UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported):
(Exact name of Registrant as Specified in Its Charter)
|
|
|
|
|
(State or Other Jurisdiction of Incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) |
|
|
|
|
|
|
|
|
|
(Address of Principal Executive Offices) |
|
(Zip Code) |
Registrant’s Telephone Number, Including Area Code: (
Not Applicable
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
|
|
Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
|
|
Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
|
|
Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
|
|
Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
|
Title of each class |
|
Trading Symbol(s) |
|
Name of each exchange on which registered |
|
|
|
|
|
|
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 8.01 Other Events.
On April 8, 2022, C4 Therapeutics, Inc. (the “Company”) issued a press release entitled “C4 Therapeutics Presents Clinical Data from Cohort A of the Ongoing Phase 1/2 Clinical Trial of CFT7455, a Novel IKZF1/3 Degrader.” The Company also posted a corporate presentation on CFT7455 AACR Data for its investor webcast on its website at https://ir.c4therapeutics.com/events-presentations. A copy of the press release and the corporate presentation are filed as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
|
Exhibit Number |
|
Description |
|
99.1 |
|
|
|
99.2 |
|
|
|
104 |
|
Cover Page Interactive Data File (embedded within the Inline XBRL document) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
|
|
|
C4 Therapeutics, Inc. |
|
|
|
|
|
|
|
Date: April 8, 2022 |
|
By: |
/s/ Lauren A. White |
|
|
|
|
Lauren A. White |
|
|
|
|
Chief Financial Officer and Treasurer |
Exhibit 99.1
C4 Therapeutics Presents Clinical Data from Cohort A of the Ongoing Phase 1/2 Clinical Trial of CFT7455, a Novel IKZF1/3 Degrader
|
|
– |
Single Agent CFT7455 Induces Deep and Durable Degradation of IKZF1/3 and Meaningful Decreases in Serum Free Light Chain at Doses Lower than Expected Based on Pre-clinical Studies – |
|
|
– |
CFT7455 Exhibits Differentiated Pharmacokinetics (PK) and Potency Relative to Approved and Investigational IKZF1/3 Degraders – |
|
|
– |
On-Target Dose Limiting Toxicity Observed; Modeling Suggests Differentiated Activity and PK Profile Provides Pathway to Increase Therapeutic Index with Alternative Dosing Schedule – |
|
|
– |
Company to Host Conference Call and Webcast Today at 2 pm ET – |
WATERTOWN, Mass., April 8, 2022 -- C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science to develop a new generation of small-molecule medicines and transform how disease is treated, today presented data from Cohort A of its ongoing Phase 1/2 clinical trial of CFT7455, a novel degrader targeting IKZF1/3 for the treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL). The data will be presented at the American Association for Cancer Research (AACR) Annual Meeting on Tuesday, April 12, 2022, at 9 AM CT by Sagar Lonial, M.D., FACP.
“The early clinical data from the ongoing Phase 1/2 trial demonstrates that CFT7455’s differentiated pre-clinical profile, including enhanced PK and increased activity, has translated to the clinical setting,” said Dr. Sagar Lonial, professor and chair, department of hematology and medical oncology, Winship Cancer Institute, Emory University. “Single agent CFT7455 has demonstrated preliminary evidence of clinical activity in a population of highly refractory and heavily pre-treated multiple myeloma patients. We continue to enroll patients in the ongoing clinical trial with the goal of providing a new treatment option for myeloma and lymphoma patients.”
“We are encouraged by the early clinical observations and the potential of CFT7455 to be a next-generation therapy to treat multiple myeloma and non-Hodgkin’s lymphomas,” said Adam Crystal, M.D., Ph.D., chief medical officer of C4 Therapeutics. “We believe this initial data highlights the ability of our TORPEDO® platform to develop highly potent and selective degraders that have the potential to demonstrate deep and durable degradation of intended targets in the clinical setting. We will leverage the unique properties of CFT7455 to optimize its schedule and increase the therapeutic index as we progress to a recommended Phase 2 dose.”
