Deucravacitinib in the treatment of psoriasis

Abstract

Purpose of the article

Psoriasis is a chronic, immune-mediated, skin disease with a significantly negative impact on patients’ quality of life. Moderate-to-severe disease often requires systemic therapies and currently available ones still have numerous disadvantages or limitations. Tyrosine kinase 2 (TYK2) mediates immune signaling of IL-12, IL-23, and type I interferons, without interfering with other critical systemic functions. This article aims to review the current knowledge on deucravacitinib, a new oral drug which selectively inhibits TYK2, granting it a low risk of off-target effects.

Materials and methods

A review of the published literature was conducted using the PubMed database, published abstracts and virtual presentations from scientific meetings, data from industry press releases, and results published on ClinicalTrials.gov regarding the deucravacitinib for the treatment of psoriasis. Manuscripts with trial results, case series, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on the topic of the article were selected.

Results

Two phase 3, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast – POETYK PSO-1 and PSO-2, enrolling 1688 patients with moderate-to-severe psoriasis. At week 16, over 50% of patients treated with deucravacitinib reached PASI75, significantly superior to placebo and apremilast. Symptomatic improvement was also reported, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities. Persistent efficacy and consistent safety profiles were reported for up to 2 years.

Conclusions

Deucravacitinib has the potential to become a safe, effective, and well-tolerated treatment for patients with moderate-to-severe disease. Future studies will be important to determine the exact role of this drug in the treatment of psoriasis.

Keywords:

• Deucravacitinib
• psoriasis
• TYK2
• BMS-986165

Introduction

Psoriasis is a chronic, immune-mediated, inflammatory skin disease that has a negative and significant impact on patients’ quality of life. The disease affects more than 125 million people worldwide, with an estimated global prevalence of 2–3%, being more common in adults and less common in children (1,2). It has a bimodal distribution in terms of age, one peak around 30–39 years and another around 50–69 years (2).

Regarding its clinical features, psoriasis has several variants or subtypes, which exhibit different clinical characteristics. The main variants of psoriasis include plaque psoriasis, pustular psoriasis, guttate psoriasis, and erythrodermic psoriasis (3). Plaque psoriasis is by far the most common subtype, accounting for approximately 90% of cases (4). Patients with this subtype usually present sharply demarcated erythematous plaques covered by silvery-white lamellar scales, which can develop anywhere on the body; however, typically affected areas include the extensor surfaces (especially elbows and knees), scalp, and gluteal fold (3–5). Nail involvement is also very common in psoriasis (up to 50% of patients), with pitting, onycholysis, and oil-drop discoloration being the most frequently seen nail changes (6,7).

Psoriasis is also a multisystem disorder, being associated with several comorbidities, such as psoriatic arthritis, cardiovascular disease, metabolic syndrome, obesity, diabetes, hypertension, autoimmune disorders, malignancy, inflammatory bowel disease, nonalcoholic fatty liver disease, and depression (8,9).

Regarding the treatment of psoriasis, while in mild disease topical therapies are usually sufficient, in patients with moderate-to-severe disease systemic therapies are often required. There are various systemic therapy options, including conventional systemic therapies, apremilast, and biologics, that, despite being widely used, have some disadvantages. Conventional systemic therapies are usually associated with various adverse effects, end-organ toxicity, drug-drug interactions, and they also require close laboratory monitoring (4,10,11). Apremilast, on the other hand, has limited efficacy (12). Lastly, biologic agents require parenteral administration and present risk of immunogenicity, loss of efficacy over time, high cost, and increased risk of infection (13–15). Thus, there is still an unmet need for accessible, efficacious, and safe therapies for patients with moderate-to-severe psoriasis.

This article aims to review the current knowledge on deucravacitinib, a new, oral, small molecule that selectively inhibits TYK2, for the treatment of psoriasis.

JAK-STAT signaling pathway and the role of TYK2 in psoriasis

Despite the pathogenesis of psoriasis is not fully understood, it is believed to be a complex disorder of both the innate and the adaptive immune systems. In the initial phase, the disease can be triggered by several factors, especially in genetically susceptible individuals, including medications (such as β-blockers and lithium), trauma, stress, infections (such as streptococcal infection), alcohol and cigarette smoking (1,10). In response to these triggers, keratinocytes secrete antimicrobial peptides (AMPs), such as LL-37. These peptides (especially LL-37) stimulate plasmacytoid dendritic cells to produce type I interferons (IFNs), namely IFN-α and IFN-β, which in turn will promote the activation and maturation of myeloid dendritic cells (16,17). When activated, myeloid dendritic cells act as antigen-presenting cells and secrete several inflammatory mediators, including tumor necrosis factor α (TNF-α), interleukin (IL)-23, and IL-12. IL-23 and IL-12 end up promoting the differentiation and proliferation of T helper 17 (Th17) and T helper 1 (Th1) cells, respectively (10,18).

In psoriasis, the dominant T cell type is Th17 cells that, when activated, produce several cytokines, including IL-17A, IL-17F, IL-22, and TNF-α (the latter also produced by Th1 cells) (3,19). These cytokines, with IL-17A being the most important effector cytokine in psoriasis, promote keratinocyte hyperproliferation (which leads to epidermal hyperplasia, a hallmark of psoriasis) and release of pro-inflammatory cytokines, chemokines, and antimicrobial peptides that act via a positive feedback loop to attract other innate and adaptive immune cells to further potentiate the psoriatic inflammation (18,20). Thus, the IL-23/IL-17 axis plays a predominant role in the pathogenesis of psoriasis.

The Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a central role in the intracellular signalization of cytokines and other molecules involved in physiological and pathological processes, such as autoimmune and inflammatory diseases, including psoriasis (21–23). In fact, IL-23, as well as IL-12 and type I IFNs, rely on the JAK-STAT signaling pathway to trigger their pathogenic effect (24,25).

The JAKs are tyrosine kinases that bind to the cytoplasmic region of type I and II cytokine receptors and, along with signal transducer and activator of transcription (STAT) proteins, play a major role in signal transduction. There are four different types of JAK proteins: JAK1, JAK2, JAK3, and TYK2; and seven types of STAT proteins: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6 (24,26,27). The signaling cascade is initiated by the binding of a cytokine (e.g. interleukins and interferons) to its transmembrane receptor and the consequent dimerization of the receptor (22,24). This leads to trans-phosphorylation and activation of the two receptor-bound JAKs by placing them in spatial proximity and inducing conformational changes that distance their kinase domains from inhibitory pseudokinase domains (23,28,29). Once activated, JAKs phosphorylate tyrosine residues within the cytoplasmic regions of the receptor, creating docking sites for proteins that contain SH2 domains, such as STAT proteins. The STAT proteins then attach to the receptor’s phosphorylated tyrosines, through their SH2 domains, and are phosphorylated by JAKs (26,28,30). This phosphorylation ultimately leads to the dimerization of the STATs and their translocation into the cell nucleus to directly regulate gene expression (24,31).

TYK2 is one of the four members of the JAK family. This protein mediates the signaling of several cytokines’ receptors implicated in the pathogenesis of psoriasis, especially IL-12, IL-23, and type I IFNs (32–34). TYK2 pairs with JAK2 to mediate the signaling of IL-12 and IL-23 receptors (35). As previously mentioned, IL-12 and IL-23 are two critical pathogenic mediators of psoriasis. IL-12 is essential in the differentiation and proliferation of Th1 cells that produce IFN-γ and TNF-α, and IL-23 is central to the survival and proliferation of Th17 cells (3,18).

TYK2 also pairs with JAK1 to mediate the signaling of type I IFNs receptors, namely IFN-α and IFN-β (35). Type I IFNs have several effects that also contribute to the pathogenesis of psoriasis: Th1 and Th17 cells polarization, dendritic cells maturation and activation, reduced regulatory T cells function, and increased B cells activation with subsequent antibody production (36).

In 2010, TYK2 was identified in a genome-wide association study as a psoriasis susceptibility gene (37). TYK2 deficiency is linked with defects in various cytokine signaling pathways that play a crucial role in the pathogenesis of psoriasis, including type I IFNs, IL-12, and IL-23 (38). A deactivating genetic variant of TYK2, which results in an impaired type I IFNs, IL-12 and IL-23 signaling, is highly protective against autoimmunity and does not lead to immunodeficiency (39).

Given the main involvement of TYK2 in signaling and functional responses downstream of IL-23, IL-12, and type I IFNs receptors, TYK2 inhibition may play an important role in the treatment of psoriasis and present itself as a safe and effective solution (40–42).

Deucravacitinib

Deucravacitinib is an orally administered selective TYK2 inhibitor recently FDA approved for the treatment of moderate-to-severe plaque psoriasis (13). It has a mechanism of action distinct from other JAK inhibitors (43,44). This drug binds allosterically to the regulatory pseudokinase (JH2) domain of TYK2 rather than to the ATP-binding active site in the catalytic (JH1) domain, where other JAK inhibitors do. Unlike regulatory domain, the catalytic domain exhibits a high degree of similarity among the four members of the JAK family (45,46). This allosteric binding locks the regulatory domain into an inhibitory conformation with the catalytic domain, inactivating TYK2 and therefore preventing receptor-mediated activation and downstream signal transduction (34,47).

Deucravacitinib inhibits TYK2 with high selectivity and shows minimal or no inhibition of JAK 1/2/3. This agent demonstrated high selectivity for the TYK2 regulatory pseudokinase domain in vitro and, in cellular assays, deucravacitinib had more than 100-fold greater selectivity for TYK2 over JAK 1/3, and more than 2000-fold greater selectivity for TYK2 over JAK 2 (34). Furthermore, another study concluded that deucravacitinib has high functional selectivity for TYK2 and does not inhibit JAK 1/2/3at clinically relevant doses (47). This high selectivity for TYK2 is expected to grant deucravacitinib a better safety profile, compared to other less selective JAK inhibitors, with fewer adverse effects generally associated with the other three members of the JAK family, such as hyperlipidemia, renal (increased serum creatinine levels) and hepatic abnormalities (increased liver enzyme levels), hematologic changes (anemia, thrombocytopenia, lymphopenia, and neutropenia), and infections, particularly herpes zoster and opportunistic infections (especially tuberculosis) (45,47,48). Thus, deucravacitinib may be an effective and safe treatment for psoriasis.

In a phase 1 clinical trial involving 108 (83 active and 25 placebo) healthy participants, deucravacitinib has shown to be safe and overall, well tolerated. No serious adverse events were observed, and the frequency of non-serious adverse events was similar in the active and placebo groups. The most frequently reported adverse events were headache, nausea, rash, and upper respiratory tract infection. After oral administration, the agent was rapidly absorbed and revealed an apparent elimination half-life of 8 to 15 h (49).

In a phase 2 trial involving 267 adult patients with moderate-to-severe psoriasis, the participants were randomly selected to receive the drug orally (3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily) or placebo. This study showed that a remarkably higher percentage of participants attained PASI 75 at week 12, with deucravacitinib 3 mg daily (39%), 3 mg twice daily (69%), 6 mg twice daily (67%), and 12 mg daily (75%) compared to placebo (7%) (50). The results mentioned above at week 12 (primary endpoint) and other relevant secondary efficacy endpoints are outlined in Table 1. A post-hoc analysis of this phase 2 trial evaluated the impact of deucravacitinib on patient-reported quality of life. The percentage of patients achieving a DLQI 0/1 in the three highest dosage groups combined, increased through week 4 to 12. Improvement in quality of life followed a similar pattern of response to treatment to that of the clinical outcomes (44). Adverse events were reported in 51% of the patients in the placebo group and in 55–80% of the patients in the active groups, with the highest percentage being recorded in the group receiving 6 mg twice daily. The most frequently reported adverse events were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection (50). During the trial, no cases of herpes zoster infection, opportunistic infections, tuberculosis, or cardiovascular events were reported, and no significant changes were observed from baseline in mean values of blood counts, serum levels of lipids, creatinine, liver enzymes, or immunoglobulins (50).

Table 1. Efficacy results at week 12 of deucravacitinib against placebo, in a phase 2 clinical trial with moderate-to-severe psoriasis patients.

Endpoint	Deucravacitinib					Placebo (N = 45)
	3 mg every other day (N = 44)	3 mg daily (N = 44)	3 mg twice daily (N = 45)	6 mg twice daily (N = 45)	12 mg daily (N = 44)
PASI 75	9%	39%	69%	67%	75%	7%
PASI 90	7%	16%	44%	44%	43%	2%
PASI 100	2%	0%	9%	18%	25%	0%
sPGA 0/1	20%	39%	76%	64%	75%	7%
DLQI 0/1	16%	16%	42%	60%	64%	4%

PASI 75–75% or greater reduction from baseline in PASI score (primary endpoint). PASI 90–90% or greater reduction from baseline in PASI score. PASI 100–100% reduction from baseline in PASI score. sPGA 0/1 – static Physician’s Global Assessment score of 0 or 1 (clear or almost clear). DLQI 0/1 – Dermatology Life Quality Index score of 0 or 1 (no effect on the quality of life).

Another phase 2 trial to evaluate the efficacy and safety of deucravacitinib in patients with active psoriatic arthritis, involving 203 participants with psoriatic arthritis, concluded that treatment with deucravacitinib is generally well-tolerated, and the safety and laboratory parameter profile of the agent demonstrated to be consistent with what was observed in the phase 2 psoriasis trial (51).

