Potential Lupus Drug Deucravacitinib Moves into Phase 3 Clinical Trial

There is an ongoing need for new targeted systemic lupus erythematosus (SLE) treatments. Despite the increased number of clinical trials recently, only 1 new SLE focused treatment Saphnelo® (anifrolumab) has been approved. And as many as half of patients may not respond adequately to current treatment options.

Bristol Myers Squibb announced that in a Phase 2 study, deucravacitinib significantly improved disease activity in SLE patients1. Deucravacitinib is a highly selective, orally bioavailable tyrosine kinase 2 (TYK2) inhibitor. Deucravacitinib selectively inhibits TYK2 within the physiological concentration range via an allosteric mechanism. TYK2 is a member of the Janus kinase (JAK) family of enzymes and signals through downstream pathways such as interleukin (IL)-12, IL-23, and type 1 interferon, key cytokines involved in lupus pathogenesis.

Eligible patients for the study experienced active SLE with moderate to severe disease and met the Systemic Lupus International Collaborating Clinics criteria. Patients were randomly assigned 1:1:1:1 to receive deucravacitinib dosed 3 mg twice daily (BID), 6 mg BID, 12 mg once daily (QD), or placebo in the Phase 2 PAISLEY study. Deucravacitinib met the primary endpoint of SLE-Responder Index (SRI)-4 disease activity score responses. The results showed that significantly greater proportion of patients on deucravacitinib 3 mg BID and 6 mg BID achieved SRI(4) at 32 weeks versus placebo (deucravacitinib 3 mg BID: 58.2%, p=0.0006; deucravacitinib 6 mg BID: 49.5%, p=0.0210; placebo: 34.4%). While the 12 mg QD group had numerically higher SRI(4) responses relative to placebo at 32 weeks, the results did not reach statistical significance on multiplicity adjustment. SRI(4) responses were sustained across all deucravacitinib groups up to Week 48. Secondary endpoints demonstrated clinically meaningful improvements at Week 48, including SRI(4), British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), and Lupus Low Disease Activity State (LLDAS), a decrease of ≥50% from baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-50), and a change in the active joint count.

Figure: Summary of key efficacy results1

“ᵃP value was significant vs placebo in multiplicity-controlled prespecified analysis. ᵇPrimary endpoint. ᶜSecondary endpoint. ᵈIn patients with a baseline CLASI-A score ≥ 10. ᵉExploratory endpoint. ᶠResponder defined as patients with ≥6 tender and swollen (active) joints at baseline, who have ≥50% decrease from baseline in active joints. 95% CI illustrated as error bars. BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; BID, twice daily; CI, confidence interval; CLASI-50, 50% improvement from baseline in Cutaneous Lupus Area and Severity Index-Activity Score; LLDAS, Lupus low Disease Activity State; QD, once daily, SRI, Systemic Lupus Erythematosus Responder Index.”

Deucravacitinib was well tolerated, with the safety profile consistent with earlier trials in psoriasis and psoriatic arthritis and with no evidence of laboratory abnormalities characteristic of JAK-1/2/3 inhibitors. Clinically meaningful results may be a tremendous step forward in the development of a new therapy for SLE. Deucravacitinib will now move into Phase 3 studies as a potential treatment.

On September 9, 2022, the U.S. Food and Drug Administration (FDA) approved deucravacitinib under the trade name Sotyktu™ for the treatment of adults with moderate to severe plaque psoriasis. It is the first and only drug of this kind approved for any disease. The approval was based on data from the Phase 3 POETYK PSO-1 and POETYK PSO-2 clinical trials, which compared a daily 6 mg dose of Sotyktu™ with both placebo and 30 mg BID Otezla® (apremilast). After 24 weeks of treatment in both trials, 69% and 58% of patients treated with Sotyktu™ had at least 75% improvement in the Psoriasis Area and Severity Index (PASI) 75 score compared with 38% of those in each Otezla® arm. Also, 42% and 32% achieved PASI 90 score, compared with 22% and 20% of those in the Otezla® cohorts2. The findings from both Phase 3 studies in psoriasis confirm that deucravacitinib has the potential to become an oral once daily treatment of choice for people living with psoriasis.

The FDA has been scrutinising JAK inhibitors used to treat autoimmune diseases such as rheumatoid arthritis because of concerns about potential side effects, such as major adverse cardiovascular events, cancer, blood clots, and death3. But deucravacitinib works differently than JAK inhibitors because it selectively targets the TYK2 pathway, posing fewer potential risks. During the studies in psoriasis, there were no reports of serious infections, thromboembolic events, or laboratory abnormalities as has been seen with some of the JAK inhibitors. Consequently, the FDA does not require Sotyktu™ to carry a black box warning, as it mandates for non-selective JAK inhibitors such as upadacitinib, baricitinib and tofacitinib.

In addition to psoriasis and SLE, deucravacitinib is being developed for the treatment of various immune disorders including psoriatic arthritis, scalp psoriasis, and inflammatory bowel disease.

The potential for deucravacitinib approval in SLE broadens the available therapies.

New SLE treatments offer hope to patients that either are unresponsive to the newly approved Saphnelo® (anifrolumab), a type I interferon (IFN) receptor antagonist indicated for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE), who are receiving standard therapy and those that continue to suffer the side effects of non-specific immunosuppressive steroid treatments that have served as the mainstay therapies for decades.

The search for the ‘holy grail’ of a disease modifying SLE treatment continues, but in the meantime, patients will benefit from the recent approvals and advancements in developmental therapies.

References

Morand, E., et al., Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: A phase II, randomized, double-blinded, placebo-controlled trial. 2023. 75 (2) : p. 242-252.
Amstrong, A.W., et al., Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 PETYK PSO-1 trial. J Am Acad Dermatol, 2023. 88 (1): p. 29-39.
Thorley, J. FDA expands JAK inhibitors warning: going beyond the data? The Lancet Rheumatology, 2021. 3 (11).