P1, N=64, Recruiting, Eilean Therapeutics

Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

P1/2, N=29, Recruiting, University of Florida | Not yet recruiting --> Recruiting

The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.

P1, N=60, Not yet recruiting, Eilean Therapeutics

P1, N=40, Not yet recruiting, AstraZeneca

P1, N=3, Terminated, Gilead Sciences | Phase classification: P1b --> P1

Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of TLR2, TLR4, and IRAK4 (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias. Overall, the expression of TLR2, TLR4, and IRAK4 could be potential biomarkers for discriminating MDS from some hematologic disorders.

Finally, pharmacological targeting of interleukin-1 receptor-associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in non-diseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.

P2, N=77, Completed, Bayer | Active, not recruiting --> Completed

P1, N=133, Recruiting, AstraZeneca | Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

P1, N=63, Completed, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Recruiting --> Completed | Trial completion date: Dec 2023 --> May 2023

P1/2, N=29, Not yet recruiting, University of Florida

The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments.

The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

Provided herein are novel IRAK4 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma, COPD, cancer, autoinflammatory diseases, and autoimmune diseases, and processes for preparing such compounds.

P2, N=72, Active, not recruiting, Bayer | Phase classification: P2a --> P2

P2, N=33, Recruiting, Gilead Sciences

In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities.

These data suggest that the anti-leukemic activity of IRAK-4 inhibition can be exploited in relapsed/refractory (R/R) AML/MDS. In this review article, we discuss the currently available pre-clinical and clinical data of emavusertib, a selective, orally bioavailable IRAK-4 inhibitor in the treatment of R/R B-cell lymphomas and myeloid malignancies.

P2, N=33, Recruiting, Gilead Sciences | Phase classification: P2a --> P2

The combination of emavusertib plus ibrutinib (ema+ibr) is well tolerated with an acceptable long-term safety profile and promising efficacy, showing several objective responses in heavily pretreated and/or BTK inhibitor resistant patients. Emavusertib may have the potential to overcome BTK inhibitor resistance and the combination of ema+ibr has the potential to show increased anti-cancer activity compared to ibrutinib monotherapy.

In primary patient cell lines from FLT3 wildtype (WT) patients, KME-0584 inhibits leukemia stem cell progenitor function as measured by the colony formation assay in methylcellulose with higher potency than IRAK4 inhibitor compounds that lack IRAK1 activity such as CA-4948 (Emavusertib)...Given that monocytic-like subtypes of AML are resistant to Venetoclax plus Azacitidine (VEN/AZA) (S Pei et...KME-0584 exhibits superior potency and efficacy to gilteritinib in the FLT3-ITD (D835Y) xenograft model after QD oral dosing, with sufficient PK and oral bioavailability across multiple species to support QD or BID dosing in the clinic. KME-0584 does not inhibit any of the major or minor cytochrome P450 enzymes at anticipated clinical concentrations and early indication from ongoing GLP toxicology studies suggest that it could be safely administered in humans. A clinical study of KME-0584 in relapsed/refractory AML and HR-MDS is currently planned to start in 1H 2024.

Through qRT-PCR and mass cytometry, we demonstrate that CA-4948 treatment dampened inflammatory cytokine production induced by IL-1β in primary MPN CD14+ monocytes. Overall, we demonstrate that targeting mediators including Rela, Myd88, and IRAK4 specifically alleviated MPN disease burden without toxicity to healthy tissue and further establish CA-4948 as a promising therapeutic avenue for the treatment of MPN.

R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract...The trial is currently recruiting at 9 US sites. The study has enrolled 7 patients in the dose escalation phase.

Key exclusion criteria: intraocular PCNSL without brain lesion or CSF involvement or significant co-morbidity. Key clinical assessments include brain imaging, CSF- and ocular examinations.

Two patients with prior gilteritinib exposure also received midostaurin therapy. In addition, mutational profiles are suggestive of disease-modifying activity of emavusertib. Enrollment in this trial is continuing at a dose of 300mg BID (phase 2 expansion cohort) for patients with ≤ 2 prior lines of therapy.

In Phase-1 findings with a selective IRAK4 inhibitor (CA-4948; Curis Therapeutics), it was found that MDS and AML patients with splicing factor mutations responded best to monotherapy IRAK4 inhibition, although the overall response rate with monotherapy was modest...CC-90009 did not result in complete cell death up to concentrations of 10mM in both WT and IRAK4KO, suggesting that the selective sensitivity of IRAK4KO AML cells to CC-885 is not due to inhibition of GSPT1...These findings suggest that IRAK4 inhibition alters the pool of neosubstrates in AML cells for certain CELMoDs. Overall, our study demonstrates that IRAK4 is a therapeutic target in AML, but that combination therapies, such as with certain CELMoDs, will be necessary to achieve better clinical responses.

P2a, N=72, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting

P1b, N=34, Recruiting, Rigel Pharmaceuticals | N=22 --> 34 | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: Apr 2024 --> May 2025

No abstract available

Ongoing studies will attempt to identify treatment response biomarkers. Future research will examine the correlations of gene expression with mutational profiles, splicing factor mutations, emavusertib dose regimens, and use of proteomics technologies to assess targeted kinase phosphorylation levels (e. g. IRAK4, NFκB) and quantification of soluble markers.

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.

No abstract available

P1, N=42, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

In combination with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, 22 showed enhanced apoptosis-inducing effect and antiproliferative potency. The most advanced compound 22 in this inhibitor series holds promise for further development into efficacious and selective IRAK4 inhibitors for the treatment of DLBCL.

R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. Phase I, Myelodysplastic syndrome, Kinase inhibitor, MDS

Initial clinical data with KT-413 demonstrate degradation of IRAK4 and Ikaros/Aiolos in PBMC and tumor. It is anticipated that higher doses will achieve the predicted degradation profile in tumors that may confer clinical benefit in MYD88-mutant patients. Dose escalation is ongoing, and analyses from additional patients will be presented at the meeting.

IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.

Emavusertib reconditions the MBM TME by mitigating the recruitment of infiltrating suppressive myeloid cells that likely confer resistance to anti-PD-1 ICI. This improves the anti-tumor efficacy of anti-PD-1 ICI, resulting in increased overall survival. Thus, emavusertib may be an effective adjuvant for improving treatment response to ICI in patients with MBM.