Deucravacitinib

Deucravacitinib is a selective tyrosine kinase 2 (TYK2) inhibitor that disrupts JAK-STAT signaling pathways involved in proinflammatory responses. By specifically inhibiting TYK2, deucravacitinib can alleviate inflammatory processes. Deucravacitinib is approved for the treatment of psoriasis.

Tyrosine kinase 2 plays both a structural and catalytic role in the signaling of numerous interleukins and interferons (IFN-alpha/beta). It associates with heterodimeric cytokine receptor complexes and activates members of the STAT family such as STAT1, STAT3, STAT4, or STAT6. The heterodimeric cytokine receptor complexes consist of (1) a TYK2-associated receptor chain (IFNAR1, IL12RB1, IL10RB, or IL13RA1) and (2) a second receptor chain associated with either JAK1 or JAK2. In response to cytokine binding to receptors, the receptors (IFNAR1, IL12RB1, IL10RB, or IL13RA1) are phosphorylated and activated, creating docking sites for STAT members . The recruited STATs are in turn phosphorylated by TYK2 (or JAK1/JAK2 at the second receptor chain), form homodimers and heterodimers, migrate to the nucleus, and regulate cytokine/growth factor responsive genes. TYK2 negatively regulates STAT3 activity by promoting phosphorylation at a specific tyrosine distinct from the site used for signaling.

Genetic TYK2 inhibition is associated with a lower risk of a variety of autoimmune diseases. Associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression, and associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There are nominal associations between genetic TYK2 inhibition and increased risk of prostate and breast cancer, but not in tissue-specific MR expression or colocalization analyses.

The efficacy of TYK2 inhibitors in plaque psoriasis has been confirmed by numerous RCTs (Yuan S et al. 2023). Fifteen studies reported data on the efficacy of treatment with TYK2 inhibitors in versch. Target diseases. In plaque psoriasis, all studies (n = 7) found improvement in disease activity, as measured by the Psoriasis Area and Severity Index, in the intervention groups at different doses compared with the control group. Similarly, disease activity improved in the intervention group compared with the control group in patients with psoriatic arthritis (n = 2), alopecia areata (n = 2), atopic dermatitis (n = 1), or active nonsegmental vitiligo (n = 1), although few studies were conducted on these diseases.

TYK2 inhibitors improved certain clinical measures of ulcerative colitis severity, such as improvement in the modified endoscopic Mayo score and Mayo sub-score for rectal bleeding in the intervention group; however, there was no clear evidence of an effect on clinical remission.

Deucravacitinib is an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor. TYK2 inhibitors represent a new class of small molecules with a unique mechanism of action. TYK2 is an intracellular kinase and mediates signaling of interleukin-23 (IL23) and other cytokines involved in psoriasis pathogenesis. Deucravacitinib binds highly selectively to TYK2, thereby inhibiting IL23, IL12 and type 1 interferon (IFN) signaling and their downstream functions. This controls inflammatory processes in plaque psoriasis.

Absorption: Following oral administration of deucravacitinib, plasma concentrations (Cmax) and area under the concentration-time curve (AUC) increased proportionally over a dose range of 3 mg to 36 mg in healthy volunteers. Absolute oral bioavailability was 99% and the median time to maximum concentration (Tmax) ranged from two to three hours. A meal high in fat and calories decreased Cmax and AUC of deucravacitinib by 24% and 11%, respectively, and prolonged Tmax by one hour, but this had clinically significant effects on absorption and exposure of the drug.

Distribution: The volume of distribution of deucravacitinib at steady-state is 140 L. The binding of deucravacitinib to proteins ranges from 82 to 90%, and the blood to plasma concentration ratio is 1.26.

Metabolism: Deucravacitinib is metabolized primarily by N-demethylation by cytochrome P-450 (CYP) 1A2 to its major metabolite BMT-153261, which has comparable pharmacologic activity to the parent drug. Deucravacitinib is also metabolized by CYP2B6, CYP2D6, carboxylesterase (CES) 2, and uridine glucuronyltransferase (UGT) 1A9.

