C4 Therapeutics, Inc. · NASDAQ:CCCC
C4 Therapeutics — Targeted Protein Degradation Summit 2020
25 slides from C4 Therapeutics's conference presentation, Oct 14, 2020
Slide 1: Pioneering Transformative Protein Degradation Therapies
PIONEERING TRANSFORMATIVE PROTEIN DEGRADATION THERAPIES A new class of small-molecule protein degraders harnessing powerful and universal cellular biology Targeted Protein Degradation Summit Rhamy Zeid October 14, 2020 © 2020 C4 THERAPEUTICS, INC. 1
Slide 2: Forward-looking Statements and Intellectual Property
Forward-looking Statements and Intellectual Property Forward-looking Statements The foregoing 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: Synovial sarcoma
Synovial sarcoma ▪ Very limited benefit of treatments for metastatic synovial Clear Unmet sarcoma or recurrence following surgery – metastatic Need median survival ~18 months ▪ Median age of diagnosis: 34 years old Defined Patient ▪ ~900 US yearly incidence of synovial sarcoma cases Population ▪ ~10
Slide 4: Overview of BRD9 as a therapeutic target
Overview of BRD9 as a therapeutic target SMARCB1 SS18-SSX SS18-SSX fusion SMARCB1 eviction BRD9 dependency BRD9 degradation Defining feature that underlies Incorporation of the SS18-SSXX fusion Loss of SMARCB1 results in a synthetic Targeted protein degradation is an synovial sarcoma pathogenesis ej
Slide 5: Overview of BRD9 as a therapeutic target
Overview of BRD9 as a therapeutic target SMARCB1 SS18-SSX SS18-SSX fusion SMARCB1 eviction BRD9 dependency BRD9 degradation Defining feature that underlies Incorporation of the SS18-SSXX fusion Loss of SMARCB1 results in a synthetic Targeted protein degradation is an synovial sarcoma pathogenesis ej
Slide 6: Synovial sarcoma
Synovial sarcoma SS18-SSX fusion ▪ Non-random chromosomal translocation t(X:18; p11:q11) ▪ Bona fide driver of pathogenesis ▪ SS18 ▪ Epigenetic chromatin regulator ▪ Member of the BAF chromatin remodeling complex ▪ SSX ▪ Potent transcriptional repressor via its KRAB Baranov et al., 2020 domain (not
Slide 7: Overview of BRD9 as a therapeutic target
Overview of BRD9 as a therapeutic target SMARCB1 SS18-SSX SS18-SSX fusion SMARCB1 eviction BRD9 dependency BRD9 degradation Defining feature that underlies Incorporation of the SS18-SSXX fusion Loss of SMARCB1 results in a synthetic Targeted protein degradation is an synovial sarcoma pathogenesis ej
Slide 8: BAF complexes are critical regulators of chromatin state
BAF complexes are critical regulators of chromatin state BAF (Brg/Brahma associated factors) or mSWI/SNF complexes ▪ Multi sub-unit (~15 proteins) ATP dependent chromatin remodeling complexes ▪ Compaction and decompaction of DNA in the nucleus Adapted from Clapier et al., 2017 ▪ Enables replication,
Slide 9: Three versions of the BAF complex collectively regulate chromatin state
Three versions of the BAF complex collectively regulate chromatin state cBAF canonical BAF complexes ▪ Three distinct versions with unique sub- unit combinations ▪ SS18 → ncBAF, cBAF ▪ SMARCB1 → cBAF, pBAF ▪ BRD9 → ncBAF ncBAF Crosstalk pBAF noncanonical Distinct polybromo localization and activity
Slide 10: SS18-SSX fusion incorporation into the BAF complex
SS18-SSX fusion incorporation into the BAF complex SMARCB1 SS18 SS18-SSX SS18-SSX Roberts et al., 2002 Adapted from McBride et al., 2018 SS18-SSX fusion incorporation results in the ejection of SMARCB1, rendering the cBAF complex dysfunctional and driving an oncogenic state Redistribution of BAF com
Slide 11: Overview of BRD9 as a therapeutic target
Overview of BRD9 as a therapeutic target SMARCB1 SS18-SSX SS18-SSX fusion SMARCB1 eviction BRD9 dependency BRD9 degradation Defining feature that underlies Incorporation of the SS18-SSXX fusion Loss of SMARCB1 results in a synthetic Targeted protein degradation is an synovial sarcoma pathogenesis ej
Slide 12: BRD9 is a selective dependency in SMARCB1 perturbed contexts
BRD9 is a selective dependency in SMARCB1 perturbed contexts Synovial sarcoma Malignant rhabdoid tumor (MRT) SS18-SSX fusion driven ejection of SMARCB1 Homozygous SMARCB1 deletion Briens et al., 2018 Wang et al., 2019 Genome-wide loss of function CRISPR screens identify BRD9 as a unique dependency i
Slide 13: Targeting aberrant BAF complexes via BRD9 degradation
