Emavusertib

Overview

Emavusertib (CA-4948) is an investigational, oral small‑molecule inhibitor of IRAK4 with additional activity against FLT3 and CDC‑like kinases (CLK1/2/4). It is being studied primarily in relapsed/refractory (R/R) acute myeloid leukemia (AML), higher‑risk myelodysplastic syndromes (hrMDS), and in combination with ibrutinib in primary CNS lymphoma (PCNSL). The recommended phase 2 dose (RP2D) for monotherapy is 300 mg twice daily (BID). (ascopubs.org)

Active clinical programs include: - TakeAim Leukemia (NCT04278768): Phase 1/2 in R/R AML and hrMDS (monotherapy; combinations planned). (ash.confex.com) - TakeAim Lymphoma (NCT03328078): Phase 1/2 in B‑cell malignancies, including an expansion in R/R PCNSL with ibrutinib. (ascopubs.org)

Mechanism of action

• Primary target: IRAK4, a kinase downstream of TLR/IL‑1R/MYD88 signaling that activates NF‑κB and MAPK. In B‑cell lymphomas (often MYD88‑mutant), IRAK4 signaling can mediate resistance to BTK inhibition. (pubmed.ncbi.nlm.nih.gov)
• Myeloid context: In MDS/AML with spliceosome mutations (e.g., U2AF1, SF3B1), aberrant splicing increases the oncogenic long isoform of IRAK4 (IRAK4‑L), creating a therapeutic dependency. (ashpublications.org)
• Kinase profile: Emavusertib inhibits IRAK4 and also FLT3 and CLK1/2/4, aiming to suppress NF‑κB/MAPK and potentially address resistance to venetoclax or FLT3 inhibitors. (ash.confex.com)

Efficacy

AML (monotherapy; TakeAim Leukemia) - ASH 2024 oral abstract: Among 48 R/R AML patients with FLT3 or spliceosome mutations treated at 200–300 mg BID, responses were most frequent at 300 mg BID. In the 300 mg cohort, 7/17 FLT3‑mutant patients responded (4 CR, 1 CRh, 2 MLFS); 5/25 spliceosome‑mutant patients responded (2 CR, 1 CRi, 1 CRh, 1 MLFS). Many responses occurred after one cycle; some patients bridged to transplant. (ash.confex.com)
- ASCO 2024 abstract (FLT3‑mutant subset): In 11 R/R AML patients (most pretreated with FLT3 inhibitors), emavusertib produced >90% marrow blast reductions in responders at 300 mg BID. (ascopubs.org)

hrMDS (monotherapy; TakeAim Leukemia) - ASH 2024 poster: In 14 hrMDS patients with spliceosome mutations treated at 300 mg BID, 4/13 response‑evaluable achieved marrow CR (mCR); two patients proceeded to transplant. A pilot intermittent‑dosing cohort (7–14 days on per 28‑day cycle) also reported mCRs. (ash.confex.com)

PCNSL (emavusertib + ibrutinib) - ASH 2024 poster and ASCO 2024 abstract: In R/R PCNSL patients previously exposed to BTK inhibitors, the combination was reported as tolerable with “promising efficacy,” including complete responses; examples included durable CRs of approximately 9–12 months among early responders. Enrollment is ongoing. (ashpublications.org)
- Rationale supported by preclinical CNS lymphoma models showing brain/CSF penetration and antitumor activity; emavusertib may overcome BTK‑inhibitor resistance. (aacrjournals.org)

Note: Data above are preliminary (conference abstracts) from ongoing early‑phase studies; mature, peer‑reviewed efficacy datasets are not yet available.

Safety

• Across TakeAim Leukemia (AML/hrMDS) through July 10, 2024 (N=145 treated at 200–500 mg BID), grade ≥3 treatment‑related adverse events (TRAEs) occurred in 28.3% and were “mostly reversible and manageable.” The monotherapy RP2D is 300 mg BID. (ash.confex.com)
• In R/R PCNSL with ibrutinib, early reports noted acceptable tolerability; ≥grade 3 treatment‑emergent AEs in 53.8% and ≥grade 3 TRAEs in 30.8% in a small cohort; no fatal TRAEs reported. (ashpublications.org)
• Regulatory history: In April 2022, the FDA placed partial clinical holds on emavusertib studies due to safety concerns including rhabdomyolysis; the holds were subsequently lifted (Lymphoma in August 2022; Leukemia in July 2023) with risk‑mitigation measures, and studies resumed at or below RP2D. (fdanews.com)

Further reading

• ASH 2024 AML oral abstract (TakeAim Leukemia): Preliminary safety/efficacy in R/R AML. (ash.confex.com)
• ASH 2024 hrMDS poster: Preliminary safety/efficacy in hrMDS with spliceosome mutations. (ash.confex.com)
• ASCO 2024 AML abstract: FLT3‑mutant R/R AML subset treated with emavusertib. (ascopubs.org)
• ASCO 2024 PCNSL abstract: Emavusertib + ibrutinib in R/R PCNSL. (ascopubs.org)
• Blood 2024 PCNSL poster: Preliminary safety/efficacy of emavusertib + ibrutinib in prior BTK‑i exposed PCNSL. (ashpublications.org)
• Review: IRAK4 inhibition and emavusertib in lymphoid/myeloid malignancies. (pubmed.ncbi.nlm.nih.gov)
• Preclinical studies: Overcoming BTK/PI3K inhibitor resistance in lymphoma; CNS lymphoma models. (pubmed.ncbi.nlm.nih.gov)

ClinicalTrials.gov identifiers: NCT04278768 (AML/hrMDS); NCT03328078 (PCNSL with ibrutinib). (ash.confex.com)

Last updated: Oct 2025