emavusertib (CA-4948) / Curis, Dr. Reddy’s - LARVOL DELTA

CA-4948 Added to Standard Chemotherapy to Treat Metastatic or Unresectable Pancreatic Cancer (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Apr 2026 | Trial primary completion date: Mar 2025 ➔ Apr 2026

Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Analysis of genetic mutation profile and CNS pharmacokinetics in relapsed/refractory primary CNS lymphoma patients responding to novel emavusertib (IRAK4i) and BTKi combination. (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT03328078 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • PK/PD data • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

Contemporary management paradigms and emerging therapeutics for myelodysplastic syndromes/neoplasms. (PubMed, Br J Haematol) - "We discuss investigational therapies in the MDS pipeline, such as venetoclax, emavusertib, canakinumab and olutasidenib...We discuss how the identification of biomarkers of response to therapeutics may help guide clinical trial design for certain subsets of patients. Finally, we discuss how multicentre randomized trials can help facilitate the clinical rollout of emerging MDS therapeutics."

Journal • Review • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • TP53

HPB-092: A novel FLT3 and IRAK4 dual inhibitor for the treatments of AML and MDS (AACR 2025) - "Compared to the approved FLT3 inhibitors gilteritinib and quizartinib, and the clinical-stage FLT3/IRAK4 dual inhibitor CA-4948, HPB-092 showed comparable or superior inhibitory potency against mutated forms of FLT3, improved IRAK4 inhibition, better selectivity, minimal inhibition of CYP3A4, no hERG activity, and an overall favorable safety profile, potentially benefiting a broader range of hematological malignancies. HPB-092 has received FDA clearance for a phase 1 dose-escalation and expansion study to assess its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in adult patients with relapsed or refractory AML, particularly those with FLT3 mutations and U2AF1 or SF3B1 mutations, at a leading cancer center in the US."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CYP3A4 • FLT3 • IRAK4 • SF3B1 • U2AF1

A Study of Oral IRAK-4 Inhibitor CA-4948 in Combination With Pembrolizumab and Stereotactic Radiosurgery in Patients With Melanoma Brain Metastases (clinicaltrials.gov) - P1/2 | N=29 | Suspended | Sponsor: University of Florida | Recruiting ➔ Suspended

Trial suspension • Melanoma • Oncology • Solid Tumor

Curis Provides Fourth Quarter 2024 Business Update (Curis Press Release) - P1/2 | N=152 | TakeAim Lymphoma (NCT03328078) | Sponsor: Curis, Inc. | "Curis provided a data update for 27 patients enrolled in the ongoing TakeAim Lymphoma study in relapsed/refractory (R/R) PCNSL as of January 2, 2025 (data cutoff). In 20 BTKi-experienced patients: 13 patients had change in tumor burden data available as of data cutoff; 9 of these 13 patients demonstrated a reduction in tumor burden, including 6 objective responses, 4 complete responses (CR) and 2 partial responses (PR), with 3 of 4 CRs lasting more than six months. In 7 BTKi-naïve patients: 6 patients had change in tumor burden data available as of data cutoff; 5 of these 6 patients demonstrated a reduction in tumor burden, including 5 objective responses, 1 CR and 4 PRs."

P1/2 data • Primary Central Nervous System Lymphoma

Curis Provides Fourth Quarter 2024 Business Update (Curis Press Release) - "Curis successfully concluded meetings with both the U.S. Food and Drug Administration (FDA) and the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) on the suitability of using the ongoing TakeAim Lymphoma study (NCT03328078) to support a potential accelerated approval path in PCNSL. Curis also announced that emavusertib has been granted Orphan Drug Designation for PCNSL in both the US and Europe."

