Background/Purpose: Adaptive and innate immune pathways are involved in inflammation and pathogenesis of rheumatoid arthritis (RA). Toll-like receptor (TLR) stimulation activates the innate immune system, and may be involved in the pro-inflammatory response to ACPA protein complexes found in severe RA.¹ Interleukin (IL) receptor-associated kinase 4 (IRAK4) is a key signal transducer downstream of the myddosome-associated TLRs and IL-1 receptors. IRAK4 inhibition blocks inflammatory cytokine production, so is a potential therapeutic target for RA.² This study evaluated the efficacy and safety of PF-06650833, a highly selective, small molecule, reversible IRAK4 inhibitor in development for RA treatment.

Methods: In this Phase 2b, multicenter, randomized, double-blind, double-dummy, placebo and active-controlled parallel-group study, patients (pts) with moderately to severely active ACPA⁺ RA and an inadequate response to methotrexate were randomized (6:6:6:5:5:5) to 12 weeks’ dosing with PF-06650833 20 mg, 60 mg, 200 mg, 400 mg modified-release tablets once daily (QD), tofacitinib 5 mg twice daily, or placebo. The primary endpoint was change from baseline (CFB) at Week 12 in simplified disease activity index (SDAI). Secondary endpoints included ACR20, 50, and 70 responder rates and CFB in disease activity score 28 with 4 components-C-reactive protein (DAS28-4[CRP]) at Week 12. Adverse events (AEs) were also monitored.

Results: Overall, 269 pts from 19 countries were randomized and treated (PF-06650833 = 187; tofacitinib = 43; placebo = 39). Mean CFB in Week 12 SDAI was significantly higher in the PF-06650833 arms vs placebo (p≤0.005) using the primary Bayesian analysis with an informative placebo prior distribution and in the 200 mg and 400 mg groups with non-informative placebo prior distribution (sensitivity analysis; p < 0.05), suggesting improved response. Statistically significantly greater ACR50 response rate vs placebo was observed at Week 12 in 20/50 (40.0%) and 21/48 (43.8%) pts in the PF-06650833 200 mg and 400 mg group (p=0.040, p=0.016), respectively. Statistically significant CFB in DAS28-4(CRP) vs placebo was observed in PF-06650833 60 mg, 200 mg, and 400 mg QD groups at Week 12 (p < 0.05). Of 222 all-causality treatment-emergent AEs (TEAEs) reported across treatment groups, 8 were serious AEs (SAEs); 64 were treatment-related (reported in 48 pts; one was an SAE due to elevated liver transaminases, resolved) and were not dose-dependent. TEAEs of the system organ class (SOC) infections and infestations were most commonly reported (55/269 [20.4%] pts). Herpes zoster occurred in 3 pts (1 treatment-related). Twelve pts permanently discontinued due to TEAEs and no deaths occurred.

Conclusion: All PF-06650833 doses displayed improvement in clinical disease scores vs placebo at Week 12 in pts with moderate to severe RA. Infections and infestations were the most common TEAE SOC, and no deaths occurred.

Study sponsored by Pfizer Inc. Medical writing support was provided by Molly MacFadyen and Claire Cairney of CMC Connect and funded by Pfizer Inc.

1. Sokolove J et al. Arthritis Rheum 2011; 63: 53-62.
2. De Nardo D et al. J Biol Chem 2018; 293: 15195-15207.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-and-safety-of-the-selective-interleukin-1-receptor-associated-kinase-4-inhibitor-pf-06650833-in-patients-with-active-rheumatoid-arthritis-and-inadequate-response-to-methotrexate/