zimlovisertib (PF-06650833) / Pfizer - LARVOL DELTA

Predicting kinase target inhibition level for efficacy in rheumatoid arthritis: A translational approach based on collagen-induced arthritis rodent studies. (PubMed, J Pharmacol Exp Ther) - "Target inhibition levels of tofacitinib, zimlovisertib, and 3 literature kinase inhibitors at efficacious and inefficacious doses were compared between patients and rodents using a new approach based on average inhibition level (IAVG). The established translation helps to predict the efficacious inhibition level and corresponding efficacious dose for future kinase inhibitors for rheumatoid arthritis. The approach may also be applicable to other small-molecule targeted therapies."

Journal • Preclinical • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Efficacy and Safety of Zimlovisertib, Ritlecitinib and Tofacitinib, Alone and in Combination, in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate. (PubMed, Arthritis Rheumatol) - "Zimlovisertib+tofacitinib was more effective than tofacitinib for the primary endpoint, while the efficacy of zimlovisertib+ritlecitinib did not achieve statistical significance vs tofacitinib. All treatments were well tolerated."

Journal • Hepatocellular Cancer • Immunology • Infectious Disease • Inflammatory Arthritis • Novel Coronavirus Disease • Oncology • Rheumatoid Arthritis • Rheumatology • Solid Tumor • CRP • IRAK4

DIFFERENTIAL EFFECTS OF NLRP3 VS. IRAK4 INHIBITORS ON INFLAMMASOME RELATED PATHWAYS IN CELLS (ADPD 2025) - "To address this question, we compared effects between specific inhibiting NLRP3 with MCC950 and inhibiting IRAK4 with Zimlovisertib through cellular assays... There are differential e ffects comparing inhibition of NLRP3 vs. IRAK4. Inhibition of NLRP3 effectively blocked inflammasome formation, IL -1β releasing and pyroptosis, while no effect on NF -kB signaling."

Inflammation • GLI2 • IL1B • IRAK4 • NLRP3

Targeting IRAK4 in Monosodium Urate Crystals Induced Inflammation (ACR Convergence 2024) - "In this study, we aimed to elucidate the anti-inflammatory mechanism of the IRAK4 inhibitor (PF06650833) by examining MSU-induced pro-inflammatory mediators in human PBMCs. Human PBMCs were pretreated with 1 µM IRAK4 inhibitor (IRAK4i) overnight, followed by stimulation with 100 µg/ml MSU for either 30 minutes or 24 hours... Our study demonstrated that IRAK4 inhibitor (IRAK4i) modulates inflammation induced by monosodium urate (MSU) in peripheral blood mononuclear cells (PBMC). Additionally, we observed effective inhibition of phagocytosis and confirmed the signaling mechanisms potentially disrupted by IRAK4i in MSU-induced pathways in PBMC. Therefore, IRAK4i appears to be a promising therapeutic strategy for gout patients by counteracting MSU and TLR-mediated inflammation."

Gout • Immunology • Inflammation • Inflammatory Arthritis • Musculoskeletal Pain • Pain • Rheumatology • CXCL8 • IL18 • IL1B • IL1R1 • IL6 • IRAK4 • MYD88 • NLRP3 • TGFB1 • TLR2 • TNFA

A Systematic Review of Pharmacological Interventions for Hidradenitis Suppurativa: A Focus on Clinical Response, Quality of Life, and Safety (ISPOR-EU 2024) - "Adalimumab, anakinra, apremilast, avacopan, bimekizumab, doxycycline, guselkumab, IFX-1, MABp1, PF-06650833, PF-06700841, PF-06826647, povorcitinib, risankizumab, RIST4721, secukinumab, upadacitinib all reported notable clinical benefits, with Hidradenitis Suppurativa Clinical Response (HiSCR) ranged from 10% (anakinra at week 24) to 88% (povorcitinib-90 mg at week 8)...In contrast, no SAEs were detected in spesolimab or anakinra, while bimekizumab had similar safety profiles to adalimumab. The results of this review demonstrate the possibility of highly personalized treatment approaches for HS management, including adalimumab and povorcitinib. The optimization of HS care requires further research on long-term outcomes."

Clinical • HEOR • Review • Dermatology • Hidradenitis Suppurativa • Immunology • Pain

Inhibiting the IRAK4/NF-κB/NLRP3 signaling pathway can reduce pyroptosis in hippocampal neurons and seizure episodes in epilepsy. (PubMed, Exp Neurol) - "IRAK4 plays a key role in the pathological process of epilepsy, and its potential mechanism may be related to pyroptosis mediated by the NF-κB/NLRP3 signaling pathway. PF-06650833 has potential as a therapeutic agent for alleviating epilepsy."

Journal • CNS Disorders • Epilepsy • Immune Modulation • Immunology • IRAK4 • NLRP3

In Retrospect: Root-Cause Analysis of Structure-Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833). (PubMed, ACS Med Chem Lett) - "The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all-syn (2S,3S,4S) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends."