CFT7455 Phase 1/2 Clinical Trial
C4T designed CFT7455 to be highly potent and selective against its intended targets, IKZF1/3. The Phase 1/2 trial is designed to primarily investigate safety, tolerability, and anti-tumor
activity. Secondary and exploratory objectives are to characterize the PK and pharmacodynamic profile of CFT7455. The Phase 1 portion of the study explores CFT7455 as a single agent in patients with relapsed or refractory (RR) MM and NHL, as well as in combination with dexamethasone in patients with RRMM. Following identification of a recommended dose(s) and schedule(s), the Phase 2 portion of the trial is expected to expand to the following four investigational arms: (1) in RRMM, single agent CFT7455; (2) in RRMM, CFT7455 combined with dexamethasone; (3) in peripheral T-cell lymphoma, single agent CFT7455; and (4) in mantle cell lymphoma, single agent CFT7455.
Cohort A, the first cohort in the clinical trial, explored CFT7455 as a single agent and enrolled five patients with MM. All patients in Cohort A were highly refractory and heavily pre-treated, having received a median of five prior lines of therapy (range of 4-14), including both lenalidomide and pomalidomide. The starting dose in the trial was 50 μg and all patients in Cohort A received single agent CFT7455 for 21 days of the 28-day treatment cycle. The data cut-off date was January 14, 2022. At the time of this data cut-off, two patients remained on therapy; however, these patients have since discontinued treatment.
Summary of Data from Cohort A:
Safety
|
|
• |
Four patients received single agent CFT7455 at the starting dose of 50 μg per day. Two of these patients were dose reduced to 25 μg per day due to neutropenia, a known on-target toxicity associated with IKZF1/3 degraders. |
|
|
• |
The fifth patient enrolled at a starting dose of 25 μg per day based on the recommendation of the safety review committee. |
|
|
• |
Two dose-limiting toxicities (DLTs) were observed at the 50 μg per day starting dose, both consistent with on-target activity: |
|
|
1. |
Grade 4 neutropenia lasting more than 5 days |
|
|
2. |
A delay (more than 7 days) in initiating treatment in Cycle 2, in the setting of persistent Grade 3 neutropenia |
|
|
• |
No patient experiencing neutropenia had a concurrent infection or fever. |
|
|
• |
There were no serious adverse events reported and no adverse events resulted in death or treatment discontinuation. |
Pharmacokinetics and Pharmacodynamics
|
|
• |
CFT7455 was rapidly absorbed, with a plasma half-life of approximately two days. Accumulation of drug was observed up to four-fold by day 15 and achieved exposures at 50 μg that were equivalent to predicted highly active exposures based on pre-clinical studies. |
|
|
• |
CFT7455 demonstrated deep and durable degradation of IKZF1/3, as quantified by mass spectrometry, throughout Cycle 1. |
Efficacy
|
|
• |
Responsiveness was measured based on International Myeloma Working Group (IMWG) criteria. |
|
|
• |
Three patients had best observed reductions in the difference of serum free light chain (dFLC) ranging from 41 percent to 78 percent. One patient had an increase of 56 percent in dFLC. |
|
|
• |
The patient who achieved a 78 percent reduction in dFLC did not achieve a partial response under IMWG criteria due to the presence of measurable plasmacytomas, which were assessed as stable. |
|
|
• |
Three patients had a best response of stable disease. Two patients had a best response of progressive disease. |
Next Steps for CFT7455
C4T has completed modeling of the Cohort A data and believes alternative dosing regimens are expected to increase the therapeutic index by allowing time for adequate neutrophil maturation during the days off drug, with limited impact on efficacy. Patients are enrolling in Cohort B1, exploring CFT7455 as a monotherapy for RRMM, and Cohort C, exploring CFT7455 as a monotherapy for NHL. Cohorts B1 and C have a starting dose of 25 μg per day at an alternative dosing schedule. Each cohort will proceed with dose finding in parallel, with the goal of achieving a recommended Phase 2 dose in each of MM and NHL.
Investor Webcast Information
C4T will host an investor webcast today, Friday, April 8, 2022, at 2 PM ET, with Sagar Lonial, M.D., FACP to discuss the CFT7455 clinical data being presented at AACR. To access the call, please dial 866-374-5140 or 404-400-0571 and provide the conference ID: 66856580. The webcast can be also accessed under “Events & Presentations” in the Investors section of the company’s website at www.c4therapeutics.com. A replay of the webcast will be available on C4T’s website for 30 days following the event.
