7 (1.1–2.8)	2.5 (2.0–3.1)
Serious infections minus COVID-19	0.8 (0.1–2.9)	1.3 (0.3–3.9)	1.5 (0.9–2.5)	0.9 (0.6–1.3)
COVID-19	0	0.4 (0.0–2.5)	0.2 (0.0–0.7)	1.6 (1.2–2.2)
Herpes zostere,f	0.4 (0.1–2.8)	0	0.8 (0.4–1.6)	0.6 (0.4–0.9)
MACEg	1.2 (0.4–3.7)	0.9 (0.2–3.5)	0.3 (0.1–0.9)	0.3 (0.2–0.6)
VTE eventh	0	0	0.2 (0.1–0.8)	0.1 (0.0–0.3)
Malignancies	0	0.9 (0.2–3.5)	1.0 (0.5–1.9)	0.9 (0.6–1.3)
NMSC	0	0.4 (0.1–3.1)	0.7 (0.3–1.5)	0.4 (0.3–0.7)
Basal cell carcinoma	0	0	0.4 (0.2–1.1)	0.3 (0.2–0.6)
Squamous cell carcinoma	0	0.4 (0.1–3.1)	0.2 (0.1–0.8)	0.1 (0.0–0.3)i
Malignancies excluding NMSC	0	0.4 (0.1–3.1)	0.3 (0.1–0.9)	0.5 (0.3–0.8)j
Lymphoma	0	0	0.1 (0.0–0.7)	0.1 (0.0–0.3)
Cutaneous events of interest
Acne	0.4 (0.1–2.8)	0	2.9 (2.0–4.2)	1.3 (1.0–1.8)
Folliculitis	0	0.9 (0.2–3.5)	2.8 (1.9–4.0)	1.1 (0.8–1.5)

Safety was assessed in the as-treated population. Not all patients were receiving deucravacitinib 6 mg QD continuously throughout this period

BID twice daily, CI confidence interval, EAIR exposure-adjusted incidence rate, LTE long-term extension, MACE major adverse cardiovascular events, NMSC nonmelanoma skin cancer, PY person-years, QD once daily, VTE venous thromboembolism

^aThis represents the pooled patient population of POETYK PSO-1 and PSO-2 (weeks 0–52)

^bThis represents the pooled POETYK PSO-1 and PSO-2 population enrolled in the POETYK LTE trial through the cutoff date of June 15, 2022

^cTotal PY corresponds to the total exposure time to deucravacitinib during the indicated time period

^dThe POETYK PSO-1, PSO-2, and LTE trials were conducted during the COVID-19 pandemic

^eOne patient treated with deucravacitinib who was coded as having herpes zoster had corneal/ocular disease related to herpes zoster infection diagnosed by an ophthalmologist with a positive qualitative chickenpox virus antigen (epithelial cells)

^fOne patient treated with deucravacitinib who was coded as having ophthalmic herpes zoster with swelling of the eyelids was referred for ophthalmology consultation, which was noted as normal; there was no corneal/ocular disease related to herpes virus infection

^gMACE were adjudicated and were defined as nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death. MACE in deucravacitinib-treated patients through 1 year: cardiac failure leading to death, n = 1; cerebrovascular accident, n = 1; myocardial infarction, n = 1. MACE through 3 years (cumulative): cerebral hemorrhage, n = 1; ischemic stroke, n = 1; cerebrovascular accident, n = 2; acute myocardial infarction, n = 3; myocardial infarction, n = 2; aortic aneurysm rupture leading to death, n = 1; cardiac arrest, n = 1

^hVTE was defined as deep vein thrombosis and pulmonary embolism. VTE events in deucravacitinib-treated patients through 1 year: deep vein thrombosis, n = 1; pulmonary embolism, n = 1. VTE events through 3 years (cumulative): deep vein thrombosis, n = 2; pulmonary embolism, n = 1 (the 1 new event of deep vein thrombosis occurred in year 2; no new VTE events occurred in year 3). Narratives of these cases have previously been reported [11, 44]. Following standard medical management, all events resolved and none recurred; no events were considered treatment related by the investigator

