Deucravacitinib, a Tyrosine Kinase 2 Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double‐Blind, Placebo‐Controlled Trial

Abstract

Objective. To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE).Methods. Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI-4) response at week 32. Secondary outcomes assessed at week 48 included SRI-4, British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts.Results. At week 32, the percentage of patients achieving SRI-4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95% CI) 1.5, 5.1]; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 [95% CI 1.0, 3.4]; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 [95% CI 0.8, 2.9]; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI-50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported.Conclusion. Deucravacitinib treatment elicited higher response rates for SRI-4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE.

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

“…A number of targeted small molecules are undergoing clinical trials in patients with SLE. Tyk2 inhibition appears to be most promising [ 70 ] and phase II/III results are eagerly awaited. However, the recent concern of thromboembolism and cancer risk in post-marketing studies of RA, particularly in older patients with a cardiovascular risk [ 172 ], has led to caution of the use of JAK inhibitors in patients with SLE, who are also prone to thrombosis and malignancies.…”

“…Deucravacitinib is a selective Tyk-2 inhibitor that blocks the downstream signaling of IL-12, IL-23, IL-10, and the type I IFNs. In a phase II RCT (PAISLEY), 363 patients with autoantibody-positive SLE with active disease (≥ 1 BILAG A or ≥ 2 BILAG B scores, clinical SLEDAI-2K ≥ 6 with skin or joint involvement) were randomly assigned to receive three dosage regimens of deucravacitinib (3 mg twice daily, 6 mg twice daily, 12 mg once daily) or PBO in addition to background medications [ 70 ]. Subjects with severe or life-threatening organ manifestations of SLE were excluded.…”

Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets

“…Elevated serum concentrations of IFN-I as measured by a high-sensitivity assay may have important clinical implications, as high levels in patients with SLE in remission were associated with shorter time to relapse 186. In addition, genetic variants encoding components of the IFN-I signalling pathway, such as TYK2, currently studied as a therapeutic target of deucravacitinib, may identify patients with particularly robust responses to IFN-I 187…”

Meeting report: the ALPHA project: a stakeholder meeting on lupus clinical trial outcome measures and the patient perspective

“…This talk highlighted that FDA has not approved LLDAS as a primary endpoint in trials due to concerns related Incorporates thresholds for disease activity and treatment burden especially glucocorticoid dose ► Formally validated in prospective multinational studies as protective against flare, damage, loss of quality of life and mortality. 18 19 Also validated in many retrospective cohort studies ► Extensive evaluation in post hoc analysis of clinical trials data, where it has good to excellent performance discriminating active treatment from placebo 20-22 ► Widely adopted prospectively as a key secondary outcome measure in SLE trials 23 Dr Ines and colleagues developed the tool to determine clinically meaningful change using 17 weighted clinical and laboratory parameters for SLE which has been fully validated. Dr Anca Askanase, a meeting attendee and member of LFA's Medical Scientific Advisory Council, reiterated to the audience that the Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL) was the first and only tool to-date with a patient-reported outcome component.…”