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The JAK-STAT pathway mediates a variety of proinflammatory responses through Janus kinases (JAK)1-3 and
tyrosine kinase-2 (TYK2).
Deucravacitinib selectively inhibits TYK2 and was shown to be effective and safe in patients with moderate to severe plaque psoriasis in the POETYK study program. The orally administered active ingredient has now been approved in the USA, the EU and several other countries. Current analyses report on the efficacy and safety of deucravacitinib over a period of up to three years.

Various treatment options with different mechanisms of action exist for the treatment of plaque psoriasis. The novel TYK2 inhibitor deucravacitinib represents an innovative therapeutic option due to its specific inhibition of the interleukin (IL)-23-mediated TYK2/JAK2 signaling cascade [1,2]. The mechanism of action of deucravacitinib differs from that of JAK1/2/3 inhibitors: by binding to the regulatory domain of TYK2, deucravacitinib achieves allosteric inhibition of TYK2 and its downstream functions in the cells [1,2]. In contrast to the JAK inhibitors, which bind with different affinities to the respective Janus kinases, deucravacitinib is highly selective for TYK2 and reduces the risk of off-target effects when used at therapeutic doses [1]. This is probably advantageous for the safety profile [1].

Convincing 3-year data

In the 52-week Phase III POETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) studies, deucravacitinib was superior to placebo and apremilast and was well tolerated [3,4]. Thaci et al. reported on the safety and efficacy of deucravacitinib up to week 148 [5]. The study participants were randomized in a 1:2:1 ratio and received either placebo, deucravacitinib 6 mg (1×/d)** or apremilast 30 mg (2×/d)**. At week 52, patients enrolled in the POETYK long-term extension study (LTE; NCT04036435) received open-label deucravacitinib. Safety was evaluated in patients who had received ≥1 dose of deucravacitinib.

** 1×/d = 1× daily; 2×/d=2× daily

Efficacy endpoints included PASI75 and PASI90 as well as sPGA ^0/1$ with an improvement of ≥2 points compared to baseline. Efficacy was reported using modified non-responder imputation. A total of 1519 patients were treated with ≥1 dose of deucravacitinib. 513 patients in POETYK PSO-1/ POETYK PSO-2 received continuous deucravacitinib therapy from day 1 and were enrolled in the long-term extension study (LTE). The cumulative exposure amounted to 3294.3 person-years (PY). Exposure-adjusted incidence rates per 100 PY were similar or decreasing over the cumulative 2- to 3-year period for AEs (154.4; 144.8), severe AEs (6.1; 5, 5), discontinuation due to AEs (2.8; 2.4), and other AEs^&.

^$ sPGA 0=appearance-free, sPGA 1=almost appearance-free
^& herpes zoster (0.7, 0.6); malignancies (0.9, 0.9); serious adverse cardiovascular events (0.4, 0.3); venous thromboembolism (0.1, 0.1); deaths (0.4, 0.3)

The clinical response rates proved to be long-lasting. At week 148, the efficacy endpoints were as follows:

• PASI75: 73.2% [95%-KI; 68.7-77.8]
• PASI90: 48.1% [95%-KI; 43.2-53.1]
• sPGA 0/1: 54.1% [95% CI; 49.1-59.1]

In a further analysis, Thaci et al. based on the POETYK PSO-1 and PSO-2 studies and the ongoing LTE on the laboratory parameters recorded during the course of deucravacitinib therapy [6]. Evaluations are available over a period of around 2 years.

Laboratory chemical values up to week 100

The changes in hematological (lymphocytes, neutrophil granulocytes, platelets, hemoglobin) and other parameters (cholesterol, creatinine, CPK, ALT) known to be affected by ^JAK inhibitors§ were examined up to week 100. Grade ≥3 laboratory abnormalities and treatment discontinuations were evaluated. A total of 1519 patients received ≥1 deucravacitinib dose in the three studies POETYK PSO-1 and PSO-2 as well as the ongoing LTE. Continuous deucravacitinib exposure of ≥52 and ≥104 weeks (median: 97 weeks) was 77.6% (n=1179) and 38.4% (n=584), respectively. No trends towards clinically significant changes in the laboratory parameters compared to the baseline value were identified. Grade 3 or 4 toxicities over 100 weeks of deucravacitinib treatment were rare, comparable to placebo and apremilast up to week 52, and did not increase in the LTE. Two patients discontinued treatment with deucravacitinib due to lymphopenia and abnormal liver function.

§ JAK-1-i, JAK-2-i, JAK-3-i

Congress: Dermatologie kompakt praxisnah

Literature:

1. Ghoreschi K, et al.: TYK2-Inhibition: Potenzial bei der Behandlung chronisch-entzündlicher Immunerkrankungen. JDDG 2021; 19(10): 1409–1420.
2. Krueger JG, McInnes IB, Blauvelt A: Tyrosine kinase 2 and Janus kinase signal transducer and activator of transcription signaling and inhibition in plaque psoriasis. JAAD 2021; 86(1): 148–157.
3. Armstrong AW, 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. JAAD 2023; 88(1): 29–39.
4. Strober B, et al.: Treatment of plaque psoriasis with deucravacitinib (POETYK PSO-2 study): a plain language summary. Immunotherapy 2023; 15(11): 787–797.
5. Thaci D, et al.: Deucravacitnib in plaque psoriasis: 3-Year Safety and Efficacy Results From The Phase 3 POETYK PSO-1 and PSO-2 Trials, P017. JDDG 2024; 22, Issue S1: 1–40.
6. Thaci D, et al.: Deucravacitnib in Plaque Psoriasis: 2-Year Laboratory Results From the Phase 3 POETYK PSO Program, P027. JDDG 2024; 22, Issue S1: 1–40.

DERMATOLOGIE PRAXIS 2024; 34(3): 34 (published on 14.6.24, ahead of print)