TYK2 inhibition: A rising star in lupus therapy?

Deucravacitinib showed convincing results as a treatment for patients with active systemic lupus erythematosus (SLE) in the phase 2 PAISLEY trial.

Primary endpoint: response criteria with deucravacitinib on week 32

The randomised-controlled phase 2 PAISLEY study (NCT03252587) evaluated the TYK2 inhibitor deucravacitinib as a treatment for active SLE1. The primary endpoint was the number of participants who met the response criteria for SRI(4) at week 32. All 363 participants were on stable background medication and lacked severe organ-threatening disease. After randomisation, they were treated in 4 separate groups, receiving either deucravacitinib 3 mg twice daily,  6 mg twice daily, 12 mg once daily, or placebo. Between week 8 and week 20 of the trial, a tapering of corticosteroids to 7.5 mg/day was obligatory. Thereafter, corticosteroids were kept stable until week 32. “Following that, there was an optional steroid taper to week 40 and an 8-week period of stable steroids to week 48, at which time multiple, multiplicity-adjusted key secondary outcomes were also measured,” Prof. Eric Morand (Monash University, Australia) explained.

Participants were about 40 years old, predominantly women, and had a mean BMI of 26.8 kg/m2. Most of them had extensive background therapy. Just over 80% were treated with corticosteroids, 49.9% of them at a ≥10 mg dosage, 51.8% took immunosuppressants, and 32.2% had a triple treatment that further included antimalarials.

SRI(4) responses were markedly different between placebo and study groups

The trial met its primary endpoint: SRI(4) response was significantly lower on placebo (34.4%) than in the study drug groups: 58.2% (3 mg twice daily; P=0.0006), 49.5% (6 mg twice daily; P=0.021), and 44.9% (12 mg once daily; P=0.0781). “All secondary outcome measures were achieved or meaningfully improved at week 48 including SRI(4), British Isles Lupus Assessment Group-based Composite Lupus Assessment [BICLA], low disease activity state, reduction in skin disease, and reduction in arthritis,” Prof. Morand highlighted.

Concerning safety up to week 48, no deaths occurred, nor any major adverse cardiac or thrombotic events. Serious adverse events were observed in 12.2% of placebo recipients and between 7.7% and 8.6% in the different deucravacitinib groups. Prof. Morand underlined that there were no signals for either COVID-19 or herpes zoster. However, skin-related adverse events were higher in the deucravacitinib groups (16.5%, 34.4%, 33.7% vs 13.3% on placebo). Prof. Morand also pointed out that deucravacitinib did not demonstrate an effect on haematologic markers or standard biochemistry.

“Deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials,” Prof. Morand concluded.

1. Morand EF, et al. Efficacy and safety of deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, in patients with active systemic lupus erythematosus: a phase 2, randomised, double-blind, placebo-controlled study. LB0004, EULAR 2022, 1–4 June, Copenhagen, Denmark.