C4 Therapeutics, Inc. · NASDAQ:CCCC
C4 Therapeutics — 4th Annual TPD (Targeted Protein Degradation) Summit (October 2021)
16 slides from C4 Therapeutics's conference presentation, Oct 27, 2021
Slide 1: Discovery of CFT8919 as an oral, CNS-active, mutant-selective allosteric degrader of EGFR L858R
Discovery of CFT8919 as an oral, CNS-active, mutant-selective allosteric degrader of EGFR L858R for the treatment of EGFR inhibitor- resistant non-small cell lung cancer October 27, 2021 4th Annual TPD (Targeted Protein Degradation) Summit Eunice Park on behalf of the C4T Team
Slide 2: Forward-looking Statements and Intellectual Property
Forward-looking Statements and Intellectual Property Forward-looking Statements The following presentation contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,”
Slide 3: Mutations in EGFR Drive Oncogenesis in Non-Small Cell Lung Cancer
Mutations in EGFR Drive Oncogenesis in Non-Small Cell Lung Cancer 25-45% of mutant EGFR NSCLC is 30-40% of mutant EGFR NSCLC 10-15% of Non-Small Cell driven by L858R activating patients will develop brain Lung cancer has mutant EGFR mutation metastases This rises to nearly 40% in Asian Patients with
Slide 4: Despite Three Generations of Approved EGFR Inhibitors, L858R Patients Have Poorer Prognosis
Despite Three Generations of Approved EGFR Inhibitors, L858R Patients Have Poorer Prognosis Median PFS L858R Exon 19 Deletion osimertinib 14.4 months 21.4 months Standard EGFR TKI 9.5 months 11.0 months L858R mutation predicts less durable response to EGFR inhibitors No evidence that L858R is a more
Slide 5: Significant Unmet Need for Patients Who Progress After Current EGFR Inhibitor Therapies
Significant Unmet Need for Patients Who Progress After Current EGFR Inhibitor Therapies Resistance mutations occur EGFRL858R around the ATP binding site osimertinib 1st-gen EGFR TKIs PFS: 14.4 mos PFS: ~9.5 mos EGFRL858R+C797S EGFRL858R+T790M osimertinib PFS: ~9.6 mos EGFRL858R+T790M+C797S © 2021 C4
Slide 6: CFT8919 is an Oral, CNS-Active, Allosteric Degrader to Overcome Resistance to Approved EGFR Inhibitors
CFT8919 is an Oral, CNS-Active, Allosteric Degrader to Overcome Resistance to Approved EGFR Inhibitors EGFRL858R CFT8919 Compelling Profile 1L Orally bioavailable, selective, osimertinib 1st-gen EGFR TKIs allosteric degrader of EGFR PFS: 14.4 mos PFS: ~9.5 mos L858R 2L CFT8919 Active in vitro and in
Slide 7: CFT8919 Selectively Targets EGFR-L858R in Human Cancer Cell Lines and is Not Impacted by EGFR T790M or C797S
CFT8919 Selectively Targets EGFR-L858R in Human Cancer Cell Lines and is Not Impacted by EGFR T790M or C797S A B C EGFR degradation* Phospho-EGFR inhibition Degradation and inhibition Potency * EGFR-L858R specific antibody was used to specifically detect degradation of mutant EGFR protein in EGFR mu
Slide 8: CFT8919 is Active in Ba/F3 Models Expressing Secondary Mutations Resistant to Approved EGFR Inhibitors
CFT8919 is Active in Ba/F3 Models Expressing Secondary Mutations Resistant to Approved EGFR Inhibitors A B Viability of Ba/F3 cells expressing the Ba/F3 cell growth inhibition potency indicated EGFR variant (GI50, nM) "# ! "# © 2021 C4 Therapeutics, Inc. 8
Slide 9: CFT8919 is Highly Selective Against Kinase Targets and Known Cereblon Neo-Substrates
CFT8919 is Highly Selective Against Kinase Targets and Known Cereblon Neo-Substrates A B Evaluation Against Known Kinome Binding Specificity CRBN Neo-substrates No SALL4 degradation No GSPT1 degradation EGFR-L861Q !! #!$!$ EGFR-L858R %$$'&'!%$ $ "!!$#$"! ! $ ! $"!%#! $ ! © 2021 C4 Therapeutics, Inc.
Slide 10: CFT8919 Demonstrates Excellent Proteome-Wide Selectivity
CFT8919 Demonstrates Excellent Proteome-Wide Selectivity Global Proteomic Evaluation # of Proteins # of Proteins with Cell Line EGFR Genotype Detected >50% Protein Level Decrease* A431 Wild-type 9190 0 H1975 L858R-T790M 8853 2 (EGFR, CCND1+) *p-value < 0.001 +Likely due to the biological effect of E
Slide 11: CFT8919 Induces Tumor Regression in Mouse Models Resistant to First and Third-Generation EGFR Inhibitors
CFT8919 Induces Tumor Regression in Mouse Models Resistant to First and Third-Generation EGFR Inhibitors 1st-generation EGFRi Resistant 3rd-generation EGFRi Resistant H1975 (L858R-T790M) Xenograft Ba/F3 (L858R-T790M-C797S) Allograft *%'( '$*% %% '"$% $!'" "" )*+ + &'( ( $( & # '+ #!") "&! )*+ + &'(
Slide 12: Dose Proportional Exposure Correlates with the Depth of PD and Tumor Regression Responses
Dose Proportional Exposure Correlates with the Depth of PD and Tumor Regression Responses in H1975 EGFR L858R-T790M Xenograft Model Plasma and Tumor PK Tumor PD Efficacy ! © 2021 C4 Therapeutics, Inc. 12
Slide 13: CFT8919 Demonstrates Activity in H1975-LUC Brain Metastasis Model (via Intracranial Implant)
CFT8919 Demonstrates Activity in H1975-LUC (EGFR-L858R-T790M) Brain Metastasis Model (via Intracranial Implant) Mean Plasma & Tumor In vivo Efficacy In vivo Body Weight Change Concentration Plasma clearance t1/2 = 3.1 hrs 50 mg/kg PO single dose © 2021 C4 Therapeutics, Inc. 13
Slide 14: CFT8919 Demonstrates Activity in H1975-LUC Brain Tumor Metastasis Model (via Intracarotid Injection)
CFT8919 Demonstrates Activity in H1975-LUC (EGFR-L858R-T790M) Brain Tumor Metastasis Model (via Intracarotid Injection) In Vivo Efficacy In vivo Body Weight Change © 2021 C4 Therapeutics, Inc. 14
Slide 15: CFT8919 is a Potent, Oral, Allosteric, Mutant-selective Degrader of EGFR L858R
CFT8919 is a Potent, Oral, Allosteric, Mutant-selective Degrader of EGFR L858R Active in vitro and in vivo in models with secondary mutations (such as T790M, C797S, T790M-C797S) that cause acquired resistance to 1st-, 2nd-, and 3rd-generation EGFR inhibitors Demonstrates intracranial activity indica
Slide 16: The C4 Therapeutics Team
The C4 Therapeutics Team © 2021 C4 Therapeutics, Inc. 16
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