TYK2 Inhibitor Shows Promise in Lupus

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COPENHAGEN — Deucravacitinib, an investigational oral drug that inhibits certain cytokines selectively, has now passed an important mid-stage test for systemic lupus erythematosus (SLE), after already showing similar potential in plaque psoriasis (PsO) and psoriatic arthritis (PsA).

In the randomized, placebo-controlled, phase II PAISLEY study, up to 58.2% of patients receiving different doses of deucravacitinib met the study’s primary efficacy endpoint, the SLE Responder Index Level 4 (SRI4), versus 34.4% of a placebo group, reported Eric Morand, MBBS, PhD, of Monash University in Victoria, Australia.

Oddly, the highest average SRI4 response came with the lowest dosage (3 mg twice daily, P=0.0006; other doses tested were 6 mg twice daily and 12 mg once a day), Morand said in a presentation at the European Alliance of Associations for Rheumatology (EULAR) annual meeting.

Despite that bit of mystery, Morand reported that the drug “shows promise as a novel therapy for SLE and warrants further investigation in phase III trials.”

Two parallel phase III trials for deucravacitinib have already been completed in PsO, and developer Bristol Myers Squibb (BMS) has applied for U.S. marketing approval in that indication, with an FDA decision slated for September. It has also completed a successful phase II study in PsA. BMS said it is exploring inflammatory bowel disease along with “other immune-mediated diseases with high unmet needs” as potential indications.

Rheumatologists have already begun discussing deucravacitinib as something approaching a wonder drug that could be used in a wide range of conditions. That’s because it has an entirely novel mechanism relative to currently approved rheumatologic drugs — it inhibits TYK2, part of the JAK family of nonreceptor signalling kinases, but in a different way than existing JAK inhibitors.

Morand explained that by inhibiting TYK2, the agent blocks certain cytokines including type I interferon and interleukins 12 and 23. But this mechanism has no action against other cytokines needed for proper metabolic and hematopoietic functions — numerous other interleukin species, interferon-gamma, and blood cell growth factors.

PAISLEY enrolled 363 patients with active SLE, randomizing them in equal numbers to placebo or the three deucravacitinib dosages. The primary endpoint was SRI(4), a composite outcome consisting of a 4-point minimum improvement in SLE Disease Activity Index (SLEDAI) scores; no more than 0.3 points of worsening in the Physicians Global Assessment scale; and British Isles Lupus Assessment Group (BILAG) ratings showing no new A-level symptoms and no more than two B-type symptoms, evaluated after 32 weeks of treatment.

Mean patient age was about 40, with women accounting for some 90% of each group. SLEDAI scores averaged 11 at baseline. All participants were positive for anti-nuclear antibodies as a condition of enrollment.

About 80% of participants came into the trial on corticosteroids; nearly 90% were using antimalarial drugs and some 50% were taking immunosuppressants, with about one-third on all three drug classes. Deucravacitinib was an add-on to patients’ existing therapies, though steroids had to be tapered to 7.5 mg/day (prednisone equivalent) during study weeks 8-20. After week 32, the trial included a further 16 weeks during which steroids could be tapered (at clinicians’ discretion) and then kept at a stable lower dose.

Efficacy parameters, including the BILAG Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS), were evaluated again at week 48. The analyses also included laboratory measures including anti-dsDNA antibodies and C4 complement.

These secondary outcomes generally reflected those in the primary 32-week SRI4 analysis, with the best responses seen with the 3-mg twice daily dose. BICLA and LLDAS responses at week 48 in the low-dose group were 47.3% and 36.3%, respectively, while corresponding figures for the placebo group were 25.6% and 13.3%, respectively (both P<0.005). Response rates in this parameter for the two higher doses were numerically higher and, with the exception of BICLA for the 12-mg once daily group, statistically significant with respect to placebo.

One explanation for the relatively poorer performance for 12 mg once daily was that this group also had the highest rate of adverse events (AEs). Some 18% of that group discontinued either because of poor efficacy or AEs, compared with 11% with 3 mg twice daily and 9% of those receiving 6 mg twice daily, and these patients were considered nonresponders for the efficacy analyses, Morand explained.

Further support for that explanation came from the lab analysis, in which a clear positive dose-response was seen for effects on anti-dsDNA and C4.

Skin-related effects (including acne and rash) were the chief type of AE that was more common with deucravacitinib versus placebo. These occurred in about one-third of patients in the two higher-dose groups and 16.5% of the low-dose participants. There was also a weak signal of increased upper respiratory infections with the active drug. However, rates of herpes zoster were the same in all groups at about 3%. No hint of blood cell, liver, or kidney toxicity was seen, either — another feature that could distinguish deucravacitinib from current JAK inhibitors.

Clinicaltrials.gov doesn’t currently list a phase III trial for deucravacitinib in SLE, but it does include a long-term extension for PAISLEY extending to a total of 178 weeks. As SLE generally requires lifelong treatment, its completion (scheduled for November 2023) may be necessary before a pivotal trial could be attempted.

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    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The study was funded by BMS. Several co-authors were company employees.

Morand and co-authors disclosed multiple relationships with industry.

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