Curis, Inc. announced positive updated clinical data from the ongoing open label Phase 1/2 dose escalation and expansion study of CA-4948, a novel, small molecule IRAK-4 inhibitor, as a monotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high risk myelodysplastic syndromes (MDS) as well as initial safety, pharmacokinetic and pharmacodynamic data from the Phase 1 dose escalation study of CI-8993, a monoclonal antibody targeting VISTA for patients with R/R solid tumors. As of December 16, 2021, 49 total patients had been administered CA-4948 in the R/R AML/MDS study across 200mg, 300mg, 400mg, and 500mg dose cohorts. The safety profile observed to date showed the following key findings: CA-4948 was well-tolerated across multiple dose levels, including at the Recommended Phase 2 Dose of 300 mg BID, Treatment-related adverse events were reversible and manageable, No dose-limiting myelosuppression, No cumulative toxicities observed, No grade 4 or 5 treatment-related adverse events.

company believe these attributes of CA-4948's emerging safety profile may provide an advantage compared to current standard of care therapies in monotherapy and could also make CA-4948 an attractive candidate for addition to combination therapy regimens. Previous data presented by Curis at the European Hematology Association in June 2021, highlighted preliminary efficacy data of CA-4948 in R/R AML/MDS patients whose disease is characterized by spliceosome or FLT3 mutation. It is this genetically-defined subset of AML/MDS that is specifically targeted by CA-4948 and therefore represents the patients most likely to benefit from treatment with CA-4948 in monotherapy.

Today's clinical data update provides an expanded data set for this genetically-defined patient population and further support the rationale for seeking a discussion with FDA in the first half of 2022 to discuss the potential for a rapid registrational path forward for CA-4948 as a monotherapy in genetically-defined patient populations. In order to assess preliminary efficacy for these patients on study, Curis presented data on patients that had enrolled as of September 30, 2021, which allowed the opportunity for at least 2 disease assessments, to determine marrow response. Based on this criterion, there were 12 evaluable patients with a U2AF1 or SF3B1 spliceosome mutation (7 MDS; 5 AML) and 3 evaluable patients with a FLT3 mutation.

There were 13 total evaluable patients; two AML patients presented with both a spliceosome mutation and FLT3 mutation and are therefore included in both subpopulations. These patients had experienced a median of 2 prior lines of therapy (range 1-4), and all patients had prior hypomethylating agent (HMA) treatment. In patients with spliceosome-mutated R/R AML, key findings included: CR/CRh rate of 40% (2 out of 5 patients), Both patients who achieved CR/CRh have been on study > 6 months and achieved negative MRD (minimal residual disease) status, Consistent tumor burden reduction observed, 3 out of 5 patients with elevated blast counts achieving = 50% reduction in blast counts.

In patients with spliceosome-mutated R/R MDS, key findings included: Objective response rate of 57% (4 out of 7 patients), One of the patients who achieved a marrow CR (mCR) proceeded to stem cell transplant after 1 cycle, Consistent tumor burden reduction observed, with 4 out of 7 patients achieving = 50% reduction in blast counts . In patients with a FLT3 mutated R/R AML, key findings included: CR rate of 33% (1 out of 3 patients) 2 out of 3 patients showed eradication of FLT3 mutation following treatment, indicating potential to modify the disease, Consistent tumor burden reduction observed; with 2 out of 3 patients with elevated blast counts achieving = 50% reduction in blast counts. Company believe the data suggest a favorable safety and anti-cancer activity profile compared to standard of care therapies for these patient populations.

Enrollment in the study of CA-4948 in R/R AML/MDS is on-going, and Curis looks forward to potential discussions with the FDA in the first half of 2022 regarding the potential for a rapid registrational path forward for CA-4948 as a monotherapy in genetically-defined patient populations. Curis expects to provide additional data from the R/R AML/MDS study at a medical meeting in 2022. Based on 13 patients treated in the first two dose cohorts of 0.15mg/kg and 0.3mg/kg, believe CI-8993 has shown a promising safety profile to date, with no dose-limiting toxicities observed.

Following the implementation of safety measures including step dosing and co-medication, the trial has successfully dose escalated through the 0.15 mg/kg and 0.3 mg/kg cohorts, the dose level at which Janssen discontinued a prior study after a patient experienced a reversible grade 3 treatment-related adverse event. The current study of CI-8993 in patients with solid tumors is currently enrolling at 0.6 mg/kg. In the prior Janssen study, CI-8993 had demonstrated that, at low doses, a "sink effect" limited the amount of CI-8993 that could be detected in the circulation of patients.

In the current Curis study, CI-8993 has shown non-linear increases in pharmacokinetic (PK) exposure at each dose level and exhibits saturation kinetics, indicating the potential to overcome this sink effect as increase dose. These findings suggest the potential for broad bioavailability at higher dose levels. The pharmacodynamic (PD) effects of CI-8993 in patients observed to date suggest the possibility that CI-8993 can activate multiple anti-cancer immune mechanisms, including mechanisms that are not addressed by currently approved checkpoint inhibitors.

Curis intends to further explore this PK/PD relationship at higher dose levels, as the study continues. Curis expects to report expanded safety and tolerability data, along with initial PK, PD and anti-cancer data from the trial in the second half of 2022.