TYK2 Inhibitor Scores Two Wins Outside Plaque Psoriasis

ORLANDO — The TYK2 inhibitor deucravacitinib (Sotyktu) showed clinical potential in two diseases other than psoriasis, according to studies reported here.

More than half of patients with psoriatic arthritis (PsA) had at least 20% improvement in disease status after 16 weeks of treatment with deucravacitinib in a large, phase III trial. In a small phase II trial of cutaneous lupus erythematosus (CLE), patients treated with the TYK2 inhibitor had as much as 50% improvement in disease status at week 16. Adverse events in both trials were consistent with deucravacitinib’s known safety profile.

Both studies were reported at the American Academy of Dermatology meeting.

“Deucravacitinib met the primary endpoint of ACR20 at week 16 and showed superior clinical benefit versus placebo across multiple core psoriatic arthritis domains,” said Diamant Thaçi, MD, of the University of Luebeck in Germany. “These results support the potential of deucravacitinib, the first oral TYK2 inhibitor evaluated in a phase III study of psoriatic arthritis, to become an efficacious and well-tolerated treatment for patients with active psoriatic arthritis domains.”

In the CLE study, deucravacitinib significantly improved the primary endpoint of CLASI-A score as well as other measures of disease activity, said Victoria Werth, MD, of the University of Pennsylvania in Philadelphia.

Following the presentations, session co-moderator Amy Paller, MD, of Northwestern University in Chicago, characterized the PsA study as “incredible and so significant for an issue that we really do not have a lot of options.”

By way of background, Thaçi noted that TYK2 mediates cytokine signaling that includes pro-inflammatory molecules known to be involved in psoriasis and PsA, such as interleukin (IL)-12, IL-23, and type I interferon. Subsequent release of inflammatory cytokines directly affects development and progression of arthritis, enthesitis, psoriasis, and dactylitis.

In a phase II randomized, placebo-controlled trial in active PsA, patients treated with either of two doses of deucravacitinib had significantly higher ACR20 response rates and multiple secondary and exploratory endpoints. Quality-of-life measures also improved in patients who received the TYK2 inhibitor.

Psoriatic Arthritis Study

Thaçi reported results from the primary analysis of the phase III, multicenter, randomized POETYK PsA-2 trial in patients with no prior biologic treatment for PsA, except a tumor necrosis factor inhibitor. Investigators randomized 729 patients 3:3:1 to deucravacitinib, placebo, or an apremilast (Otezla) safety reference group. The primary endpoint was the proportion of patients in the deucravacitinib and placebo arms who met ACR20 response criteria at week 16.

The study population had a mean PsA duration of 5-6 years, and 85-90% had received no prior biologic therapy. Tender joint count averaged 15-17 across the three groups, and swollen joint count averaged 9-10. About half of the patients had psoriasis involving more than 3% body surface area.

The primary analysis showed that 54.2% of patients randomized to deucravacitinib achieved ACR20 responses, compared with 39.4% of patients in the placebo group (P=0.0002). Significantly more patients randomized to the TYK2 inhibitor achieved ACR50 (28.8% vs 16.3%, P=0.0002) and ACR70 (10.6% vs 5.4%, P=0.0180) responses.

Additionally, 40.9% of patients randomized to deucravacitinib had at least 75% improvement in the Psoriasis Activity and Severity Index, versus 15.4% of the placebo group (P<0.0001). The deucravacitinib arm also had more improvement in a validated disability index (P=0.0013).

Serious adverse events (AEs) occurred in 1-2% of patients in the placebo and deucravacitinib arms and in 3.8% of the apremilast arm. AE-related discontinuation rates were 1.3% with placebo, 2.2% with deucravacitinib, and 10.5% with apremilast.

CLE Study

CLE is an autoimmune disorder that has a wide range of cutaneous manifestations and represents a major unmet therapeutic need, said Werth. CLE may occur in association with systemic lupus erythematosus (SLE). The most common subtypes are discoid (DLE) and subacute (SCLE), accounting for 80% and 16% of cases, respectively. Both TYK2 and types I and III interferon are involved in CLE pathophysiology.

In a phase II trial of patients with SLE and baseline CLASI-A score ≥10, patients treated with any of three doses of deucravacitinib had CLASI-50 response rates of 56-70% as compared with 17% for a placebo control group. Subgroups with concomitant DLE and SCLE also had significantly higher CLASI-50 response rates.

Werth reported findings from the phase II randomized PAISLEY CLE trial, limited to patients with DLE or SCLE of at least 3 months’ duration. They were randomized to one of two doses of deucravacitinib or to placebo and followed for 16 weeks, at which time patients randomized to the TYK2 inhibitor continued follow-up to week 52. Patients in the placebo arm were randomized again to the two doses of the TYK2 inhibitor for follow-up to week 52.

The trial involved a total of 74 patients, and the primary endpoint was change in CLASI-A score at 16 weeks. Baseline CLASI-A score averaged 14-18 across treatment groups, and 70-80% of patients in each group had a baseline CLASI-A score >10.

After 16 weeks, patients randomized to the higher dose of deucravacitinib had a 50% reduction in CLASI-A score as compared with 28.4% for the placebo group (P=0.0385). Patients who received the lower dose of the TYK2 inhibitor had a 47.5% reduction in the CLASI-A score, which did not reach statistical significance versus placebo (P=0.0670).

An analysis of mean change in CLASI-A score yielded slightly different results. Patients randomized to the higher dose of deucravacitinib had a mean change from baseline of -8.7, which did not achieve statistical significance versus the placebo group reduction of 5.3 (P=0.0805). However, patients assigned to the lower dose of the TYK2 inhibitor had a mean change of -9.3, which proved to be significantly better than placebo (P=0.0425).

Analysis of CLASI-50 and CLASI-70 response rates were significantly higher in both deucravacitinib groups but favored the lower dose of the TYK2 inhibitor. The CLASI-50 response rates were 19.0% with placebo, 56.7% with lower-dose deucravacitinib (P=0.0092), and 52.3% with the higher dose (P=0.0193). CLASI-70 response rates were 15.9%, 49.5% (P=0.0184), and 29.5% (P=0.2713).

Serious AEs occurred in no more than two patients in any groups, and no patients discontinued treatment because of AEs.

Werth said the results supported initiation of two ongoing phase III trials of deucravacitinib in patients with SLE.

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