European regulatory • FDA event • Primary Central Nervous System Lymphoma

Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy (clinicaltrials.gov) - P1 | N=27 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Initiation date: Feb 2025 ➔ Nov 2025

Enrollment open • IO biomarker • Trial initiation date • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD68 • CRP • PD-L1

Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy (clinicaltrials.gov) - P1 | N=25 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2025 ➔ Jun 2027 | Trial primary completion date: Oct 2025 ➔ Jun 2027

IO biomarker • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD68 • CRP • PD-L1

CA-4948-101: Open-Label, Dose Escalation and Expansion Trial of Emavusertib (CA-4948) in Relapsed or Refractory Primary Central Nervous System Lymphoma (R/R PCNSL) (clinicaltrials.gov) - P1/2 | N=152 | Recruiting | Sponsor: Curis, Inc. | N=80 ➔ 152

Enrollment change • CNS Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

CA-4948 in Combination With FOLFOX/PD-1 Inhibitor +/- Trastuzumab for Untreated Unresectable Gastric and Esophageal Cancer (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Jun 2027 ➔ Jun 2028 | Trial primary completion date: Sep 2026 ➔ Sep 2027

Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Solid Tumor • HER-2

Targeting of Various Inflammatory Circuits Does Not Ameliorate Ineffective Hematopoiesis: Results of the Lucas and Canfire Studies Investigating IRAK4 or IL-1β Blockade to Target Anemia in Lower-Risk MDS (ASH 2024) - "Emavusertib treatment was associated with a reduction in neutrophil counts...Canakinumab treatment was well-tolerated with no reported SAEs...Despite the observed anti-inflammatory effects in the bone marrow, in LUCAS there was a paradoxical increase in inflammatory markers in peripheral blood, potentially due to compensatory mechanisms. These findings suggest that targeting multiple inflammatory pathways simultaneously may offer a more promising therapeutic strategy, such as the combination of IL-1β and IRAK4 inhibitors."

Anemia • Cardiovascular • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • ASXL1 • CSF1 • IL10 • IL15 • IL1B • IL1R1 • IL7 • IRAK4 • SETBP1 • U2AF1

Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Combination with Ibrutinib in Relapsed/Refractory Primary Central Nervous System Lymphoma Patients with Prior Exposure to BTK Inhibitor (ASH 2024) - P1/2 | "The combination of emavusertib + ibrutinib may overcome BTKi resistance and has the potential to show improved anti-cancer activity. Enrollment in this trial is ongoing (NCT03328078)."

Clinical • Combination therapy • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • IL1R1 • IRAK4 • MYD88

Preliminary Safety, Efficacy and Molecular Characterization in Patients with Higher-Risk Myelodysplastic Syndrome Treated with Single Agent Emavusertib (CA-4948) (ASH 2024) - P1/2 | "Aim We present preliminary efficacy data of emavusertib hrMDS patients with SFm who failed prior treatment with either venetoclax (VEN) or hypomethylating agents (HMA) based regimens, either as monotherapy or in combination. Enrollment in this monotherapy trial is ongoing at 300 mg BID in hrMDS patients with < 3 lines of prior anti-cancer therapies. Combination trials across the emavusertib program are ongoing with HMA, BCL2 and BTK-inhibitors."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • BCL2 • BCOR • FLT3 • IRAK4 • RUNX1 • SF3B1 • SRSF2 • TET2 • U2AF1

Preliminary Safety, Efficacy, and Molecular Characterization of Emavusertib (CA-4948) in Relapsed/Refractory Acute Myeloid Leukemia Patients (ASH 2024) - P1/2 | "Patients with relapsed/refractory (R/R) AML who have failed standard therapies, including venetoclax (VEN), hypomethylating agents (HMA), and/or FLT3 inhibitors (FLT3i) have limited therapeutic options. Enrollment in this trial is ongoing at 300 mg BID in patients with < 3 lines of prior anti-cancer therapies. Combination trials across the emavusertib program are ongoing with HMA, BCL2 and BTK-inhibitors."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • BCL2 • BCOR • FLT3 • IRAK4 • NRAS • RUNX1 • SF3B1 • SRSF2 • U2AF1 • WT1

