Deucravacitinib (Sotyktu): First-In-Class, Allosteric Tyrosine Kinase 2 (Tyk2) Inhibitor For Adults With Moderate-To-Severe Plaque Psoriasis Approved

Psoriasis is a chronic, immune-mediated skin disorder that affects millions of people worldwide, causing significant physical and emotional distress. With a prevalence of at least 100 million individuals globally, affecting 2-3% of the total population [1], psoriasis poses a serious global health concern. While effective systemic therapies exist, many patients with moderate-to-severe psoriasis are undertreated or remain untreated, leading to dissatisfaction with current treatment options.

In March 2023, the European Commission (EC) approved Deucravacitinib (Sotyktu), an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, for the treatment of moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy [2,3]. This approval signifies the first innovation in oral treatment for moderate-to-severe plaque psoriasis in nearly 10 years. 

Sotyktu targets TYK2 and inhibits the signalling of interleukin (IL)-23 and Type 1 interferon (IFN). These are key cytokines involved in the pathogenesis of multiple immune-mediated diseases. At therapeutic doses, Sotyktu does not inhibit Janus kinase (JAK)1, JAK2 or JAK3 [4].

The approval is based on results from the pivotal Bristol Myers Squibb’s Phase 3 POETYK PSO-1 and POETYK PSO-2 clinical trials. Once-daily treatment of Sotyktu demonstrated superior efficacy compared to placebo and twice-daily Otezla® (apremilast) in 1,684 patients aged 18 years and older with moderate-to-severe plaque psoriasis. These results were demonstrated at 16 and 24 weeks, and responses with Sotyktu were maintained through 52 weeks.

POETYK PSO-1 and POETYK PSO-2: Efficacy and Safety Outcomes [5,6]

Phase 3 POETYK PSO-1 and POETYK PSO-2 clinical trials evaluated the efficacy and safety of Sotyktu (6 mg once daily) compared to placebo and Otezla® (apremilast) (30 mg twice daily) in patients with moderate-to-severe plaque psoriasis. All patients suffered from ≥6 months of moderate-to-severe plaque psoriasis (defined as a body surface area involvement of ≥10%, a Psoriasis Area and Severity Index (PASI) score ≥12, and a static Physician’s Global Assessment (sPGA) ≥3). Patients were also all candidates for phototherapy or systemic therapy.

Patients were randomized 2:1:1 to Deucravacitinib 6 mg every day, placebo, or apremilast twice a day

Coprimary efficacy endpoints were achievement of PASI 75 and sPGA 0/1 (clear/almost clear) with a ≥2-point improvement from baseline for Deucravacitinib versus placebo at week 16. Key secondary endpoints included the percentage of patients who achieved PASI 75, PASI 90 and sPGA 0/1 compared to Otezla at Week 16 and Week 24.

Efficacy

Table 1 POETYK PSO-1 Trial Outcomes 

Week 16

• A significantly greater number of patients treated with Deucravacitinib achieved PASI 75 and sPGA 0/1 compared to placebo and apremilast (P<0.0001 for all)

Week 24 

• Deucravacitinib was also superior to apremilast in achieving PASI 75 and sPGA 0/1 (P<0.0001 for both)

Table 2 POETYK PSO-2 Trial Outcomes 

Week 16

• A significantly greater number of patients treated with Deucravacitinib achieved PASI 75 compared to placebo (P<0.0001) and apremilast (P=0.0004)
• A significantly greater number of patients treated with Deucravacitinib achieved sPGA 0/1 compared to placebo and apremilast (P<0.0001 for both)

Week 24 

• Deucravacitinib was also superior to apremilast in achieving PASI 75 and sPGA 0/1 (P<0.0001 for both)

Both trials demonstrated the superiority of Deucravacitinib versus placebo and apremilast for moderate-to-severe psoriasis.

Safety

POETYK PSO-1: Serious AEs during the trial were reported in 7 patients (2.1%) in the Deucravacitinib group, in 9 (5.5%) patients in the placebo group, and in 4 (2.4%) in the Apremilast group

POETYK PSO-2: Serious AEs during the trial were reported in 8 patients (1.6%) in the Deucravacitinib group, in 3 (1.2%) patients in the placebo group, and in 1 (0.4%) in the Apremilast group

In both trials, nasopharyngitis and upper respiratory tract infection were the most common AEs in Deucravacitinib-treated patients, whereas headache, diarrhoea, and nausea were more common in apremilast-treated patients. No new safety signals occurred during weeks 16-52 versus weeks 0-16. The incidence of serious AEs was also low and similar across groups.

References

1. National Psoriasis Foundation. Get the facts about psoriasis and psoriatic arthritis. The National Psoriasis Foundation: National Psoriasis Foundation. Retrieved from https://www.psoriasis.org/psoriasis-statistics/ 
2. SOTYKTU Prescribing Information. SOTYKTU U.S. Product Information. September 2022. Princeton, N.J.: Bristol-Myers Squibb Company.
3. Chimalakonda A, Burke J, Cheng L, et al. Selectivity profile of the tyrosine kinase 2 inhibitor deucravacitinib compared with janus kinase 1/2/3 inhibitors. Dermatol Ther (Heidelb) 2021;11(5):1763–1776. doi: 10.1007/s13555-021-00596-8.
4. SOTYKTU™ (Deucravacitinib) mechanism of action | for hcps. Retrieved from https://www.sotyktuhcp.com/mechanism-of-action 
5. Armstrong AW, Gooderham M, Warren RB, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. J Am Acad Dermatol. 2023;88(1):29-39. doi:10.1016/j.jaad.2022.07.002
6. Strober B, Thaçi D, Sofen H, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program fOr Evaluation of TYK2 inhibitor psoriasis second trial. J Am Acad Dermatol. 2023;88(1):40-51. doi:10.1016/j.jaad.2022.08.061