TYK2 inhibition: the future of treating lupus erythematosus?

Active systemic lupus erythematosus (SLE) treated with deucravacitinib led to promising response rates measured as SLE Responder Index (SRI) 4. In the phase 2 PAISLEY trial, up to 58.2% of participants met the endpoint of SRI (4), significantly more than the 34.4% on placebo.

"TYK2 is a Janus kinase that only mediates signalling through the type-1 interferon, IL-12 and IL-23 receptors, and it is not involved in the signalling of other cytokine pathways. This is an attractive therapeutic target for lupus,” Prof. Eric Morand (Monash University, Australia) explained the rationale of the PAISLEY study (NCT03252587) [1]. This randomised-controlled, phase 2 trial evaluated TYK2 inhibition through deucravacitinib as a treatment for active SLE. 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. They were randomised 1:1:1:1 to 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. Morand stated.

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 daily dosage, 51.8% took immunosuppressants, and 32.2% had a triple treatment that further included antimalarials.

The trial met its primary endpoint: SRI (4) response was significantly lower on placebo (34.4%) than in the deucravacitinib 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), BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment), low disease activity state, reduction in skin disease, and reduction in arthritis,” Prof. Morand highlighted. A reduction in anti-dsDNA antibody titer and an increase in C4 levels were also observed.

Concerning safety up to week 48, no deaths occurred, nor did 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 (the nature of which were not defined in the abstract) 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 affect haematologic markers or standard biochemistry. He concluded that “Deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials.” It is also noted that the obligatory corticosteroid tapering strategy during the trial may be a novel way to evaluate promising new agents for SLE.

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 Congress, 1–4 June, Copenhagen, Denmark.

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Posted on 21 July, 202229 February, 2024