CA-4948 Added to Standard Chemotherapy to Treat Metastatic or Unresectable Pancreatic Cancer (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Curis Announces Additional Data from TakeAim Leukemia Study (PRNewswire) - P1/2 | N=366 | TakeAim Leukemia (NCT04278768) | Sponsor: Curis, Inc. | "The additional data presented include data for 21 patients with a FLT3 mutation (FLT3m) who had received fewer than 3 lines of prior therapy and were treated with emavusertib as monotherapy at the Recommended Phase 2 Dose (RP2D) of 300 mg BID. This brings the total number of patients dosed at the RP2D from 12 to 21 patients...Data show 10 objective responses in 19 response-evaluable patients: 6 complete remission (CR), 2 CR with either a complete remission with incomplete hematological recovery (CRi) or a partial hematological recovery (CRh) and 2 morphologic leukemia-free state (MLFS)....Two patients who achieved a CR and CRi, respectively, proceeded to allogenic stem cell transplantation. Responses were achieved rapidly in this population, with 7 of 10 responses reported at the first assessment (Cycle 2 Day 1)."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Orphan Designation: treatment of primary central nervous system lymphoma (FDA) - Date Designated: 12/03/2024

Orphan drug • CNS Lymphoma

Clinical Trial of an Anti-cancer Drug, CA-4948 (Emavusertib), in Combination With Chemotherapy Treatment (FOLFOX Plus Bevacizumab) in Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

Combination therapy • Metastases • New P1 trial • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • CCL2 • CXCL1 • IFNG • IL6 • IRAK4

Curis Provides Third Quarter 2024 Business Update (PRNewswire) - "TakeAim Leukemia....The Company will have both an oral presentation and a poster presentation at the 66th American Society of Hematology (ASH) annual meeting in December."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches. (PubMed, Adv Biol Regul) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IRAK4 • SF3B1 • SRSF2 • U2AF1

Curis Announces the 3rd Annual Symposium on IRAK4 in Cancer (PRNewswire) - "Curis, Inc...announced the 3rd Annual Symposium on IRAK4 in Cancer taking place virtually on September 26, 9:00 AM-1:00 PM E.T...Hosted by Dr. Eric S. Winer (Dana-Farber Cancer Institute) and Dr. Grzegorz S. Nowakowski (Mayo Clinic Comprehensive Cancer Center), this symposium will focus on IRAK4, an emerging target in the treatment of hematologic malignancies and solid tumors. Experts will discuss the promise of IRAK4 inhibition in cancer, including current clinical studies of emavusertib and opportunities for future development....Symposium presentations will include updated data for 10 evaluable R/R PCNSL patients as of the July 10, 2024 cutoff date. The Company continues to enroll patients in the PCNSL study and is on track to enroll 15-20 patients by year-end."

Clinical • Enrollment status • P1/2 data • CNS Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

TakeAim Lymphoma Tests Proof of Concept for Dual IRAK4/FLT3 Blockade in B-Cell Malignancy Treatment (OncLive) - P1/2 | N=366 | TakeAim Leukemia (NCT04278768) | Sponsor: Curis, Inc.| "Following encouraging data seen with emavusertib as monotherapy and in combination with ibrutinib (Imbruvica), the phase 1/2 TakeAim Lymphoma trial (NCT03328078) is currently enrolling patients with PCNSL to the part B expansion cohort of the trial to receive the combination...Preliminary efficacy from the dose escalation portion of the trial (part A2) with emavusertib plus ibrutinib showed that 5 of the 16 evaluable patients experienced a complete response (CR) to treatment with the combination...Regarding safety findings from part A2 of TakeAim Lymphoma, grade 3 treatment-related adverse effects occurred in 74% of patients in the safety population (n = 19), which included those treated at the 100 mg (n = 2), 200 mg (n = 10), and 300 mg (n = 7) twice daily doses of emavusertib plus ibrutinib."

P1/2 data • Trial status • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma

LUCAS: Treatment of Anemia in Patients With Very Low, Low or Intermediate Risk Myelodysplastic Syndromes With CA-4948 (clinicaltrials.gov) - P2 | N=38 | Terminated | Sponsor: University of Leipzig | Trial completion date: Mar 2024 ➔ Jul 2024 | Trial primary completion date: Mar 2024 ➔ Jul 2024

Trial completion date • Trial primary completion date • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy (clinicaltrials.gov) - P1 | N=25 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Aug 2024 ➔ Dec 2024

Combination therapy • IO biomarker • Metastases • Trial initiation date • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD68 • CRP • PD-L1