Elimination: After a single dose of radiolabeled deucravacitinib, approximately 13% of the dose was recovered unchanged in urine and approximately 26% in feces. The terminal half-life of deucravacitinib was 10 hours. The renal clearance of deucravacitinib varied between 27 and 54 mL/min.

Deucravacitinib (Sotyktu®⁾ is the first TYK2 inhibitor from the Janus kinase inhibitor class. It is used orally and is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are eligible for systemic therapy.

The use of deucravacitinib in pregnant women has been studied to a limited extent. Although animal studies showed no evidence of adverse effects, deucravacitinib should not be used during pregnancy for safety reasons.

Breastfeeding: It is not known whether deucravacitinib or its metabolites pass into breast milk. However, animal studies indicate that this is possible. Therefore, a risk to breastfed infants cannot be excluded. Before a decision is made to continue breastfeeding or treatment with deucravacitinib, the welfare of the infant and the benefit of therapy to the mother should be carefully weighed.

The recommended (oral) dose is 6 mg of deucravacitinib once daily. If no improvement is evident after 24 weeks, treatment discontinuation should be considered.

No dose adjustment is necessary for elderly patients 65 years of age or older or patients with renal impairment, including patients requiring dialysis.

However, caution should be exercised in patients over 75 years of age because clinical experience is limited.

No dose adjustment is necessary in mild or moderate hepatic impairment, while use is not recommended in severe hepatic impairment.

Potential adverse effects of TYK2 inhibitors: The most common complaints in individuals treated with TYK2 inhibitors are headache, upper respiratory tract infections (18.9%), most commonly nasopharyngitis. Furthermore, nausea, diarrhea, and elevated blood creatinine and liver enzyme levels. Two RCTs reported carcinoma formation (prostate and breast carcinoma) as a possible adverse effect of TYK2 inhibitors (Yuan S et al. 2023).

Deucravacitinib does not significantly affect plasma exposure to rosuvastatin, methotrexate, mycophenolate mofetil, or oral contraceptives.

Similarly, no significant effects on deucravacitinib plasma exposure were observed when drugs that inhibit or induce CYP enzymes or transporters, such as ciclosporin, fluvoxamine, ritonavir, diflunisal, pyrimethamine, famotidine, or rabeprazole, were used concomitantly.

Deucravacitinib must not be used in cases of hypersensitivity to the active substance or any of the other ingredients, or in cases of clinically significant active infections such as active tuberculosis.

Deucravacitinib (^Sotyktu®);

Deucravacitinib has been approved since March 24, 2023, for the treatment of moderate-to-severe plaque psoriasis in adults eligible for systemic therapy. Important basis for the approval are the results of the phase III studies POETYK PSO-1 and POETYK PSO-2. In the studies, once-daily administration of deucravacitinib showed superior efficacy compared to placebo and twice-daily administration of apremilast after 16 as well as after 24 weeks, with a sustained response over 52 weeks (Lé AM et al. 2022; Estevinho T et al. 2023).

Deucravacitinib may increase the risk of infection. Treatment should not be started until active infections have resolved or been adequately treated.Malignancies such as lymphoma and skin cancer have been observed in patients taking deucravacitinib in clinical trials. It is unclear whether this is related to tyrosine kinase 2 (TYK2) inhibition. The relationship between deucravacitinib and carcinoma risk is still unclear. Long-term safety studies are ongoing. It remains unclear whether TYK2 inhibition is associated with adverse events such as serious cardiovascular events, deep vein thrombosis, and pulmonary embolism. No increased risk has been observed in clinical trials, but long-term studies are ongoing.

1. Estevinho T et al (2023) Deucravacitinib in the treatment of psoriasis. J Dermatolog Treat 34:2154122.
   
2. Lé AM et al (2022) Deucravacitinib for the Treatment of Psoriatic Disease. Am J Clin Dermatol 23:813-822.
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4. Rani MR et al (1999) Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase. J Biol Chem 274:32507-32511
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