CFT7455, a novel IKZF1/3 degrader, demonstrates potent activity in peripheral and CNS models of NHL as a single agent or in combination with clinically approved agents

Abstract

Immunomodulatory drugs, such as pomalidomide and lenalidomide are approved for the treatment of multiple subtypes of NHL. These drugs induce an interaction between Ikaros family zinc finger proteins 1 and 3 (IKZF1/3) and cereblon (CRBN), an E3 ligase, resulting in IKZF1/3 degradation. Clinically, immunomodulatory drugs are active as single agents or when used in combination with several classes of targeted therapies, in both first line and relapsed/refractory NHL subtypes. We previously described the preclinical characterization of CFT7455 as a novel IKZF1/3 degrader with 800-fold increased potency over pomalidomide in CRBN binding. We demonstrated that this increased activity translates into dramatically greater efficacy compared to pomalidomide in cellular and in vivo preclinical models of multiple myeloma and NHL. Here we show that the increased catalytic activity and improved potency of CFT7455 also translates into potent anti-tumor activity as a single agent or in combination with clinically approved agents in multiple in vivo models of NHL. In addition, the enhanced activity of CFT7455 demonstrates CNS activity in both the Raji and OCI-Ly10 intracranial xenograft models. CFT7455 (100 µg/kg/day) led to a significant increase in survival probability in comparison to pomalidomide (3000 µg/kg/day) and two investigational IKZF1/3 degraders in both models. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. M. J. Thomenius Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics S. Perino Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics J. Kirby Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics R. Agafonov Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics P. Chaturvedi Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics S. Eron Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics A. Good Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics J. A. Hart Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics M. He Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics A. Phillips Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics D. A. Proia Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics J. A. Henderson Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics C. Nasveschuk Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics S. L. Fisher Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics R. M. Pollock Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics