On January 6, 2022 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported 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 (Press release, Curis, JAN 6, 2022, View Source [SID1234598340]).
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"These data continue to build on what we believe to be a compelling profile for CA-4948, showing its activity as a monotherapy in a targeted population of patients living with R/R AML/MDS, for whom prior lines of therapy have been unsuccessful," said James Dentzer, President and Chief Executive Officer of Curis. "We are especially pleased that these results demonstrate both a favorable safety profile and improved anti-cancer activity compared with standard of care therapies for these patients. Furthermore, we have been able to successfully identify and enroll these patients using existing genetic diagnostic panels. We remain on track to enroll additional patients with a spliceosome mutation to prepare for potential discussions with the U.S. Food and Drug Administration (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."
"We are also encouraged by the safety data from the CI-8993 trial, which we believe demonstrate that the procedures we implemented to manage the expected cytokine release effect have been successful – and have allowed us to escalate patient dosing up to and beyond 0.3 mg/kg," he continued. "We have recently begun dosing at 0.6 mg/kg; and look forward to providing another update on our progress in the second half of 2022. We are thrilled to have achieved this key safety and dose escalation milestone, as it brings us one step closer to providing anti-VISTA therapy for patients living with solid tumors."
Phase 1/2 monotherapy study of CA-4948 in R/R AML/MDS
Well Tolerated and Manageable Safety Profile at 300 mg BID Dose Level
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
We 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.
In Expanded Data Set, Findings Support Earlier Data Presented in June 2021
Previous data presented by Curis at the European Hematology Association (EHA) (Free EHA Whitepaper) 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
We 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.
Phase 1 monotherapy study of CI-8993 in R/R solid tumors
Promising Safety Profile – No DLTs
Based on 13 patients treated in the first two dose cohorts of 0.15mg/kg and 0.3mg/kg, we 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.
Encouraging PK/PD Activity
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 we 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.
Conference Call Information
Curis management will host a conference call today, January 6, 2022, at 8:00 a.m. ET, to discuss these results with Dr. Daniel DeAngelo, Chief, Division of Leukemia at Dana-Farber Cancer Institute.
To access the live conference call, please dial 1-888-346-6389 from the United States or 1-412-317-5252 from other locations, shortly before 8:00 a.m. ET. The conference call can also be accessed on the Curis website at www.curis.com in the Investors section.
About CA-4948
CA-4948 is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with AML and MDS. Third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutation such as SF3B1 and U2AF1. In addition to inhibiting IRAK4, CA-4948 was also designed to inhibit FLT3, a known oncologic driver, which may provide additional benefit in patients with AML and MDS.
About CI-8993
CI-8993 is a monoclonal IgG1κ antibody with active Fc, designed to antagonize the V-domain Ig suppressor of T-cell activation (VISTA) signaling pathway. VISTA is a novel negative checkpoint ligand expressed on myeloid cells and T cells that is homologous to PD-1/PD-L1. VISTA enhances T cell quiescence and myeloid derived immune suppressor cells (MDSCs). CI-8993 relieves negative regulation by hematopoietic cells and enhances protective anti-tumor immunity. Preclinically, VISTA monoclonal antibody treatment increased the number of tumor-specific T cells in the periphery, and enhanced the infiltration, proliferation and effector function of tumor-reactive T cells within the tumor microenvironment (TME). VISTA blockade alters the suppressive feature of the TME by decreasing the presence of monocytic and granulocytic MDSCs and increasing the presence of activated dendritic cells (DCs) within the TME leading to enhanced T cell mediated immunity. VISTA monoclonal antibody administration as a monotherapy has been shown to suppress the growth of both transplantable and inducible melanoma in preclinical models. CI-8993 was originally developed as part of a license and collaboration agreement between ImmuNext and Janssen Biotech, Inc (Janssen). In 2016, Janssen initiated clinical development of CI-8993 in a Phase 1 study of CI-8993 in patients with advanced solid tumors. The study enrolled 12 patients, in which one patient experienced dose-limiting side effects related to cytokine release syndrome. Afterwards, Janssen opted to close the study and ImmuNext regained control of the asset. Curis is engaged in a collaboration with ImmuNext for the development of CI-8993.