Journal • IRAK4

Brepocitinib, Zimlovisertib, and Ropsacitinib in Hidradenitis Suppurativa. (PubMed, NEJM Evid) - "At 16 weeks, only brepocitinib, a JAK1/TYK2 inhibitor, achieved a higher clinical response than placebo (52% vs. 33%). The other two agents were no better than placebo."

Journal • Dermatology • Hidradenitis Suppurativa • Immunology • JAK1 • TYK2

Utilizing a human TLR selective ligand in a humanized immune system mouse model to investigate human TLR4 signaling. (PubMed, J Biol Methods) - "To assess efficacy of inhibiting a key protein in the TLR4 signaling pathway, PF-06650833, a small molecule inhibitor of IRAK4, was used as a tool molecule...Taken together, our data suggests that human selective TLR ligands could preferentially drive cytokine production from human cells in huNOG-EXL mice. This model will allow for investigation of pharmacological inhibition of human TLR signaling pathways in an in vivo model system."

Journal • Preclinical • CD34 • IL6 • IRAK4 • TNFA

Methotrexate Augments the Release of Granulocyte-macrophage Colony-stimulating Factor from Activated Rheumatoid Arthritis Fibroblast-like Synoviocytes - Possible Consequences for Persistence of Joint Inflammation (ACR Convergence 2023) - "FLS were pre-treated with methotrexate (MTX), tofacitinib (TOFA, janus kinase inhibitor), zimlovisertib (IRAK4 inhibitor) or vehicle followed by stimulation with platelet-derived growth factor (PDGF) and interleukin-1ß (IL-1ß) for 24-72 hours (Fig.1, top). Methotrexate treatment augments the release of GM-CSF from RA-FLS and leads to sustained cytokine production from synoviocytes. This off-target effect might contribute to the persistence of synovitis. Primary RA-FLS were pre-treated with MTX, TOFA, or vehicle at 1-2,5 uM for 24 hours followed by stimulation with 20 ng/mL PDGF-BB and 2 ng/mL IL-1beta in medium with the drug or vehicle for 48 hours and finally processed for RNAseq."

Immunology • Inflammation • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • CDKN1A • CSF2 • CXCL10 • IL1A • IL1B • IL6 • IRAK4

R851, a Potent Second Generation IRAK1 and IRAK4 Inhibitor Suppresses IL-6 in Vitro and in Vivo for the Treatment of Rheumatoid Arthritis (ACR Convergence 2023) - "As a result, inhibition of IRAK4 has been investigated as a means of attenuating a range of autoimmune diseases including rheumatoid arthritis, with zimlovisertib demonstrating encouraging results in a Phase 2 rheumatoid arthritis study. Using the knowledge gained in the development of R835, we have identified R851 as a second generation dual IRAK1 and IRAK4 inhibitor. The increased potency in whole blood assays is believed to be driven by a reduction in protein binding. We predict that R851 will require a significantly lower exposures for efficacy in humans which should position this molecule for a chronic condition like rheumatoid arthritis."

Preclinical • Hematological Malignancies • Immunology • Inflammation • Inflammatory Arthritis • Myelodysplastic Syndrome • Oncology • Rheumatoid Arthritis • Rheumatology • IL23A • IL6 • IRAK4 • TLR3 • TNFA

Targeted Nanocarriers for Systemic Delivery of IRAK4 Inhibitors to Inflamed Tissues. (PubMed, Small) - "Herein, the first nanoparticle-based platform for the targeted systemic delivery of a clinically tested IRAK4 inhibitor, PF-06650833, with limited aqueous solubility (57 µg mL ) is presented...Importantly, repeated injections of IRAK4 inhibitor-loaded nanocarriers have no acute toxic effect on major organs of mice. Therefore, the developed nanocarriers have the potential to significantly improve the therapeutic efficacy of IRAK4 inhibitors for different inflammatory diseases."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IRAK4

Targeting interleukin-1 receptor-associated kinase 1/4 in acute myeloid leukemia stem cells (AACR 2023) - "Next, we treated murine MLL-AF9 AML cells and human MDSL cells with UR241-2 and two IRAK4 inhibitors (PF-06650833 and CA-4948) that are currently in clinical or preclinical studies. Taken together, our findings demonstrated that targeting IRAK1/4 using the novel compound UR241-2 is able to impair LSC clonogenicity and engraftment capability in AML following treatment and disease progression. This provides a potential therapeutic strategy to eradicate the LSC population and improve the outcome of AML patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IRAK1 • IRAK4 • NF-κβ