Targeting aberrant BAF complexes via BRD9 degradation BRD9 ▪ Bromodomain containing protein 9 ▪ Alternate names ▪ Sarcoma antigen NY-SAR-29 St. Pierre & Kadoch., 2017 ▪ Rhabdomyosarcoma antigen MU-RMS-40.8 ▪ Small and compact with two annotated domains ▪ Bromodomain: acetyl lysine reader function ▪
Slide 14: BRD9 dependency in synovial sarcoma
BRD9 dependency in synovial sarcoma Normal cells Synovial sarcoma cells cBAF ncBAF cBAF ncBAF SS18-SSX fusion SMARCB1 Crosstalk Crosstalk Normal Normal **Compromised** **Aberrant** ▪ Normal chromatin structure ▪ SMARCB1 null state Normal cells spared Anti-tumor response via eliminating oncogenic ▪ W
Slide 15: Overview of BRD9 as a therapeutic target
Overview of BRD9 as a therapeutic target SMARCB1 SS18-SSX SS18-SSX fusion SMARCB1 eviction BRD9 dependency BRD9 degradation Defining feature that underlies Incorporation of the SS18-SSXX fusion Loss of SMARCB1 results in a synthetic Targeted protein degradation is an synovial sarcoma pathogenesis ej
Slide 16: Targeted protein degradation of BRD9 is an effective therapeutic strategy
Targeted protein degradation of BRD9 is an effective therapeutic strategy Inhibition Small molecule inhibition of BRD9 is ineffective St. Pierre & Kadoch., 2017 ▪ Limited to the disruption of acetyl-lysine bromodomain reader function alone Targeted protein degradation results in the complete loss of
Slide 17: Opportunity to develop a first and best-in-class BRD9 degrader
Opportunity to develop a first and best-in-class BRD9 degrader Degradation activity BRD9 ▪ Potent ▪ Selective ▪ Complete ▪ Durable CFT7503 Complete disruption of oncogenic BRD9/ncBAF activity ▪ Selective in vitro growth inhibitory activity in human synovial sarcoma cell lines ▪ Complete tumor growth
Slide 18: Cellular degradation activity
Cellular degradation activity CFT8634 (100 nM, 4hr) in Yamato-SS 100 nM 4HRS % degradation [HiBiT] 293T cells BRD9 [2HRS] BRD4 [24HRS] BRD7 [24HRS] Dose [nM] Dose response degradation Degradation across cellular contexts Degradation selectivity Engineered 293T HiBiT cell lines Endogenous degradation
Slide 19: Cellular consequences of BRD9 degradation
Cellular consequences of BRD9 degradation Yamato [SS18-SSX fusion; BAF perturbed] SW982 [BAF wildtype] Single dose long term growth evaluation Single dose long term growth evaluation 100 BRD9i 100 BRD9i DMSO DMSO 104nM 104nM 1000nM 1000nM 316nM 316nM 100nM 100nM 50 32nM 50 32nM Confluence (%) 10nM 1
Slide 20: In vivo properties – pharmacokinetics (PK) and pharmacodynamics (PD)
In vivo properties – pharmacokinetics (PK) and pharmacodynamics (PD) Tumor PK Tumor PD Synovial sarcoma CDX (Yamato-SS) BRD9 degradation in synovial sarcoma tumors BRD9 100000 CFT7503, 10mg/kg CFT-17503, 10 mg/kg 1.00 Vehicle Vehicle CFT7503, 75mg/kg CFT-17503, 75 mg/kg CFT7503, 10mg/kg10 mg/kg CFT-
Slide 21: In vivo activity – efficacy in synovial sarcoma
In vivo activity – efficacy in synovial sarcoma Efficacy Tolerability Synovial sarcoma CDX (Yamato-SS) Synovial sarcoma CDX (Yamato-SS) 3000 Yamato-SS Mean Tumor Volume (mm3) + SEM Vehicle (PO QD) Vehicle 20 Vehicle Vehicle (PO QD) CFT-17503, CFT7503, 6 mg/kg 6mg/kg (PO QD) (PO QD) CFT7503, 6mg/kg C
Slide 22: In vivo activity – efficacy in synovial sarcoma
In vivo activity – efficacy in synovial sarcoma Efficacy Tolerability Synovial sarcoma PDX (SA13412) Synovial sarcoma PDX (SA13412) 1500 20 Vehicle Vehicle (POQD) (PO QD) Vehicle (PO(PO QD)QD) SA13412 Mean Tumor Volume (mm3) + SEM Vehicle CFT7503, 40mg/kg CFT-17503, (PO(PO 40 mg/kg QD)QD) CFT7503, 4
Slide 23: Cross-species pharmacokinetic profiles
Cross-species pharmacokinetic profiles CLEARANCE VOLUME Concordant cross-species PK profiles enable confident and favorable human dose predictions © 2020 C4 THERAPEUTICS, INC. 23
Slide 24: Opportunity to develop a first and best-in-class BRD9 degrader
Opportunity to develop a first and best-in-class BRD9 degrader BRD9 Degradation activity ▪ Potent ✓ ▪ Selective ▪ Complete ▪ Durable CFT7503 Complete disruption of oncogenic BRD9/ncBAF activity ▪ ✓ Selective in vitro growth inhibitory activity in human synovial sarcoma cell lines ▪ Complete tumor gr
Slide 25: The C4 Therapeutics Team
The C4 Therapeutics Team © 2020 C4 THERAPEUTICS, INC. 25
C4 Therapeutics — Targeted Protein Degradation Summit 2020 on 6ix