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 ({"type":"clinical-trial","attrs":{"text":"NCT03210961","term_id":"NCT03210961"}}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.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Tyrosine kinase 2 (TYK2) inhibitors offer therapeutic promise for the many patients with inflammatory conditions in which IL‐12/23 signaling is implicated, and who have an inadequate response to existing systemic treatment options.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ PF‐06826647 is an oral TYK2 inhibitor with potency against TYK2‐dependent signaling. We aimed to assess the safety, tolerability, and pharmacokinetics of PF‐06826647 in healthy participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ PF‐06826647 was well‐tolerated, with an acceptable safety profile at a single dose of up to 1,600 mg, or multiple doses up to 1,200 mg daily.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ PF‐06826647 may offer a future oral treatment option for patients with inflammatory and autoimmune conditions in which IL‐12/23 signaling is implicated.

Tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK) family, is essential for IL‐12/T‐helper cell 1 and IL‐23/T‐helper cell 17 signaling ¹ , ² and IFN type I/II receptor functioning, ² , ³ and both preclinical and clinical studies have implicated these pathways in the pathogenesis of autoimmune disorders, including psoriasis, inflammatory bowel disease, and systemic lupus erythematosous. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ In large, human, genome‐wide association studies, single nucleotide polymorphisms of the TYK2 gene have been shown to confer protection against psoriasis, ankylosing spondylitis, Crohn’s disease, multiple sclerosis, and ulcerative colitis. ⁵ Blocking signaling from the pro‐inflammatory cytokines, as well as their downstream pathways, with the TYK2 JH2 domain inhibitor BMS‐986165, ¹⁰ the TYK2/JAK1 inhibitor brepocitinib, ¹¹ or with the monoclonal antibodies ustekinumab (anti‐IL‐12 and IL‐23), ¹² , ¹³ , ¹⁴ risankizumab (anti‐IL‐23), ¹⁴ , ¹⁵ secukinumab (anti‐IL‐17A), ¹⁶ mirikizumab (anti‐IL‐23), ¹⁷ or guselkumab (anti‐IL‐23), ¹⁸ , ¹⁹ has shown efficacy in the treatment of various autoimmune conditions.PF‐06826647 is an oral TYK2 inhibitor with potency against TYK2‐dependent signaling (IFNα/IL‐12/IL‐23), but may have dose‐dependent inhibitory activity against other, TYK2‐independent pathways (IFNγ/erythropoeitin). PF‐06826647 is a compound with a low pKa (< 1.7), low solubility across physiological pH (~ 0.3 μg/mL at pH 6.5), and high cellular permeability (~ 17 × 10^‐6 cm/s). However, based on preclinical exposure data in rats, using a spray‐dried dispersion formulation, it was expected to be moderately‐to‐well absorbed at the predicted clinically effective dose range in the clinic. In addition, preclinical studies demonstrated limited drug clearance via renal and biliary excretion in rats, and the major human clearance pathway for PF‐06826647 was identified to be cytochrome P450 (CYP)‐mediated (via CYP1A2, CYP2D6, and CYP3A) metabolism. ²⁰ PF‐06826647 has shown minimal inhibition of transporter proteins (i.e., MATE1, MRP1, MRP2, MRP3, sodium/Na+ taurocholate co‐transporting polypeptide, OATP1B1, OATP1B3, and OCT2), with the exception of MATE2 inhibition. ²⁰ In a phase I, first‐in‐human study ({"type":"clinical-trial","attrs":{"text":"NCT03210961","term_id":"NCT03210961"}}NCT03210961), we evaluated the safety, tolerability, and pharmacokinetics (PK) of PF‐06826647 in healthy participants. In this report, we present safety, tolerability, and PK data for escalating single and multiple doses of PF‐06826647. We also present the impact of food on PK parameters, and a comparison of PK parameters in plasma and urine between Western participants and a Japanese cohort during the multiple ascending dose (MAD) period at an expected clinically relevant dose of 400 mg q.d. Doses for the single ascending dose (SAD) and MAD study periods were initially selected based on data from in vitro pharmacologic/toxicologic studies. ²⁰ During the dose escalation, the available safety data (adverse events (AEs), vital signs, electrocardiogram (ECG), clinical laboratory, hematology, and urinalysis) from the ongoing cohort were reviewed and the appropriate dose for the next cohort was selected to provide the projected average exposure (based on available PK data from all doses) being ~ ≤ 3‐fold of the exposure and less or equal to the PK stopping limit.