ⁱIncludes preferred terms of squamous cell carcinoma, squamous cell carcinoma of skin, and Bowen’s disease

^jIncludes events of breast cancer (n = 2), invasive ductal breast carcinoma (n = 1), intraductal proliferative breast lesion (n = 1), lung adenocarcinoma (n = 1), colon cancer (n = 1), colorectal cancer (n = 1), pancreatic carcinoma (n = 1), hepatocellular carcinoma (n = 1), B cell lymphoma (n = 1), nodal marginal zone B cell lymphoma (n = 1), Hodgkin’s disease (n = 1), acute promyelocytic leukemia (n = 1), malignant melanoma (n = 2), and squamous cell carcinoma of the oral cavity (n = 1)

Select Infections

The EAIR of serious infections, including COVID-19, in the 3-year cumulative period was 2.5/100 PY (95% confidence interval [CI] 2.0–3.1). Excluding COVID-19, the cumulative EAIR of serious infections through 3 years (0.9/100 PY [95% CI 0.6–1.3]) decreased compared with that observed through the first year, prior to the start of the pandemic (1.7/100 PY [95% CI 1.1–2.8]), and is comparable to the rates reported in trials and real-world registries of patients receiving other antipsoriatic treatments (Fig. 1a) [12, 13, 14, 15, 16, 17, 18, 19–20]. The rate of serious COVID-19 infections (1.6/100 PY [95% CI 1.2–2.2]) did not reflect an increased risk as compared to contemporaneous reference populations [21, 22]. The EAIR for herpes zoster at 3 years (0.6/100 PY [95% CI 0.4–0.9]) decreased slightly compared with the EAIR in the deucravacitinib group at 1 year (0.8/100 PY [95% CI 0.4–1.6]). These EAIRs are comparable to rates of herpes zoster in patients receiving other systemic therapies for psoriasis, including anti-IL-17, anti-IL-23, anti-IL-12/23, and tumor necrosis factor inhibitor therapies (0.5–1.3/100 PY) [23].

[See PDF for image]

Fig. 1

Incidence rates of a serious infections, b malignancies excluding NMSC, and c MACE with deucravacitinib (through 3 years) versus other systemic therapies for psoriasis and in the US general population. BADBIR British Association of Dermatologists Biologic and Immunomodulators Register, CI confidence interval, EAIR exposure-adjusted incidence rate, IL interleukin, MACE major adverse cardiovascular events, NMSC nonmelanoma skin cancer, PSOLAR Psoriasis Longitudinal Assessment and Registry, PY person-year, SEER Surveillance, Epidemiology, and End Results, TNF tumor necrosis factor

Malignancies

The overall EAIR of malignancies through 3 years (0.9/100 PY [range 0.6–1.3]) was comparable to the EAIR through 1 year (1.0/100 PY [range 0.5–1.9]), with no trends or clusters of malignancy types observed. Rates of malignancies excluding NMSC were consistent with findings from long-term clinical trial safety studies, disease registries, and real-world claims data of other approved psoriasis treatments (Fig. 1b) [12, 13–14, 18, 24, 25–26]. At 3 years, the cumulative EAIR of NMSC was 0.4/100 PY (95% CI 0.3–0.7), a decrease from the 1-year cumulative EAIR of 0.7/100 PY (95% CI 0.3–1.5). These rates are consistent with rates seen in long-term safety in clinical trials of other approved psoriasis treatments (0.3–0.5/100 PY) [12, 13]. The ratio of basal cell carcinoma to squamous cell carcinoma remained close to 2:1. The EAIR of lymphoma through 3 years (0.1/100 PY [95% CI 0.0–0.3]) remained consistent with the EAIR at 1 year (0.1/100 PY [95% CI 0.0–0.7]). Per the US Surveillance, Epidemiology, and End Results (SEER) database, the standardized incidence ratio (SIR) for lymphoma through 3 years was not significantly higher than in the general US population (SIR 3.2, 95% CI 0.6–9.2) [27]. Additionally, the risk of lymphoma in patients with psoriasis (EAIR 0.04–0.14/100 PY) has been shown to be higher than the general population (EAIR 0.02–0.03/100 PY) [28, 29, 30, 31, 32, 33, 34, 35–36].

