Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study.

BACKGROUND: Psoriasis treatments lack durable efficacy and have inconvenient administration, highlighting the need for new therapies. OBJECTIVE: To evaluate the efficacy and safety of tyrosine kinase 2 inhibitor, PF-06826647, in moderate-to-severe plaque psoriasis. METHODS: This phase 2b, double-blind study randomized participants to oral, once-daily PF-06826647 (1:1:2:2:2) 50:100:200:400 mg:placebo (16 weeks), then 200 or 400 mg (24 weeks) (NCT03895372). The primary end point was a proportion of participants achieving psoriasis area severity index (PASI) 90 at week 16. Secondary end points (PASI50/75/90/100; Physician's Global Assessment) and safety were assessed to week 40. RESULTS: Overall, 178 participants were treated. A significantly greater proportion of participants (risk difference % [90% CI]) achieved PASI90 in the 200-mg (33.0 [18.0, 47.1], P = .0004) and 400-mg (46.5 [30.6, 60.6], P < .0001; week 16) groups versus placebo. Significant increases from placebo were observed for all secondary end points (200 and 400 mg; weeks 6-16; P < .05); increases were evident to week 40 (categorical data). PF-06826647 was well tolerated and most treatment-emergent adverse events were mild/moderate. Eighteen participants discontinued due to treatment-emergent adverse events (14 arising from laboratory abnormalities). LIMITATIONS: Limitations included the large proportion of White males and non-placebo-controlled extension. CONCLUSION: PF-06826647 200 and 400 mg once daily showed significant efficacy versus placebo at week 16 and was well tolerated over 40 weeks.

Safety and Pharmacokinetics of the Oral TYK2 Inhibitor PF-06826647: A Phase I, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study.

Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro-inflammatory cytokine signaling. In this first-in-human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF-06826647, in healthy participants. This phase I, randomized, double-blind, placebo-controlled, parallel-group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period (NCT03210961). Participants were randomly assigned to PF-06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF-06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5-fold) after multiple dosing and low urinary recovery. PF-06826647 was well-tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients.

Safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of the oral TYK2 inhibitor PF-06826647 in participants with plaque psoriasis: a phase 1, randomised, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Blockade of tyrosine kinase 2 (TYK2) signalling has previously shown therapeutic potential in the treatment of psoriasis. The primary objective of this study was to assess the safety and tolerability of the TYK2 inhibitor PF-06826647. METHODS: This phase 1, randomised, double-blind, placebo-controlled, parallel-group study assessed once daily oral dosing of PF-06826647 in participants with plaque psoriasis, at a single clinical research site in the USA. Eligible participants (aged 18-65 years) had plaque psoriasis covering at least 15% of total body surface area and a psoriasis area and severity index (PASI) score of at least 12 at baseline. Participants received PF-06826647 (100 mg or 400 mg), or placebo once daily for 28 days. Using a computer-generated randomisation schedule with a block size of 3, participants were sequentially randomly assigned into two cohorts by the investigator; in the first cohort, participants were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 400 mg or placebo once daily, whereas participants in the second cohort were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 100 mg or placebo once daily. Site, investigator, Pfizer personnel, and participants, were masked to treatment. The primary endpoint was the safety of multiple-dose PF-06826647 in participants with plaque psoriasis. Secondary endpoints were the characterisation of the pharmacokinetics of multiple-dose PF-06826647 in plasma and the change in PASI score at day 28. Safety analysis was done in all participants who received at least one dose of study drug. Efficacy analysis was done in all participants who received at least one dose of randomised study drug, and had a baseline and at least one post-baseline measurement. This study is registered as a randomised, controlled trial with ClinicalTrials.gov, NCT03210961 and is completed. FINDINGS: The trial was done between July 14, 2017, and Jan 25, 2019. Overall from 91 participants assessed, 40 participants with moderate-to-severe psoriasis were randomly assigned to treatment (placebo 14 [35%] of 40; PF-06826647 100 mg, 11 [28%] of 40; PF-06826647 400 mg, 15 [38%] of 40). Treatment-emergent adverse events (TEAEs) were reported in 12 (80%) of 15 participants in the PF-06826647 400 mg group, seven (50%) of 14 in the placebo group and five (45%) of 11 in the 100 mg group. All TEAEs were mild in severity, except one moderate TEAE of vomiting reported in the placebo group. There were no deaths, serious TEAEs, severe TEAEs, dose reductions, or temporary discontinuations. Compared with placebo, the change from baseline in PASI score at day 28 showed a significant reduction in least squares mean difference for the PF-06826647 400 mg group (-13·05; 90% CI -18·76 to -7·35; p=0·00077) but not for the PF-06826647 100 mg group (-3·49; -9·48 to 2·50; p=0·33). Both the area under the concentration-time curve over the dosing interval and the maximum concentration increased in a less than dose proportional manner with increasing dose from 100 mg to 400 mg PF-06826647. INTERPRETATION: PF-06826647 showed significant improvement in disease activity within 4 weeks of dosing with an acceptable safety profile. PF-06826647 holds promise over conventional oral treatments for psoriasis that have shown limited efficacy or unfavourable safety profiles. FUNDING: Pfizer.