Drug ‘TYKs’ All the Boxes in Two Plaque Psoriasis Trials

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A majority of patients with plaque psoriasis had at least 75% improvement, and complete or near-complete clearance by physician assessment, after 16 weeks in two randomized trials of the TYK2 inhibitor deucravacitinib.

The parallel POETYK PSO-1 and PSO-2 trials showed that 58.7% and 53.6% of patients treated with deucravacitinib had 75% improvement in the Psoriasis Area and Severity Index (PASI 75). Additionally, 50%-54% of patients in the two trials met the coprimary endpoint of Physician Global Assessment (PGA) score of 0/1. Both outcome values were significantly higher than those observed in placebo-treated patients and in patients randomized to apremilast (Otezla).

All secondary outcomes favored deucravacitinib and achieved statistical superiority versus placebo and apremilast in most cases, reported April Armstrong, MD, of the University Southern California in Los Angeles, at the American Academy of Dermatology virtual meeting.

“Significantly greater proportions of patients in the deucravacitinib compared with apremilast arms achieved PASI 75 response at week 16 in both trials,” said Armstrong. “Deucravacitinib responses increased beyond week 16 and were also superior to apremilast at week 24. More than 80% of deucravacitinib patients who achieved PASI 75 at week 24 and continued treatment maintained PASI 75 response at week 52 in both studies.”

Results for the coprimary outcome mirrored the PASI 75 data, as significantly more patients in the deucravacitinib arm achieved PGA 0/1 status at 16 and 24 weeks as compared with placebo and apremilast, she added.

“Based on these findings, deucravacitinib has the potential to become an efficacious and well tolerated treatment of choice for patients with moderate-to-severe plaque psoriasis,” Armstrong concluded.

Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of nonreceptor signaling kinases, and regulates cytokine signaling implicated in the pathophysiology of autoimmune disorders, including psoriasis. Deucravacitinib has a mechanism of action distinct from that of JAK inhibitors, resulting in greater selectivity for TYK2 versus JAK1/3 or JAK2. The drug demonstrated activity in phase II trials of moderate-to-severe plaque psoriasis and active psoriatic arthritis.

Armstrong reported findings from two global phase III, randomized trials to evaluate deucravacitinib in moderate-to-severe plaque psoriasis. Investigators enrolled adults with moderate-to-severe plaque psoriasis associated with a PASI score ≥12, PGA score ≥12, and body surface area (BSA) ≥10%. Patients in both trials were randomized 2:1:1 to deucravacitinib, apremilast, or placebo. Coprimary endpoints were PASI 75 and PGA 0/1 plus at least a two-step improvement from baseline, both assessed at 16 weeks. Patients assigned to placebo could cross over to deucravacitinib at week 16.

Data analysis included 666 patients in POETYK PSO-1 and 1,020 patients in POETYK PSO-2. Results from POETYK PSO-1 showed that significantly more patients randomized to deucravacitinib attained a PASI 75 response at week 16 (58.7%) as compared with the apremilast (35.1%) or placebo (12.7%) arms (P<0.0001). Follow-up at week 24 showed PASI 75 response rates of 69% with deucravacitinib and 38.1% with apremilast (P<0.0001).

Similar results emerged from an analysis of POETYK PSO-2, as 53.6% of deucravacitinib-treated patients had a PASI 75 response after 16 weeks as compared with 40.2% with apremilast (P=0.0003) and 9.4% with placebo (P<0.0001). At 24 weeks, the deucravacitinib arm maintained a significant advantage versus apremilast (59.3% vs 37.8, P<0.0001).

PGA response data from POETYK PSO-1 showed that 53.6% of the deucravacitinib group had met response criteria by week 16 as compared with 32.1% of those in the apremilast arm and 7.2% of the placebo arm (P<0.0001). At 24 weeks, response rates were 58.4% with the TYK2 inhibitor versus 31% with apremilast (P<0.0001). In POETYK PSO-2, PASI 75 rates were 50.3%, 34.3%, and 8.6% at 16 weeks (P<0.0001) and 50.4% with deucravacitinib versus 29.5% with apremilast at week 24 (P<0.0001).

Armstrong said the safety profiles for deucravacitinib and apremilast were consistent with the drugs’ mechanisms of action. Pooled data for the two trials showed that overall rates of adverse events (AEs) were similar across the three treatment arms as were rates of serious AEs. Rates of discontinuation because of AEs were 11.6% with apremilast, 9.4% with placebo, and 4.4% with deucravacitinib.

Nasopharyngitis and upper respiratory tract infection occurred in 23%-26% of patients and 12%-14% of patients across the treatment arms. Headache, diarrhea, and nausea occurred substantially more often with apremilast (26.0%, 26.5%, and 22.9%) than with deucravacitinib (8.5%, 7.3%, and 2.1%).

Deucravacitinib has potential for broad applicability in immune-mediated diseases, according to Armstrong. Regulatory submission is pending for psoriasis, phase III trials in psoriatic arthritis have begun, and phase II trials in ulcerative colitis, Crohn’s disease, and lupus are scheduled to begin later this year and in 2022.

Last Updated April 25, 2021

Disclosures

The POETYK PSO-1 and POETYK PSO-2 trials were supported by Bristol Myers Squibb (BMS).

Armstrong disclosed relevant relationships with AbbVie, BMS, Eli Lilly, Janssen, LEO Pharma, Novartis, Celgene, Boehringer Ingelheim/Parexel, Dermavant, Genentech, GlaxoSmithKline, Menlo Therapeutics, Merck, Modernizing Medicine, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, Genzyme, Science 37, Sun Pharma, Valeant, Dermira, Kyowa Hakko Kirin, and UCB.

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