Inhibition of Both IRAK1 and IRAK4 Is Required for Complete Suppression of NF-Kb Signaling across Multiple Receptor-Mediated Pathways in MDS and AML (ASH 2022) - "Using the IRAK4-selective antagonists PF-06650833 and BAY 1834845 we find that both compounds fully suppress signaling through TLR2 (IC50 vs. Pam3CSK4 = 7.2 and 150 nM, respectively). We find a correlation between kinase activity for both IRAK1 and IRAK4 and NF-κB activity that extends to the leukemia colony forming assays. This suggests that NF-κB signaling contributes to leukemia progenitor cell function and that optimal inhibition requires potent antagonism of both IRAK1 and IRAK4 in the setting of MDS and AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • GLI2 • IL1B • IL1R1 • IRAK4 • TLR2 • TRAF6

Binding Energy Partition of Promising IRAK-4 Inhibitor (Zimlovisertib) for the Treatment of COVID-19 Pneumonia. (PubMed, Chemphyschem) - "The Interacting Quantum Atoms method reveals the adequacy (or lack of) of the chemical changes throughout the design of this IRAK4 inhibitor. Read the full text of the Research Article at 10.1002/cphc.202200455."

Journal • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • IRAK4

Design of Novel IRAK4 Inhibitors Using Molecular Docking, Dynamics Simulation and 3D-QSAR Studies. (PubMed, Molecules) - "A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. We designed few IRAK4 inhibitors based on these results, which possessed higher activity (predicted pIC) than the most active compounds of the dataset selected for this study. Moreover, ADMET properties of these inhibitors revealed promising results and need to be validated using experimental studies."

IO biomarker • Journal • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Inflammation • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Waldenstrom Macroglobulinemia • IL1R1 • IRAK4 • MYD88

Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome. (PubMed, Biomed Pharmacother) - "We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling."

Journal • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • IL17A • IRAK4

Binding Energy Partition of Promising IRAK-4 Inhibitor (Zimlovisertib) for the Treatment of COVID-19 Pneumonia. (PubMed, Chemphyschem) - "We determined the energetics of the interaction of different functional groups in the ligands with the IRAK-4 protein target and thereby demonstrated the adequacy (or lack thereof) of the changes made across the design of this drug. This analysis permits to verify whether a given alteration of a prospective drug leads to the intended tuning of non-covalent interactions with its protein objective.  Overall, we expect that the  methods exploited in this paper will prove valuable in the understanding and control of chemical modifications across FBDD processes."

Journal • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • IRAK4

Preclinical Efficacy of an Oxazolopyridine IRAK4 Inhibitor in Rodent Models of Inflammation (EULAR 2022) - "Objectives: Determine whether a highly specific oxazolopyridine IRAK4 inhibitor demonstrates efficacy in mouse models of arthritis and systemic inflammation; compared to an isoquinoline inhibitor PF-06650833. A highly specific oxazolopyridine IRAK4 inhibitor, CA-4948, demonstrated potent therapeutic efficacy in mouse models of arthritis and systemic inflammation."

IO biomarker • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • IL1B • IL1R1 • IL6 • IRAK4 • TNFA

Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer. (PubMed, J Hematol Oncol) - "IL1RAP knockdown significantly reduced cell viability, invasiveness, and clonogenic growth in pancreatic cancer cell lines. Inhibition of the downstream interleukin-1 receptor-associated kinase 4 (IRAK4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in reduced growth in pancreatic cancer cell lines and in xenograft models."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • IL1RAP • IRAK4 • KRAS

A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a C-Microtracer Approach. (PubMed, Clin Pharmacol Drug Dev) - "Zimlovisertib (PF-06650833) is a selective, reversible inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with anti-inflammatory effects...There were no deaths, serious adverse events (AEs), severe AEs, discontinuations or dose reductions due to AEs, and no clinically significant laboratory abnormalities. These results demonstrate that zimlovisertib had low absolute oral bioavailability and low absorption (<50%)."

Journal • P1 data • IRAK4

TO ASSESS THE EFFICACY AND SAFETY OF PF-06650833, PF-06651600, AND TOFACITINIB ALONE AND IN COMBINATION IN PARTICIPANTS WITH ACTIVE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE (clinicaltrials.gov) - P2 | N=460 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

A Study to Evaluate the Safety and Efficacy of PF-06650833, PF-06700841, and PF 06826647 in Adults With Hidradenitis Suppurativa (clinicaltrials.gov) - P2a | N=197 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Acne Vulgaris • Dermatology • Hidradenitis Suppurativa

TO ASSESS THE EFFICACY AND SAFETY OF PF-06650833, PF-06651600, AND TOFACITINIB ALONE AND IN COMBINATION IN PARTICIPANTS WITH ACTIVE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE (clinicaltrials.gov) - P2; N=460; Active, not recruiting; Sponsor: Pfizer; Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

A Study To Estimate The Effect of PF-06650833 On The Pharmacokinetics (PK) of Oral Contraceptive (OC) (clinicaltrials.gov) - P1; N=10; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Clinical • Trial completion