MACE and VTE Events

The cumulative EAIR of MACE through 3 years (0.3/100 PY [95% CI 0.2–0.6]) remained consistent with the cumulative rate through 1 year. These rates of MACE were comparable to those in long-term clinical trials and background rates in patients treated with other antipsoriatic agents (Fig. 1c) [13, 14–15, 17, 18, 37]. VTE events were uncommon, and the cumulative EAIRs were comparable at 1 year (0.2/100 PY [95% CI 0.1–0.8]) and 3 years (0.1/100 PY [95% CI 0.0–0.3]). The incidence rate for VTEs was consistent with published background rates in patients with mild to severe psoriasis (0.19–0.32/100 PY) and the general population (0.1–0.2/100 PY) [38, 39].

Cutaneous Events

The cumulative 3-year EAIRs of cutaneous events of interest (acne, 1.3/100 PY [95% CI 1.0–1.8]; folliculitis, 1.1/100 PY [95% CI 0.8–1.5]) reflected a reduction in the cumulative rate of these AEIs compared with results through 1 year (Table 1). In the analysis through 1 year, most acne and folliculitis events were mild to moderate in severity, occurred early, and resolved spontaneously or with antimicrobial therapy [8].

Discussion

Overall, the cumulative rates of AEIs through 3 years in the POETYK PSO-1, PSO-2, and LTE trials remained similar or decreased compared with the corresponding rates through the first year. The COVID-19 pandemic was a critical variable during years 2 and 3 of the LTE trial, which led to a higher serious infection rate. The 3-year cumulative rate of serious infections excluding COVID-19 (0.9/100 PY) was decreased compared with the serious infection rates through 1 year among patients treated with deucravacitinib or apremilast (1.7/100 PY and 1.8/100 PY, respectively) and aligned with serious infection rates reported for other psoriatic agents in clinical trials, disease registries, and real-world claims data [12, 15, 16, 17, 18, 19–20]. Of the 10 deaths that occurred through 3 years of follow-up in the POETYK PSO-1, PSO-2, and LTE trials, seven were due to COVID-19. Of these seven patients, one had received one dose of COVID-19 vaccine, four contracted COVID-19 before vaccines were widely available, and two had unknown vaccine status. Rates of serious COVID-19 infection and mortality were not higher than contemporaneous COVID-19 background rates [21, 22, 40].

The cumulative EAIRs of malignancies, MACE, and herpes zoster were generally comparable in patients originally randomized to placebo, apremilast, and deucravacitinib through 3 years. Rates of cutaneous events, such as acne and folliculitis, were higher in patients taking deucravacitinib through year 1 than in the comparator groups but decreased through 3 years.

Deucravacitinib was also efficacious and well tolerated in phase 2 trials of systemic lupus erythematosus (NCT03252587) [41] and psoriatic arthritis (NCT03881059) compared with placebo [42]. With the exception of cutaneous events, the AEIs reported in those studies were comparable between placebo and deucravacitinib at doses up to 12 mg daily in patients who were also taking background immunosuppressants, such as methotrexate and glucocorticoids [41, 42].

In safety data reported to date, deucravacitinib was well tolerated in clinical trials without increased risk of many of the AEs of a more serious nature, such as malignancies and cardiovascular events, which have been reported with JAK1,2,3 inhibitors [43].

Conclusion

In adults treated with deucravacitinib for moderate to severe plaque psoriasis in the POETYK PSO-1, PSO-2, and LTE trials, incidence rates of non-COVID-19 serious infections, malignancies excluding NMSC, and MACE through 3 years were consistent with rates reported in other clinical trials, disease registries, and real-world claims data of other agents, although cross-comparisons should be interpreted with caution.