Two large, phase 3, trials (POETYK PSO-1 and POETYK PSO-2) which compared the efficacy and safety of deucravacitinib versus placebo and apremilast in patients with plaque psoriasis were recently completed. These clinical trials involved a total of 1686 patients with moderate-to-severe psoriasis (666 in PSO-1 and 1020 in PSO-2), of whom at least one-third had been previously treated with biologics. Participants were randomized to deucravacitinib 6 mg once daily, apremilast 30 mg twice daily, or placebo (2:1:1). The trials ran for 52 weeks, during which time patients receiving placebo switched to deucravacitinib at week 16 in both trials, and patients receiving apremilast who relapsed (< PASI 50 in PSO-1 and < PASI 75 in PSO-2) switched to deucravacitinib at week 24. PSO-2 also included a randomized withdrawal phase starting at week 24, in which patients receiving deucravacitinib from day one who achieved a PASI 75 response were re-randomized to placebo or deucravacitinib (1:1), while those who did not achieve a PASI 75 response continued to receive deucravacitinib (52,53).

In both studies, deucravacitinib demonstrated to be notably more effective than apremilast and placebo at week 16,58.7% and 53.6% (PSO-1 and PSO-2, respectively) of patients receiving deucravacitinib reached a PASI 75 response compared to 35.1% and 40.2% receiving apremilast, and 12.7% and 9.4% receiving placebo. Similarly, also in week 16, 53.6% and 50.3% of patients receiving deucravacitinib achieved a static Physician’s Global Assessment (sPGA) 0/1 response compared to 32.1% and 34.3% receiving apremilast, and 7.2% and 8.6% receiving placebo. The efficacy results mentioned above at week 16 (coprimary endpoints) and other pertinent secondary endpoints are outlined in Table 2 (52,53).

Table 2. Efficacy results at week 16 of deucravacitinib against placebo and an active comparator (apremilast), in two phase 3 clinical trial with moderate-to-severe psoriasis patients.

	Endpoint	Clinical trial	Deucravacitinib 6 mg once daily	Apremilast 30 mg twice daily	Placebo
Coprimary endpoints	PASI 75	POETYK PSO-1	58.7%	35.1%	12.7%
		POETYK PSO-2	53.6%	40.2%	9.4%
	sPGA 0/1	POETYK PSO-1	53.6%	32.1%	7.2%
		POETYK PSO-2	50.3%	34.3%	8.6%
Secondary endpoints	DLQI 0/1	POETYK PSO-1	40.7%	28.6%	10.6%
		POETYK PSO-2	38.0%	23.1%	9.8%
	ss-PGA 0/1	POETYK PSO-1	70.8%	39.1%	17.4%
		POETYK PSO-2	60.3%	37.3%	17.3%

PASI 75–75% or greater reduction from baseline in PASI score. sPGA 0/1 – static Physician’s Global Assessment score of 0 or 1 (clear or almost clear). DLQI 0/1 – Dermatology Life Quality Index score of 0 or 1 (no effect on the quality of life). ss-PGA 0/1 – scalp-specific Physician’s Global Assessment score of 0 or 1 (clear or almost clear).

At week 24, deucravacitinib maintained its superiority over apremilast, with 69% and 59.3% (PSO-1 and PSO-2, respectively) of patients reaching a PASI 75 response (versus 38.1% and 37.8% with apremilast), and 58.4% and 50.4% of patients achieving an sPGA 0/1 response (versus 31% and 29.5% with apremilast) (52,53).

In POETYK PSO-1, participants who received continuous deucravacitinib treatment maintained PASI 75 and sPGA 0/1 responses (65.1% and 52.7%, respectively, at week 52) from week 16 to week 52. Furthermore, participants who switched from placebo to deucravacitinib at week 16 exhibited PASI 75 and sPGA 0/1 responses at week 52 (68.3% and 53.8%, respectively) comparable to those observed in patients who received continuous deucravacitinib treatment (54,55).

In POETYK PSO-2, the majority of deucravacitinib participants who achieved PASI 75 at week 24 maintained PASI 75 and sPGA 0/1 responses (80.4% and 70.3%, respectively, at week 52) on continuous treatment through week 52. On the other hand, those who discontinued treatment (placebo) had PASI 75 and sPGA 0/1 responses of 31.3% and 23.5%, respectively, at week 52 (53,54,56).

