Post-hoc analyses of phase II PAISLEY trial in patients with SLE treated with deucravacitinib

The Lupus Hub previously reported results from the phase II PAISLEY trial (NCT03252587), demonstrating the efficacy and safety of deucravacitinib vs placebo in patients with systemic lupus erythematosus (SLE). Here, we summarize several post-hoc analyses of the PAISLEY trial presented at the American College of Rheumatology (ACR) annual meeting (ACR Convergence 2023).

Key findings

• Furie et al.¹ and Morand et al.² demonstrated a shorter median time to response and higher response rate at Week 48 with deucravacitinib treatment (Figure 1A; Figure 1B).
• Arriens et al.³ showed that deucravacitinib resulted in a higher proportion of patients achieving Cutaneous Lupus Erythematosus Disease Area and Severity Index-70 at Week 48 (Figure 1B).

BICLA, British Isles Lupus Assessment Group–based Composite Lupus Assessment; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; LLDAS, Lupus Low Disease Activity State; NE, not estimable; SLE, systemic lupus erythematosus; SRI(4), SLE Responder Index-4.
*Data from Furie, et al.¹; Morand, et al.²; and Arriens, et al.^3
†Because they exceeded the period of the study (48 weeks/336 days).
^‡Due to a less than 50% probability of achieving LLDAS at any time point.

Transcriptomic analysis by Wu et al.⁴ revealed that:

• Patients with SLE expressed higher levels of interferon (IFN)-regulated genes, including IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) and interferon induced protein 44, which were significantly reduced following treatment with deucravacitinib.
• CMPK2 (cytidine/uridine monophosphate kinase 2) and interferon induced protein 44 appear to be particularly relevant to SLE pathophysiology.

Further, a novel IFN 5 gene (MX1 [MX Dynamin Like GTPase 1], HERC5 [HECT and RLD domain containing E3 ubiquitin protein ligase 5], IFIT1 [interferon-induced protein with tetratricopeptide repeats 1], RSAD2 [radical S-adenosyl methionine domain containing 2], and EIF2AK2 [eukaryotic translation initiation factor 2 alpha kinase 2]) signature was developed by Wu et al.⁵ to classify patients with SLE into IFN high or IFN low subgroups. Pharmacodynamic analysis revealed that deucravacitinib:

• Reduced IFN 5 gene score and anti-double stranded DNA antibody titers in both groups.
• At Week 32, higher SRI(4) was observed with a dosage of 3 mg twice daily and 12 mg once daily, along with an increased British Isles Lupus Assessment Group–based Composite Lupus Assessment response rate at Week 48.

Mosca et al.⁶ assessed patient-reported outcomes and revealed that deucravacitinib achieved clinically meaningful improvements (meeting or exceeding minimal clinically important/minimally important differences) in pain, fatigue, and health-related quality of life from baseline at Week 48 (Figure 2).

MCID, minimal clinically important difference; MID, minimally important difference; NRS, numeric rating scale; PROMIS, Patient-Reported Outcomes Measurement Information System.
*Adapted from Mosca, et al.⁶

Key learnings

The post-hoc analyses support the robust efficacy of deucravacitinib across multiple SLE response indices, including disease activity, cutaneous manifestations, and improvements in patient-reported outcomes. The novel pharmacodynamic biomarker, IFN 5 gene score, categorizes patients into IFN high and low subgroups. While the clinical response improvement may vary, this score affirms the mechanism of action of deucravacitinib and may aid in phase III dose selection. Two phase III trials (NCT05617677; NCT05620407) investigating deucravacitinib in patients with SLE are currently ongoing.