Acknowledgements

We thank the participants in all three 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

Joseph F. Merola, Laura K. Ferris, Jeffrey M. Sobell, Howard Sofen, John Osborne, John Vaile, Ying-Ming Jou, Carolin Daamen, Julie Scotto, Thomas Scharnitz, and Mark Lebwohl contributed to the study concept and design. John Vaile, Ying-Min Jou, Carolin Daamen, Julie Scotto, and Thomas Scharnitz contributed to the data acquisition and statistical analysis. Joseph F. Merola, Laura K. Ferris, Jeffrey M. Sobell, Howard Sofen, John Osborne, John Vaile, Ying-Ming Jou, Carolin Daamen, Julie Scotto, Thomas Scharnitz, and Mark Lebwohl contributed to the data interpretation, critically reviewed the manuscript for intellectual content, and provided final approval for publication.

Funding

This study as well as the journal’s publication process fee were sponsored by Bristol Myers Squibb.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Mark Lebwohl is an Editorial Board member of Dermatology and Therapy. Mark Lebwohl was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Disclosure of potential conflict of interest: Joseph F. Merola has served as a consultant and/or investigator for AbbVie, Amgen, Biogen, Bristol Myers Squibb, Dermavant, Janssen, Leo Pharma, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Laura K. Ferris has served as an investigator for AbbVie, Acelyrin, Amgen, Apogee, Arcutis, Aristea, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, DermTech, Galderma, GRAIL, Incyte, Janssen, Leo Pharma, Lilly, Moberg, Mobius, Novartis, Regeneron, SkinAnalytics, Takeda, and UCB; consultant for AbbVie, Amgen, Apogee, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Dermavant, DermTech, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, and Takeda; speaker for AbbVie, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, and Regeneron. Jeffrey M. Sobell has served as a consultant, speaker, and/or investigator for Amgen, AbbVie, Arcutis, Biogen, Bristol Myers Squibb, Dermavant, Janssen, Lilly, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB. Howard Sofen has served as a clinical investigator for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Leo Pharma, Lilly, Novartis, and Sun Pharma. John Osborne has served on a speakers bureau for Amarin, Boehringer Ingelheim, Esperion Therapeutics, Lilly, and Novo Nordisk. John Vaile, Ying-Ming Jou, Carolin Daamen, and Julie Scotto are employees of and shareholders in Bristol Myers Squibb. Thomas Scharnitz was an employee of and shareholder in Bristol Myers Squibb at the time of study conduct and is now an employee of Novartis. Mark Lebwohl is an employee of Mount Sinai and has received research funds from AbbVie, Arcutis, Avotres, Boehringer Ingelheim, Cara Therapeutics, Clexio, Dermavant, Incyte, Inozyme, Janssen, Lilly, Pfizer, Sanofi-Regeneron, and UCB, and is a consultant for Almirall, AltruBio, Apogee, Arcutis, AstraZeneca, Atomwise, Avotres, Boehringer Ingelheim, Bristol Myers Squibb, Castle Biosciences, Celltrion, CorEvitas Psoriasis Registry, Dermavant, Dermsquared, Evommune, Facilitation of International Dermatology Education, Forte Biosciences, Galderma, Genentech, Incyte, Leo Pharma, Meiji Seika Pharma, Mindera Health, Pfizer, Sanofi-Regeneron, Seanergy, Strata, Takeda, Trevi, and Verrica.

Ethical Approval

These studies were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines of the International Council for Harmonisation and in accordance with the European Union Directive 2001/20/EC and the US Code of Federal Regulations, Title 21, Part 50 (21CFR50), as well as applicable local requirements. The study protocols and amendments were approved by an institutional review board or independent ethics committee before initiation of the study at each site. All patients or their legal representatives provided written informed consent prior to study participation.

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