In both clinical trials, deucravacitinib proved to be safe and well-tolerated. At week 16, the deucravacitinib group had a slightly lower percentage of patients with adverse events leading to treatment discontinuation than the apremilast and placebo groups (2.4% vs. 5.2% vs. 3.8%, respectively). The most frequently reported adverse events with deucravacitinib were nasopharyngitis and upper respiratory tract infection. Headache, diarrhea, and nausea were also reported, with a similar frequency in the deucravacitinib and placebo groups and a higher frequency in the apremilast group. In terms of laboratory parameters, no significant changes were observed in total cholesterol, creatine phosphokinase, neutrophils, or platelets. No cases of herpes zoster were serious or led to discontinuation, and no cases of opportunistic infections or tuberculosis were reported with deucravacitinib (53,56,57).

At the end of the 52-week POETYK PSO-1 and 2, 1221 patients were switched to an open-label deucravacitinib extension trial for up to 240 weeks. Data concerning long-term extension (LTE) results were recently presented (56,58). From week 0 to 60 of POETYK PSO-LTE (NCT04036435), patients who were already on deucravacitinib at week 0 kept improving (PASI75 from 70.8 to 79.4% and PASI90 from 43.6 to 50.7%). Patients who switched from apremilast to deucravacitinib at week 0 also clinically improved (PASI75 from 73.8 to 87.1% and PASI90 from 40.0 to 62.9%) (56,58). Aside from COVID-19, the safety profile was consistent across POETYK PSO-1, PSO-2 and LTE. An increase in serious infections was observed, which is attributable to COVID-19 infections (56,58).

Discussion

Psoriasis has a significant prevalence worldwide and a markedly negative impact on patients’ quality of life. Although there is a wide range of systemic therapies for the treatment of moderate to severe disease, due to the numerous disadvantages of these drugs, there is still an unmet need for safe, well-tolerated, and effective oral therapies.

JAK inhibitors have been of particular interest due to their ability to target multiple cytokines simultaneously. JAK inhibitors, as a class, although proven to be effective in the treatment of psoriasis, are also associated with some off-target effects that translate into changes in laboratory parameters (hemoglobin, platelets, neutrophils, lipid panel, creatine phosphokinase), higher risk of infections, malignancy, and thromboembolic events. TYK2 plays a key role in the pathogenesis of psoriasis by mediating IL-12, IL-23, and type I IFNs receptors signaling and functional responses downstream. The ability to bind allosterically to the regulatory domain rather than to the active site in the catalytic domain, confers to deucravacitinib a high selectivity for TYK2. Hence, inhibition with deucravacitinib is expected to avoid the adverse effects that arise from JAK 1–3 inhibition.

Overall, in phase 2 and phase 3 trials, deucravacitinib showed promising results, both in terms of safety and efficacy. In the phase 2 trial, the use of deucravacitinib at doses of 3 mg daily and higher resulted in greater clearance of psoriasis compared to placebo. The efficacy was significantly higher with deucravacitinib 3 mg twice daily, 6 mg twice daily, and 12 mg once daily. Improvements in quality of life were only seen in the groups receiving 3 mg twice daily and higher doses of deucravacitinib.

In both phase 3 trials, deucravacitinib 6 mg once daily showed a far superior efficacy compared to apremilast 30 mg twice daily (active control) and placebo, at week 16. At week 24, the superiority of deucravacitinib over apremilast was even greater, with a proportion of patients achieving a PASI 75 response 1.8 and 1.6 times (PSO-1 and PSO-2, respectively) higher than the active control. Deucravacitinib also demonstrated superior efficacy results in scalp psoriasis, as well as a greater impact on quality of life (versus apremilast and placebo).

At week 52, in PSO-1, patients who received continuous deucravacitinib treatment maintained clinical responses, and patients who switched from placebo to deucravacitinib at week 16 had similar responses to those who received continuous deucravacitinib treatment from day 1. In PSO-2, clinical responses were also maintained on continuous treatment through week 52 in the majority of deucravacitinib patients who achieved PASI 75 at week 24, and durable responses were observed after withdrawal of treatment in week 24 responders.

Globally, deucravacitinib was well-tolerated and safe. The safety results were consistent with the mechanism of action of deucravacitinib and its high selectivity for TYK2, with no relevant adverse effects associated with JAK 1-3 inhibition observed. Overall, it had low rates of adverse events, with the most frequently reported being nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea.

In short, deucravacitinib has the potential to become a safe, effective, and well-tolerated treatment for patients with moderate-to-severe psoriasis. Future studies evaluating long-term response beyond 52 weeks and comparing deucravacitinib versus biologic agents will be important to determine the exact role of this drug in the treatment of psoriasis.

Disclosure statement

Ana Maria Lé and Tomás Estevinho have no conflicts of interest.

Additional information

Funding

No funding was received for the preparation of this manuscript.