zabedosertib (BAY 1834845) / Bayer - LARVOL DELTA

Zabedosertib, a novel interleukin-1 receptor-associated kinase-4 inhibitor, shows a favorable pharmacokinetic and safety profile across multiple phase 1 studies. (PubMed, Front Pharmacol) - P1 | "Based on the projected target occupancy, favorable pharmacokinetics, and safety profile, as well as on distinct pharmacodynamic effects in a proof-of-mechanism study, zabedosertib 120 mg twice daily was selected for further clinical development in patient studies. https://clinicaltrials.gov/, identifier SAD: NCT03054402, MAD: NCT03493269 (part 1), FE/abs.BA study NCT03244462 (EudraCT numbers: 2016-002668-15, 2017-001817-10, and 2016-004393-18)."

Journal • P1 data • PK/PD data • Infectious Disease • Inflammation • IRAK4

The oral IRAK4-Inhibitors Zabedosertib (BAY1834845) and BAY1830839 suppress immune complex induced interferon-α production by plasmacytoid dendritic cells in a dose dependent manner (EULAR 2025) - "In addition, we asked if the IRAK4 effect is additive to hydroxychloroquine (HCQ), which most patients with SLE receive as standard of care. Both IRAK4 inhibitors investigated in the present study efficiently suppressed the IFN-a production in an in vitro SLE model system. Moreover, both drugs enhanced the pharmacological effect of HCQ. BAY1830839 and BAY1834845 should therefore be further explored as therapeutic options for oral treatment of patients with SLE and CLE."

Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CD14 • CXCL8 • IFNA1 • IL6 • IRAK4 • TLR7 • TLR9 • TNFA

Efficacy and safety of the oral interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor zabedosertib in adult patients with moderate-to-severe atopic dermatitis – Results of the phase 2a DAMASK study (EADV 2024) - P2 | "In this Phase 2a study, zabedosertib, a development candidate targeting IRAK4 in AD, was well tolerated with no safety concerns, but no treatment effect across the efficacy endpoints was observed and no significant differences in biomarkers were detected. These results contrast with the clear pharmacodynamic effect of zabedosertib in a recent proof-of-mechanism study (1) and suggest that inhibition of IRAK4 is not a promising approach for the treatment of AD. Other immune-mediated diseases with different molecular involvement of IRAK4, including other inflammatory skin diseases, may still be targeted successfully with zabedosertib."

Clinical • IO biomarker • Late-breaking abstract • P2a data • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Infectious Disease • Pruritus • IRAK4 • TSLP

The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers. (PubMed, Clin Transl Sci) - "Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment. Both IRAK4 inhibitors significantly suppressed the serum TNF-α and IL-6 responses (≥80% suppression vs. placebo, p < 0.05) and inhibited C-reactive protein, procalcitonin, and IL-8 responses to intravenous LPS. This study demonstrated the pharmacological effectiveness of BAY1834845 and BAY1830839 in suppressing systemically and locally induced inflammatory responses in the same range as prednisolone, underlining the potential value of these IRAK4 inhibitors as future therapies for dermatological or other immune-mediated inflammatory diseases."

Journal • Dermatitis • Dermatology • Inflammation • CRP • CXCL8 • IL6 • IRAK4 • TNFA

Damask: A Study to Learn How Well the Study Treatment Zabedosertib (BAY1834845) Works and How Safe it is Compared to Placebo in Adult Participants With Moderate-to-severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=77 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Trial completion • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839. (PubMed, J Med Chem) - "By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients."

Journal • Inflammation • IRAK4

Damask: A Study to Learn How Well the Study Treatment Zabedosertib (BAY1834845) Works and How Safe it is Compared to Placebo in Adult Participants With Moderate-to-severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=72 | Active, not recruiting | Sponsor: Bayer | Phase classification: P2a ➔ P2

Phase classification • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

Damask: A Study to Learn How Well the Study Treatment Zabedosertib (BAY1834845) Works and How Safe it is Compared to Placebo in Adult Participants With Moderate-to-severe Atopic Dermatitis (clinicaltrials.gov) - P2a | N=72 | Active, not recruiting | Sponsor: Bayer | Recruiting ➔ Active, not recruiting

Enrollment closed • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

Demonstration of pharmacological activity of the oral Interleukin-1-receptor associated kinase 4 inhibitor Zabedosertib in a clinical phase 1 study by an ex-vivo challenge assay and design of the Proof-of-concept study with Zabedosertib in adult patients with atopic dermatitis (DAMASK study) (EADV-Sp 2023) - P2a | "Discussion From the described results of this explorative biomarker analysis, weconcluded that Zabedosertib exerts target engagementand further clinical evaluation was supported. Results of the placebo-controlled Proof-of-concept DAMASK study (NCT number: NCT05656911) areexpected for 2024"

P1 data • Preclinical • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • IRAK4 • TNFA

An innovative phase 1b trial demonstrating proof-of-pharmacology for two novel IRAK4-inhibitors using a local (Imiquimod) and systemic (LPS) driven immune response (ISID 2023) - "CONTROL ID: 3888739. This study demonstrated the effectiveness of the orally administered IRAK4-specific inhibitors BAY 1834845 and BAY 1830839 in suppressing the systemic and local inflammatory response upon specific topical or systemic challenges. The results suggest that both tested IRAK4-inhibitors showed pharmacodynamic responses upon IMQ- and LPS-challenges with a similar effect size as prednisolone."

P1 data • Dermatitis • Dermatology • Inflammation • CXCL8 • IL6 • IRAK4 • TNFA

Damask: A Study to Learn How Well the Study Treatment Zabedosertib (BAY1834845) Works and How Safe it is Compared to Placebo in Adult Participants With Moderate-to-severe Atopic Dermatitis (clinicaltrials.gov) - P2a | N=72 | Recruiting | Sponsor: Bayer | Not yet recruiting ➔ Recruiting

Enrollment open • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

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

Damask: A Study to Learn How Well the Study Treatment Zabedosertib (BAY1834845) Works and How Safe it is Compared to Placebo in Adult Participants With Moderate-to-severe Atopic Dermatitis (clinicaltrials.gov) - P2a | N=72 | Not yet recruiting | Sponsor: Bayer

New P2a trial • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

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

A Trial to Learn How BAY1834845 and BAY1830839 Affect Inflammation When Taken by Mouth Twice a Day for 7 Days in a Row in Healthy Male Participants (clinicaltrials.gov) - P1 | N=50 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Trial completion • Immunology • Inflammation • CRP • IL6 • TNFA

A Trial to Learn How BAY1834845 and BAY1830839 Affect Inflammation When Taken by Mouth Twice a Day for 7 Days in a Row in Healthy Male Participants (clinicaltrials.gov) - P1; N=50; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Immunology • Inflammation • CRP • IL6 • TNFA

A Trial to Learn How BAY1834845 and BAY1830839 Affect Inflammation When Taken by Mouth Twice a Day for 7 Days in a Row in Healthy Male Participants (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: Bayer

New P1 trial • Immunology • Inflammation • CRP • IL6 • TNFA

A Multiple Dose Study of BAY1834845 in Healthy Male Subjects and in Patients With Psoriasis (clinicaltrials.gov) - P1; N=72; Completed; Sponsor: Bayer; Active, not recruiting ➔ Completed

Clinical • Trial completion • Dermatology • Immunology • Psoriasis

A Multiple Dose Study of BAY1834845 in Healthy Male Subjects and in Patients With Psoriasis (clinicaltrials.gov) - P1; N=72; Active, not recruiting; Sponsor: Bayer; Trial completion date: Apr 2021 ➔ Dec 2020

Clinical • Trial completion date • Dermatology • Immunology • Psoriasis

A Multiple Dose Study of BAY1834845 in Healthy Male Subjects and in Patients With Psoriasis (clinicaltrials.gov) - P1; N=72; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting; Trial primary completion date: Mar 2021 ➔ Sep 2020

Clinical • Enrollment closed • Trial primary completion date • Dermatology • Immunology • Psoriasis

A Multiple Dose Study of BAY1834845 in Healthy Male Subjects and in Patients With Psoriasis (clinicaltrials.gov) - P1; N=78; Recruiting; Sponsor: Bayer; Trial completion date: Nov 2020 ➔ Apr 2021; Trial primary completion date: Oct 2020 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date • Dermatology • Dermatopathology • Immunology • Psoriasis

Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. (PubMed, Expert Opin Investig Drugs) - "The role of IRAK-4 as a key component of Toll/Interleukin-1 receptor signalling and its potential for a low rate of infectious complications is particularly exciting and this may facilitate their use in combination treatment. A key aspect of upcoming clinical trials will be the identification of biomarkers predictive of treatment efficacy, which will help to define if and how they will be used in the clinic."

Journal

A Multiple Dose Study of BAY1834845 in Healthy Male Subjects and in Patients With Psoriasis (clinicaltrials.gov) - P1; N=78; Recruiting; Sponsor: Bayer; Trial completion date: Aug 2020 ➔ Nov 2020; Trial primary completion date: Jul 2020 ➔ Oct 2020

Clinical • Trial completion date • Trial primary completion date

A Multiple Dose Study of BAY1834845 in Healthy Male Subjects and in Patients With Rheumatoid Arthritis (RA) or Psoriasis (clinicaltrials.gov) - P1; N=88; Recruiting; Sponsor: Bayer; Trial completion date: Mar 2020 ➔ Aug 2020

Clinical • Trial completion date