Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors

Abstract

Introduction: Deucravacitinib, a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling, acts via an allosteric mechanism by binding to the enzyme's regulatory domain instead of the catalytic domain. This unique binding provides high functional selectivity for TYK2 versus the closely related Janus kinases (JAKs) 1/2/3. Deucravacitinib was efficacious in phase 2 and 3 psoriasis trials, without clinical or laboratory parameters indicative of JAK 1/2/3 inhibition being observed. This analysis compared the kinase specificities of deucravacitinib versus JAK 1/2/3 inhibitors at therapeutic exposures.Methods: Signaling via JAK 1/3, JAK 2/2, and TYK2/JAK 2 dimers was measured in in vitro whole blood assays. Concentrations providing half-maximal inhibition (IC 50 ) in these assays were determined for deucravacitinib and the JAK 1/2/3 inhibitors tofacitinib, upadacitinib, and baricitinib. Newly derived whole blood IC 50 values were plotted against available pharmacokinetic profiles using doses evaluated in phase 2/3 trials. Simulated average daily inhibition and durations over which concentrations exceeded IC 50 were evaluated. Results: At clinically relevant exposures, projected steady-state deucravacitinib plasma concentrations were higher than TYK2 IC 50 for approximately 9-18 h. Maximal plasma concentrations (C max ) of deucravacitinib were 8-to James Burke: employee at the time the analysis was conducted.

Deucravacitinib for the Treatment of Psoriatic Disease

“…Therefore, due to safety concerns with JAK 1, 2 and 3 inhibitors, interest has shifted to more selective inhibition of TYK2. At clinically relevant doses and exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 [30,34,36].…”

“…The use of deucravacitinib in psoriatic patients decreases IL-23 pathway biomarkers in lesional skin towards non-lesional levels and normalizes IFN and IL-12 pathway genes, without affecting JAK 1, 2 and 3 biomarkers. Through this mechanism of action, deucravacitinib blocks IL-12, IL-23 and type I interferon downstream signalling, without interfering with JAK2-dependent hematopoietic functions [17,36]. Preclinical studies initially showed its efficacy in mouse models with lupus erythematosus and inflammatory bowel disease [37][38][39].…”

TYK2 in Immune Responses and Treatment of Psoriasis

“…This mode of binding, which differs from that of JAK1/2/3 inhibitors, is associated with the high selectivity of BMS-986165. 9 , 69 …”

“…This mode of binding, which differs from that of JAK1/2/3 inhibitors, is associated with the high selectivity of BMS-986165. 9,69 In a phase 2 clinical trial, adults with moderate to severe plaque psoriasis were randomized into six groups. Patients received oral medication at 3 mg every other day, 3 mg once daily (QD), 3 mg twice daily (BID), 6 mg BID, 12 mg QD, or placebo.…”

A Review of the Clinical Trial Landscape in Psoriasis: An Update for Clinicians

“…Therefore, inhibition of each subtype of JAK can interfere with various downstream signaling pathways, acting as a powerful treatment for limiting inflammation in psoriasis [57]. Deucravacitinib (BMS-986165, Sotyktu; Bristol-Myers Squib) is a highly selective once-daily oral TYK2 inhibitor, recently approved by the FDA (9 September 2022) for the treatment of moderate-to-severe plaque psoriasis [49,58]. Avoiding the enzyme's catalytic domain, which is highly between JAKs, deucravacitinib instead binds to its regulatory/pseudokinase (JH2) domain, allowing for more potent blocking of downstream IL-12, IL-23, and type-1 interferon signaling [58].…”