CFT7455: A novel, IKZF1/3 degrader that demonstrates potent tumor regression in IMiD- resistant multiple myeloma (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 Elotuzumab 2003 CC-220 2019 Selinexor 1962 Bortezomib 2015 Panobinostat Prednisone
1960 1970 1980 1990 2000 2010 2020
2013 Pomalidomide 2017 1958 1983 2006 Lenalidomide CC-92480 Melphalan Auto Transplantation 2006 Thalidomide 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 antibodies (“mAbs”) § Relapsed/refractory MM remains a high unmet medical need HDAC inhibitor XP01 inhibitor Auto, autologous; Dex, dexamethasone; 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
Vehicle (QDx21, PO) CFT7455 Pomalidomide Pomalidomide (3000 μg/kg QDx21, PO) KMS-26 CFT7455 (100 μg/kg QDx21, PO) 2500 QD Dosing Dosing Holiday RPMI 8226 ) 3
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10-2 10-1 100 101 102 103 104 105 0 0 7 14 21 28 35 42 49 56 63 IC50 (nM) Day
*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
QD Dosing Dosing Holiday 500 )
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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