Background/Purpose: IRAK‑4 is a key node in innate immune signaling and is activated by the interleukin (IL)‑1 family receptors (IL‑1R, IL‑18R, and IL‑33R), in addition to the Toll‑like receptors (TLRs). Inhibition of IRAK‑4 blocks the production of inflammatory cytokines such as type I interferons, IL‑6, tumor necrosis factor (TNF), IL‑1, and IL‑12 that are key drivers of autoimmune and inflammatory diseases. Therefore, IRAK‑4, would be an attractive therapeutic target for autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). PF-06650833 is a recently described, small molecule, reversible, highly potent and specific inhibitor of IRAK-4. Nonclinical studies of PF-06650833 have been conducted in rats and dogs that support studies up to 3 months in duration. The current abstract describes the results from the single and multiple ascending dose (SAD, MAD) studies of PF-06650833 in healthy subjects.

Methods: The SAD and MAD studies of PF-06650833 were conducted in male and female (of nonchildbearing potential) healthy subjects. The first-in-human study was a 5-way crossover SAD study that explored extemporaneously (extemp) prepared immediate (IR)- and modified release (MR) formulations of PF-06650833 from 1 – 6000 mg. The MAD study was a 14 day sequential ascending dose study of extemp IR and MR tablet formulations administered after a standard meal. Doses from 25 mg BID to 1000 mg QID of the IR formulation and 300 mg MR tablets were explored. Standard clinical, ECG, and laboratory safety monitoring were performed as well as exploratory biomarkers.

Results: PF-06650833 was generally safe and well tolerated after both SD and MD up to the maximal planned doses, with dose limiting toxicity. Safety profile in both the SAD and MAD studies were similar, with the most common adverse events (AEs) being headache, and gastrointestinal symptoms (mainly nausea and abdominal pain). There were no clinically significant changes in vital signs, ECGs, or any laboratory parameter (including LFTs). PK analyses showed a moderate absorption rate with median T_max from ~2 h for IR doses and ~4 h for MR tablets after a standard meal at steady state. Exposures increased proportionally up to about 100 mg and somewhat less than proportionally > 100 mg. In the MAD study, T_½ ranged from ~25 – ~31 h across the top IR and MR doses after a standard meal.

Conclusion: PF-06650833, a highly selective and potent inhibitor of IRAK-4, is shown to be generally safe and well tolerated up to 6000 mg SD and 1000 mg QID in healthy subjects, with an MR PK profile sufficient to support QD dosing in patient populations. To the authors’ knowledge, PF-06650833 is the first IRAK-4 inhibitor to advance to Phase 2 clinical studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-pf-06650833-a-novel-potentially-first-in-class-inhibitor-of-interleukin-1-receptor-associated-kinase-4-irak-4-in-healthy-subjects/