CFT7455: A novel, IKZF1/3 degrader that demonstrates potent tumor regression in IMiD- resistant (MM) xenograft models

James A. Henderson, R. Jason Kirby, Samantha Perino, Roman V. Agafonov, Prasoon Chaturvedi, Bradley Class, David Cocozziello, Scott J. Eron, Andrew Good, Ashley A. Hart, Christina Henderson, Marta Isasa, Brendon Ladd, Matthew Schnaderbeck, Michelle Mahler, Roy M. Pollock, Adam S. Crystal, Christopher G. Nasveschuk, Andrew J. Phillips, Stewart L. Fisher, David A. Proia

C4 Therapeutics, Inc Watertown, MA USA Disclosure Information

David Proia, PhD § I have the following financial relationships to disclose: • Stockholder in: C4 Therapeutics • Employee of: C4 Therapeutics § I will not discuss off label use and/or investigational use in my presentation. Myeloma Therapies Have Improved OS But High Unmet Need Remains

2015 Daratumumab Improvement in OS From Median of 3 Years to 8-10 Years 2007 Doxorubicin 2015 Ixazomib 2018 Denosumab 1986 2016 High-dose Dex 2015 2003 CC-220 2019 1962 2015 Panobinostat Prednisone

1960 1970 1980 1990 2000 2010 2020

2013 Pomalidomide 2017 1958 1983 2006 CC-92480 Melphalan Auto Transplantation 2006 2012 CC-122 2020 Belantamab 2012 Carfilzomib

§ Multiple myeloma (MM) is an incurable disease of the plasma cells Alkylators Steroid § MM patient survival has increased steadily since 2000, mirroring the Anthracycline introduction of several novel therapies Proteasome inhibitors (“mibs”) § IMiDs (thalidomide, lenalidomide, pomalidomide) are widely used in Immunomodulators (“IMiDs” or “mids”) MM treatment regimens Monoclonal (“mAbs”) § Relapsed/refractory MM remains a high unmet medical need HDAC inhibitor XP01 inhibitor Auto, autologous; Dex, ; IMiD, immunomodulatory imide drug; OS, overall survival Investigational and not yet approved by the FDA Figure adapted from Anderson KC. Clin Cancer Res. 2016;22:5419–27. Ikaros Transcription Factors are Central to Lymphoid Differentiation and Myeloma

T-CELL LINEAGE

T CELL PTCL DEPENDENT ON IKZF1 / IRF4 FOR GROWTH

IKZF1 (Ikaros) and IKZF3 (Aiolos) control transcriptional programs central to the differentiation of lympho-myeloid multipotent progenitor cells through mature immune cells, including T cells and plasma cells HEMATOPOETIC LMPP STEM CELL Lymphoid-primed multipotent progenitors PLASMA Multiple Myeloma CELL DEPENDENT ON IKZF3 / IRF4 FOR GROWTH B-CELL LINEAGE

MCL, DLBCL DEPENDENT ON IKZF1 / IRF4 FOR GROWTH

DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; PTCL, peripheral T-cell lymphoma CFT7455: Potent Small Molecule IKZF1/3 Degrader Optimized for Catalytic & Pharmacologic Properties

Goal: Develop an IKZF1/3 Monofunctional Ub Degradation Activating Compound Ub (MonoDAC) with these properties: Ub Ub Ub Ub Ub IKZF3 IKZF3 Ub Ub § Class-leading catalytic activity to enable Ub Ub Ub potent, rapid, and deep target degradation IKZF1 IKZF1 IKZF1 IKZF3 Br J Haematol § High binding affinity to overcome IMiD IKZF1, IKZF3 degradation . 2016 Mar;172(6):889-901 Ub resistance CRBN E2 § Selective to reduce off-target liabilities DDB1 RBX1 Death of myeloma cells § Optimized pharmacologic profile to enable CUL4 sustained IKZF1/3 degradation CFT7455 E3 Ubiquitin Ligase Complex High Catalytic Activity of CFT7455 Improves Anti-Cancer Activity in H929 MM Cells

Binding Affinity (FP) Degradation Kinetics MM Cell Viability

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In-Cell CRBN Competition IKZF1/3 Degradation Apoptosis CFT7455 Pomalidomide CFT7455 Pomalidomide 6 ; 2×10 t y

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CFT7455 Has Broad Antiproliferative Activity CFT7455 Promotes Durable Tumor Regression

Vehicle (QDx21,PO) CFT7455 (10 μg/kg QDx21, PO) CFT7455 Pomalidomide Pomalidomide (3000 μg/kg QDx21, PO) CFT7455 (30 μg/kg QDx21, PO) CFT7455 (3 μg/kg QDx21, PO) KMS-26 2500 QD Dosing Dosing Holiday QD Dosing RPMI 8226 ) 3

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*Open symbol indicates highest tested concentration at which growth was not inhibited by more than 50%

D, day; QD, once daily CFT7455 Demonstrates High Potency in MM Cell Lines and Xenografts

CFT7455 Has Broad Antiproliferative Activity CFT7455 Promotes Durable Tumor Regression

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*Open symbol indicates highest tested concentration at which growth was not inhibited by more than 50%

D, day; QD, once daily Durable CFT7455 Single-Agent Activity in a Systemic MM Tumor Model

Lower Disease Burden in the MM.1S Model Early and Stable Regression of Disease

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- 100 S 1 . 50 M M 0 29 36 43 50 57 64 71 78 Days Post Tumor Cell Inoculation

BLI, bioluminescence imaging Depth and Duration of IKZF3 Degradation Associated with CFT7455 Efficacy

Dose Dependent Efficacy Dose-Dependent IKZF3 Degradation Loss of IRF-4 via IKZF1/3 Degradation

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C 04 24 48 72 96 120 144 04 24 48 72 96 120 -100 % Time (hr), post CFT7455 QD dosing Time (hr), post CFT7455 (100 μg/kg, QD) CFT7455 is Efficacious in MM Models Resistant or Insensitive to IMiDs

Reduction in CRBN Expression CFT7455 Retains Activity in CFT7455 Promotes Regression in with Chronic IMiD Dosing Len- & Pom-Resistant MM Cells Tumors Insensitive to Pom

Pom à 3000 Vehicle (QDx35, PO) LTC Len Len Parental CFT7455; IMiD resistant Pom; IMiD resistant Pomalidomide (3000 μg/kg, QD Day 0-17) ) 3 CFT7455 (100 μg/kg, QD Day 18-35)

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Len, lenalidomide; L/P-R, Len/Pom-Resistant Expected Efficacy and Survival Outcomes When CFT7455 is Combined With Dexamethasone

CFT7455 Yields Robust Efficacy as Monotherapy Significant Improvement in Survival with CFT7455 + and in Combination with Dexamethasone Dexamethasone Combination

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Dex, dexamethasone; QW, once weekly Summary

§ In vitro data with CFT7455 demonstrated: • High CRBN binding affinity (Kd = 0.9 nM) • Rapid, deep degradation of IKZF1/3 that is associated with apoptosis • Broad, potent antiproliferative activity in a panel of MM cell lines § In vivo MM models treated with CFT7455 demonstrated: • Regression in multiple treatment-naïve MM tumor models at doses ≥10 µg/kg/day • Durable antitumor responses consistent with long-lived pharmacodynamic activity • Efficacy in models unresponsive to approved IMiDs • Expected efficacy and survival outcomes when combined with dexamethasone § These encouraging data support the initiation of a first-in-human clinical trial to assess the safety and tolerability of CFT7455 in patients with R/R MM or non-Hodgkin lymphoma (NCT04756726) in the first half of 2021