On June 21, 2021 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company pioneering a new class of small-molecule medicines that selectively destroy disease-causing proteins through degradation, reported that pre-clinical data for CFT7455, the Company’s lead program. CFT7455 is an orally bioavailable MonoDAC targeting IKZF1/3 for the treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL), including peripheral T-cell lymphoma (PTCL) and mantle cell lymphoma (MCL) (Press release, C4 Therapeutics, JUN 21, 2021, View Source [SID1234584183]). These results, which support clinical evaluation of CFT7455 in non-Hodgkin’s lymphomas, were delivered as a poster presentation at the 16th Annual International Conference on Malignant Lymphoma (ICML).
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"We are pleased to share these pre-clinical data, which further validate the potential of our lead candidate, CFT7455, to generate deep and durable antitumor responses in non-Hodgkin’s lymphomas. IKZF1/3 proteins are essential transcription factors for B cell malignancies, including non-Hodgkin’s lymphomas, and we believe there is a compelling opportunity to explore the potential of optimized IKZF1/3 degradation as a much-needed therapeutic alternative," said Adam Crystal, M.D., Ph.D., chief medical officer of C4 Therapeutics. "These results, which are consistent with recent pre-clinical data in multiple myeloma presented at the AACR (Free AACR Whitepaper) Annual Meeting 2021, reinforce our belief that CFT7455 will provide significant clinical value in the treatment of hematologic malignancies as we advance the Phase 1/2 trial and prepare to share data in 2022."
Summary of Results
C4T conducted in vitro studies which demonstrated that CFT7455 binds to cereblon with high affinity, inducing potent and deep degradation of IKZF1 in pre-clinical NHL models. Notable observations include:
Cellular competition studies confirmed the high potency of CFT7455 as a cereblon binder (IC50 = 0.4 nM).
Treatment of the KiJK cell line of anaplastic large cell lymphoma (ALCL) with CFT7455 for 6 hours led to an 89% reduction in IKZF1 protein levels.
CFT7455 demonstrated potent antiproliferative activity across a panel of NHL cell lines with MYC, BCL2, and/or BCL6 translocations or rearrangements. This includes in vitro models of cutaneous T-cell lymphoma (CTCL), anaplastic large cell lymphoma (ALCL), mantle cell lymphoma (MCL), and high-grade B-cell lymphoma.
In xenograft models of NHL, CFT7455 achieved improved in vivo potency and efficacy, including deeper and more durable tumor regressions in models of ALCL, diffuse large B-cell lymphoma (DLBCL) and MCL, when compared to approved and investigational IMiD therapies. Notable observations include:
CFT7455 treatment (100 µg/kg/day, PO) led to durable tumor regression associated with deep IKZF1 degradation and IRF4 downregulation (7% and 25% remaining, respectively) in KiJK xenografts, where pomalidomide treatment was ineffective at a clinically relevant dose (3000 µg/kg/day).
In the TMD8 DLBCL xenograft model, which proved insensitive to IMiD treatment, CFT7455 (100 µg/kg) promoted tumor regression.
In the REC1 MCL xenograft model, doses of CFT7455 ≥ 10 µg/kg promoted tumor regression. Pharmacodynamic studies showed that CFT7455 (30 µg/kg) promoted degradation of IKZF1 and downregulation of cyclin D1 and E2F1.
CFT7455 achieved dose-dependent efficacy in both ALK- (DL-40) and ALK+ (KiJK) xenograft models, from 3-100 µg/kg with regressions at doses ≥ 30 µg/kg. In addition, CFT7455 was shown to be between >30-100 times more potent than other IKZF1/3 degraders in development.
Global proteomic studies showed only IKZF1/3 proteins were significantly degraded in DL-40 tumors with treatment of CFT7455, resulting in modulation of IFN-regulated genes.
These results support continued development of CFT7455, which C4T is currently exploring for the treatment of relapsed or refractory multiple myeloma and non-Hodgkin’s lymphomas following the initiation of a Phase 1/2 clinical study in June 2021.
C4T’s ICML poster presentation will be archived on the "Scientific Publications" page in the Investors section of the Company’s website, located at www.c4therapeutics.com.
About CFT7455
CFT7455 is an orally bioavailable MonoDAC (Monofunctional Degradation Activating Compound) designed to bind with high affinity to the E3 ligase adapter protein, cereblon, to target and degrade IKZF1/3 for the treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHLs), including peripheral T cell lymphoma (PTCL) and mantle cell lymphoma (MCL). In preclinical studies, CFT7455 has demonstrated potent and selective protein degradation with favorable pharmacological properties. The Company initiated a Phase 1/2 clinical trial for CFT7455 in June 2021. More information about this trial may be accessed at www.clinicaltrials.gov (identifier: NCT04756726).