On June 7, 2021 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a biopharmaceutical company pioneering a new class of small-molecule medicines that selectively destroy disease-causing proteins through degradation, reported that new pre-clinical data on CFT8919, a novel mutant-selective degrader of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) at the Keystone Symposium on Targeted Protein Degradation (Press release, C4 Therapeutics, JUN 7, 2021, View Source [SID1234583640]). The poster presentation shares pre-clinical data that suggests CFT8919 may be active as a single agent in patients with resistance to EGFR inhibitors due to secondary mutations in EGFR, including T790M and C797S, as well as in the front-line setting with the potential to avoid the emergence of resistance-causing secondary EGFR mutations seen with currently approved EGFR inhibitors.

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"We are excited to share strong preclinical data that establishes CFT8919 as a potent and selective degrader of EGFR L858R, a mutation responsible for more than a third of mutant EGFR lung cancer diagnoses. Patients with this mutation are commonly treated with approved EGFR inhibitor therapies, but often have worse clinical outcomes than individuals diagnosed with other driver mutations such as Exon19del," said Adam Crystal, M.D., Ph.D., chief medical officer of C4 Therapeutics. "Across our portfolio, we see the potential for targeted protein degradation to transform patient care. We believe our decision to advance CFT8919 recognizes promising early data that indicate CFT8919 may have the potential to treat patients who develop resistance to first-line EGFR inhibitors as well as a path to inclusion in front-line therapeutic regimens. We look forward to learning more about CFT8919 as we advance the program into IND-enabling studies and initiate the Phase 1 clinical trial in 2022."

Summary of CFT8919 Pre-clinical Results
C4T conducted in vitro and in vivo studies that show CFT8919 is a potent and highly selective orally bioavailable degrader of EGFR L858R with broad coverage of on-target resistance mutations as well as intracranial activity. Notable observations include:

In cancer cell lines, CFT8919 induces degradation of EGFR L858R at low nanomolar concentrations while no degradation of wild type is induced up to 10 µM.
CFT8919 demonstrates equipotent activity against EGFR mutations resistant to EGFR inhibition, including L858R-C797S, L858R-T790M, and L858R-T790M-C797S compared to L858R single mutation in Ba/F3 cell models in vitro.
Kinome profiling and global proteomic evaluation did not identify any significant off-target activity of CFT8919. CFT8919 does not induce degradation of known cereblon neo-substrates SALL4 or GSPT1, indicating that the potential associated toxicities will not be liabilities.
Additionally, in vivo data demonstrates the following:

CFT8919 degrades and inhibits mutant EGFR in tumors upon oral administration. In the NCI-H1975 EGFR-L858R-T790M xenograft model, after a single oral dose of CFT8919, up to 85 percent of mutant EGFR was degraded in tumors accompanied with near-complete inhibition of phospho-EGFR.
In this model, twice-daily oral administration of CFT8919 showed dose-dependent anti-tumor activity and regressions comparable to osimertinib.
In BaF3 allograft model expressing EGFR-L858R-T790M-C797S, CFT8919 demonstrates anti-tumor activity resulting in tumor regression, while osimertinib is inactive.
CFT8919 demonstrates rapid and significant reductions in tumor burden in the H1975-LUC (EGFR L858R-T790M) brain metastasis model after oral dosing, indicating its potential to be active in the central nervous system.
This promising pre-clinical data supports the Company’s decision to advance CFT8919 into investigational new drug (IND)-enabling studies this year. C4T anticipates filing an IND for CFT8919 by mid-2022, with the goal to initiate a Phase 1 clinical trial by year-end 2022.

C4T will host an investor event and webcast today, June 7, 2021, at 8 am E.T. to further discuss the pre-clinical data. Details of this event are included below.

In addition, the poster presentation from the Keystone Symposium on Targeted Protein Degradation will be archived on the "Scientific Publications" page in the Investors section of the Company’s website, located at www.c4therapeutics.com.

Investor Event and Webcast Information
C4T will host a live webcast today, Monday, June 7, 2021, at 8:00 a.m. E.T. to discuss the CFT8919 data presented at the Keystone Symposium. The webcast can be accessed through the Events and Presentations page on the Investors section of C4T’s website at www.c4therapeutics.com. A replay of the webcast will be available on C4T’s website for 30 days following the event.