emavusertib (CA-4948)

The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.

P2, N=38, Terminated, University of Leipzig | Trial completion date: Mar 2024 --> Jul 2024 | Trial primary completion date: Mar 2024 --> Jul 2024

P1, N=25, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Aug 2024 --> Dec 2024

P1, N=25, Not yet recruiting, National Cancer Institute (NCI)

P2, N=38, Terminated, University of Leipzig | N=84 --> 38 | Trial completion date: Apr 2025 --> Mar 2024 | Recruiting --> Terminated; First interim analysis for cohort A performed, due to safety concerns cohort B closed prematurely

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.

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.

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

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.

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.

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.

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.

No abstract available

These results correlated with increased response to the proapoptotic drugs talazoparib, teniposide and the IRAK4 inhibitor emavusertib(p=0.043/0.037/0.027). The combination of emavusertib and alpelisib had the greatest synergy in MUT and WT HER2 BC cells.ConclusionThe 9177 mutation, present in 15% of HER2+ patients, impacts expression of HER2 amplicon genes and altered expression of apoptosis regulating proteins. The dual inhibition of IRAK and PI3K pathways has synergistic anti-proliferative effects and represents a potential novel treatment for HER2 BC patients.

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

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.

P1, N=42, Not yet recruiting, Washington University School of Medicine | Trial completion date: Apr 2027 --> Jul 2027 | Trial primary completion date: Jun 2026 --> Sep 2026

Emavusertib (CA-4948), an IRAK4/FLT3 inhibitor, is currently in phase I clinical trials. In addition, no rhabdomyolysis side-effect was observed upon histological analysis. These results underscore the potential therapeutic benefit and safety profile of HPB-092 for the treatment of AML, especially in patients with mutations in U2AF1 or SFF3B1 spliceosome.

Therapeutic inhibition of IRAK-4 in MBM mitigates immune suppression mediated by tumor-associated cells, allowing for improved immune surveillance and tumor infiltration by effector T lymphocytes, resulting in enhanced anti-tumor activity. Thus, CA-4948 may be an effective treatment alongside anti-PD-1 ICB for patients with MBM.

Emavusertib exerted its activity via inhibition of NF-κB signaling and induction of apoptosis. Considering the early safety data from clinical trials, our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored in trials for patients with MYD88-mutated indolent B cell lymphomas as single agent and as combination partner with BTK or PI3K inhibitors in unselected populations of patients.

P1, N=42, Not yet recruiting, Washington University School of Medicine | Trial primary completion date: Mar 2026 --> Jun 2026

Patients with targeted mutations responded to emavusertib, even in the presence of co-mutations of ASXL1 that are typically associated with poor prognosis. We will continue to explore potential genomic biomarkers of emavusertib sensitivity and resistance

P1/2, N=325, Recruiting, Curis, Inc. | Active, not recruiting --> Recruiting | N=178 --> 325

P1/2, N=221, Recruiting, Curis, Inc. | Active, not recruiting --> Recruiting | Trial completion date: May 2025 --> Aug 2026 | Trial primary completion date: Nov 2023 --> Aug 2026

Pharmacological inhibition of IRAK4 has shown efficacy in pre-clinical studies and in MDS clinical trials, with higher response rates in patients with splicing factor mutations. Our increasing knowledge of the effects of splicing factor mutations in MDS is leading to the development of new treatments that may benefit patients harboring these mutations.

Following implantion of B16.F10 tumor both intracranially and into the flank of C57BL6 mice we treated mice with the oral IRAK-4 inhibitor CA-4948 with or without anti-PD-1 mAb therapy or vehicle control...We posit IRAK-4 inhibition as a mechanism of restoring the inflammatory balance in MBM to improve immune checkpoint inhibition. We propose the further investigation of IRAK-4 inhibition with combination immunotherapy approaches in MBM patients.

Our data supports that emavusertib demonstrates anti-tumor activity in the CNS space, warranting further preclinical and clinical evaluation of this agent for the treatment of PCNSL.

P1, N=42, Not yet recruiting, Washington University School of Medicine | Trial completion date: Oct 2026 --> Jan 2027 | Initiation date: Aug 2022 --> Nov 2022 | Trial primary completion date: Dec 2025 --> Mar 2026

Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models...We acknowledge support of this research from The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C34874GG. MS is supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420).

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.

IRAK4 drives T cell dysfunction in PDAC and is a novel, promising immunotherapeutic target.

No dose-limiting myelosuppression was reported, suggesting emavusertib may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing.

Finally, one patient who could not tolerate standard therapies and was resistant to Ibrutinib achieved complete response when treated with the combination of emavusertib and Ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib. Conclusion Herein we confirm for the first time that targeted inhibition of IRAK-4 with the oral small molecule inhibitor emavusertib demonstrates preclinical and clinical therapeutic activity against CNS lymphoma. Further evaluation of this agent for the treatment of PCNSL is warranted.

Conclusion Emavusertib as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib.