C4 takes the Ikaros/Aiolos battle to Bristol

C4 Therapeutics' decision to focus almost exclusively on its Ikaros/Aiolos degrader cemsidomide makes sense given the lacklustre data its other big hope, the BRAF V600X degrader CFT1946, generated last year. The company's stock fell when in an ESMO presentation CFT1946 yielded an ORR of just 7% in patients who had previously received a BRAF inhibitor, and Wednesday's decision to drop the molecule was received well by the markets. The question now is how cemsidomide squares up to more advanced projects, especially Bristol Myers Squibb's "celmods" iberdomide, mezigdomide and golcadomide. Bristol describes these compounds, which could help it weather patent expiries on Revlimid and Pomalyst, as cereblon E3 ligase modulators, and the substrates they degrade are the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). C4 calls cemsidomide a non-celmod IKZF1/3 degrader, and reports a 50% ORR among 10 multiple myeloma patients given 100µg daily, and 40% among 20 given 75µg. It says the first data in non-Hodgkin's lymphoma will be reported in the fourth quarter, and in the meantime awaits regulatory feedback on a registrational plan. Beyond Bristol, C4's furthest-advanced competitors are the Chinese companies InnoCare and GluBio.

Ikaros/Aiolos degradation beyond Bristol Myers Squibb’s celmods

Note: Aiolos (IKZF3) & Ikaros (IKZF1) are zinc finger protein lymphoid transcription factors. Source: OncologyPipeline.