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Clinical Trial
. 2023 Feb;75(2):242-252.
doi: 10.1002/art.42391. Epub 2022 Nov 11.

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

Eric Morand  1 , Marilyn Pike  2 , Joan T Merrill  3 , Ronald van Vollenhoven  4 , Victoria P Werth  5 , Coburn Hobar  6 , Nikolay Delev  6 , Vaishali Shah  6 , Brian Sharkey  6 , Thomas Wegman  6 , Ian Catlett  6 , Subhashis Banerjee  6 , Shalabh Singhal  6
Affiliations
Clinical Trial

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

Eric Morand et al. Arthritis Rheumatol. 2023 Feb.

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.

Trial registration: ClinicalTrials.gov NCT03252587.

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Figures

Figure 1
Figure 1
Key efficacy end points of patient groups receiving deucravacitinib 3 mg twice daily (BID), deucravacitinib 6 mg twice daily, deucravacitinib 12 mg once daily (QD), or placebo for treatment of systemic lupus erythematosus. Nonresponder imputation was used to impute missing data for all end points except change from baseline in joint count. A, Patient response rates using the Systemic Lupus Erythematosus Responder Index 4 (SRI‐4) at week 32, and SRI‐4, British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA), Lupus Low Disease Activity State (LLDAS), and Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI‐50) at week 48. B, Adjusted mean change from baseline in the number of active (swollen plus tender), swollen, and tender joint counts at week 48. The adjusted mean change in each joint count was calculated using the mixed model for repeated measures approach. For analysis visits where the nonresponder imputation criteria were met, the observed values were set to missing and the overall cohort response modeled. C, Patient response rates using Joint Count‐50 at week 48 assessed in patients with ≥6 active (both swollen and tender) joints at baseline. In A and B, multiplicity‐controlled primary and secondary end points, between‐group differences (Δ), and odds ratios (ORs) for treatment groups versus placebo, along with their respective 95% confidence intervals (95% CIs), are shown. P values were not calculated for exploratory end points. * = primary end point; † = multiplicity‐adjusted secondary end point; ‡ = in patients with a baseline CLASI activity score ≥10. § = exploratory non–multiplicity‐controlled end point.
Figure 2
Figure 2
Adjusted mean percentage change from baseline (BL) over 48‐week follow‐up in levels of anti–double‐stranded DNA (anti‐dsDNA) antibodies in patients with detectable anti‐dsDNA at baseline (A), C3 complement in patients with C3 <0.9 gm/liter at baseline (B), and C4 complement in patients with C4 <0.1 gm/liter at baseline (C) for patient groups receiving deucravacitinib 3 mg twice daily (BID), deucravacitinib 6 mg twice daily, deucravacitinib 12 mg once daily (QD), or placebo for treatment of systemic lupus erythematosus. In A–C, vertical bars indicate 95% confidence intervals (95% CIs). Imputation was done using a mixed‐effects model. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42391/abstract.
Figure 3
Figure 3
Adjusted mean percentage change in interferon gene signature from baseline (BL) over 44‐week follow‐up in patient groups receiving deucravacitinib 3 mg twice daily (BID), deucravacitinib 6 mg twice daily, deucravacitinib 12 mg once daily (QD), or placebo for treatment of systemic lupus erythematosus. Vertical bars indicate 95% confidence intervals (95% CIs). Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42391/abstract.
Figure 4
Figure 4
Mean change in laboratory parameters over 48‐week follow‐up in patient groups receiving deucravacitinib 3 mg twice daily (BID), deucravacitinib 6 mg twice daily, deucravacitinib 12 mg once daily (QD), or placebo for treatment of systemic lupus erythematosus. Vertical bars represent standard deviations. ALT = alanine aminotransferase. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42391/abstract.
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