medwireNews: The phase 2 PAISLEY study, presented at the EULAR 2022 Congress in Copenhagen, Denmark, suggests that the tyrosine kinase 2 (TYK2) inhibitor deucravacitinib may be a promising novel therapeutic option for systemic lupus erythematosus (SLE).
This agent “binds to the regulatory domain of TYK2, locking the enzyme in the inactive state, differentiating itself therefore from JAK [Janus kinase] inhibitors, which bind to the ATP active site,” Eric Morand (Monash University, Melbourne, Victoria, Australia) told the audience.
He explained that TYK2 is involved in signaling via the type 1 interferon and interleukin (IL)-12/23 pathways, which represent “an attractive pair of therapeutic targets for lupus,” but deucravacitinib “does not inhibit cytokines involved in metabolic or hematopoietic pathways.”
In the PAISLEY study, 363 patients with active SLE – most of whom were on multiple background therapies including antimalarials (86.8%), corticosteroids (80.4%), and immunosuppressants (51.8%) – were randomly assigned to receive one of three doses of deucravacitinib or placebo. Corticosteroid tapering was required from week 8–20, with optional further tapering from week 32–40.
At week 32, the primary endpoint of SRI(4) response rate was higher among participants given deucravacitinib 3 mg twice daily, 6 mg twice daily, or 12 mg once daily than in their counterparts given placebo, at 58.2%, 49.5%, and 44.9% versus 34.4%, respectively. These differences reached statistical significance with the two lower deucravacitinib doses versus placebo.
In addition, SRI(4), BICLA, and LLDAS response rates were evaluated at week 48, with “results favoring deucravacitinib at all doses compared to placebo,” said Morand. The proportion of patients achieving at least a 50% improvement in Cutaneous Lupus Area and Severity Index score at this timepoint was also significantly greater with deucravacitinib versus placebo.
In response to a question from the audience about whether the TYK2 inhibitor had any benefits for lupus manifestations outside of the skin and joints, the presenter said that analyses of other endpoints are ongoing, but data are not yet available.
Turning to safety, Morand reported that deucravacitinib was well tolerated, with a safety profile consistent with that seen previously in psoriatic arthritis and psoriasis trials, despite patients in PAISLEY having “a significant burden of standard-of-care therapy including immunosuppression and steroids.” During 48 weeks of follow-up, there were no deaths, thrombotic events, or major adverse cardiovascular events.
He said that there was “no signal” for increased rates of serious infections, herpes zoster, or COVID-19 with deucravacitinib treatment, but there were higher rates of urinary tract infections in the TYK inhibitor versus placebo arms (6.5–11.0 vs 3.3%), as well as a signal for skin-related adverse events (16.5–34.4 vs 13.3%).
“There was no evidence of laboratory abnormalities that are seen in some patients treated with JAK inhibitors,” noted Morand.
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