About C4 Therapeutics®
C4 Therapeutics (C4T) (Nasdaq: CCCC) is a clinical-stage biopharmaceutical company dedicated to delivering on the promise of targeted protein degradation science to create a new generation of medicines that transform patients’ lives. C4T is leveraging its TORPEDO® platform to efficiently design and optimize small-molecule medicines that harness the body’s natural protein recycling system to rapidly degrade disease-causing proteins, offering the potential to overcome drug resistance, drug undruggable targets and improve patient outcomes. C4T is advancing multiple targeted oncology programs to the clinic and expanding its research platform to deliver the next wave of medicines for difficult-to-treat diseases. For more information, please visit www.c4therapeutics.com.
About CFT7455
CFT7455 is an orally bioavailable MonoDAC™ (Monofunctional Degradation Activating Compound) degrader designed to be highly potent and selective against its intended targets of Ikaros (IKZF1) and Aiolos (IKZF3). CFT7455 binds with high affinity to the E3 ligase adapter protein, cereblon, to target and degrade IKZF1/3 for the treatment of multiple myeloma and non-Hodgkin's lymphomas, including peripheral T cell lymphoma and mantle cell lymphoma. In early clinical data, CFT7455 demonstrated deep and durable degradation of IKZF1/3. C4T is
actively enrolling patients in its ongoing Phase 1/2 clinical trial. More information about this trial may be accessed at www.clinicaltrials.gov (identifier: NCT04756726).
Forward-Looking Statements
This press release contains “forward-looking statements” of C4 Therapeutics, Inc. within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements may include, but may not be limited to, express or implied statements regarding our ability to develop potential therapies for patients; that alternative dosing regimens may increase the therapeutic index of CFT7455 with limited impact on efficacy; the design and potential efficacy of our therapeutic approaches; the predictive capability of our TORPEDO® platform in the development of novel, selective, orally bioavailable degraders; the potential timing, design and advancement of our pre-clinical studies and clinical trials, including the potential timing for regulatory authorization related to clinical trials; our ability and the potential to successfully manufacture and supply our product candidates for clinical trials; our ability to replicate results achieved in our pre-clinical studies or clinical trials in any future studies or trials; and regulatory developments in the United States and foreign countries. Any forward-looking statements in this press release are based on management’s current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: uncertainties related to the initiation, timing, advancement and conduct of pre-clinical and clinical studies and other development requirements for our product candidates; the risk that any one or more of our product candidates will cost more to develop or may not be successfully developed and commercialized; and the risk that the results of pre-clinical studies and/or clinical trials will or will not be predictive of results in connection with future studies or trials. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in C4 Therapeutics’ most recent Annual Report on Form 10-K and/or Quarterly Report on Form 10-Q, as filed with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and C4 Therapeutics undertakes no duty to update this information unless required by law.
Investor Contact:
Kendra Adams
SVP, Communications & Investor Relations
Kendra.Adams@c4therapeutics.com
Media Contact:
Loraine Spreen
Director, Corporate Communications & Patient Advocacy
LSpreen@c4therapeutics.com
CFT7455 Phase 1/2 Cohort A Data Investor Call American Association for Cancer Research Annual Meeting 2022 Abstract CT186 April 8, 2022 Exhibit 99.2
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,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions. These forward-looking statements include, but are not limited to, statements regarding the therapeutic potential of C4 Therapeutics, Inc.’s technology and products. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. Among the factors that could cause actual results to differ materially from those described or projected herein include uncertainties associated generally with research and development, clinical trials and related regulatory reviews and approvals, as well as the fact that the product candidates that we are developing or may develop may not demonstrate success in clinical trials. Prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. C4 Therapeutics, Inc. undertakes no obligation to update or revise the information contained in this presentation, whether as a result of new information, future events or circumstances or otherwise. Intellectual Property C4 Therapeutics, Inc. owns various registered and unregistered trademarks in the U.S. and internationally, including, without limitation, C4 THERAPEUTICS, our housemark logo, the name of our TORPEDO platform, and the names of our BIDAC and MONODAC degrader products. All trademarks or trade names referred to in this presentation that we do not own are the property of their respective owners. Solely for convenience, the trademarks and trade names in this presentation are referred to without the symbols ® and ™, but those references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto. Forward-looking Statements and Intellectual Property © 2022 C4 Therapeutics, Inc. 2
Today’s Agenda © 2022 C4 Therapeutics, Inc. 3
Robust Pipeline of Degrader Medicines Pursuing Meaningful Targets Enrolling Recommended Phase 2 Dose Initiate Phase 1 trial Submit IND application and initiate Phase 1 trial Complete IND-enabling activities 4 targets 5 targets 1 target through March 2023 © 2022 C4 Therapeutics, Inc. 4 Number of targets represents the total number of active or potentially active research programs remaining under the applicable collaboration
C4T Presentations at AACR Annual Meeting 2022 Jim Henderson, Ph.D., Vice President of Chemistry, C4 Therapeutics Abstract Number: 7922, Oral Time: Monday, 4/11/22, 10:15 AM –11:45 AM CT Location: La Nouvelle Orleans A-B Session: New Drugs on the Horizon: Part 3 New Orleans Convention Center, La Nouvelle Orleans APRIL 8–13 • #AACR22 Kate Jackson, Ph.D., Senior Director of Chemistry, C4 Therapeutics Abstract Number: 7756, Oral Time: Sunday, 4/10/22, 3:00 PM – 4:30 PM CT Location: La Nouvelle Orleans A-B Session: New Drugs on the Horizon: Part 2 Mathew Sowa, Ph.D., Senior Director, Proteomics and Ubiquitin Proteasome System Biology, C4 Therapeutics Abstract Number: 2158, Oral Time: Monday, 4/11/22, 2:30 PM – 4:30 PM CT Location: Great Hall AD Session: Emerging New Anticancer Agents Chris Nasveschuk, Ph.D., Senior Vice President, Chemistry, C4 Therapeutics Time: Friday, 4/8/22, 5:50 PM 5:30 PM CT Location: New Orleans Theater A Session: Targeted Protein Degradation: Access to New Medicines by Drugging Challenging Targets Sagar Lonial, M.D., FACP Chief Medical Officer Winship Cancer Institute of Emory University; Professor and Chair, Dept. Hematology and Medical Oncology, Emory University School of Medicine Abstract Number: CT186, Poster Time: Tuesday, 4/12/22, 9:00 AM - 12:30 PM CT Location: Exhibit Halls D-H, Poster Section 33 “The Discovery and Characterization of CFT7455: A potent, selective degrader of IKZF1/3 for the treatment of relapsed/refractory multiple myeloma” “The Discovery and Characterization of CFT8634: A Potent and Selective Degrader of BRD9 for the treatment of SMARCB1-Perturbed Cancers” “Preclinical Evaluation of CFT1946 as a Selective Degrader of Mutant BRAF for the Treatment of BRAF Driven Cancers” “Targeted Protein Degradation: Access to New Medicines by Drugging Challenging Targets” “Pharmacokinetic (PK) Profile of a Novel IKZF1/3 Degrader, CFT7455, Enables Significant Potency Advantage over Other IKZF1/3 Degraders in Models of Multiple Myeloma (MM) and the Results of the Initial Treatment Cohort from a First-in-Human (FIH) Phase 1/2 Study of CFT7455 in MM”
Advancing Multiple Oncology Programs to Patients © 2022 C4 Therapeutics, Inc. 6
IKZF1/3 are transcription factors required for cancer cell growth and survival in multiple myeloma (MM) Approved IMiDs (lenalidomide, pomalidomide) are widely used in MM treatment and are IKZF1/3 degraders Relapsed/refractory MM remains a high unmet medical need Class-leading catalytic activity to enable potent, rapid, and deep target degradation High binding affinity to overcome IMiD resistance Selective to reduce off-target liabilities Pharmacologic profile that enables sustained IKZF1/3 degradation CFT7455: Potent Small Molecule IKZF1/3 Degrader with Enhanced Catalytic & Pharmacologic Properties Goal: Develop an IKZF1/3 Monofunctional Degradation Activating Compound (MonoDAC) with these properties: CRBN, cereblon; CUL4, cullin 4; DDB1, DNA damage-binding protein 1; IKZF1/3, Ikaros family zinc finger proteins 1 and 3; IMiD, immunomodulatory imide drug; monoDAC, monofunctional degradation activating compound; MM, multiple myeloma; RBX1, ring box protein 1; Ub, ubiquitin. © 2022 C4 Therapeutics, Inc. 7
High Catalytic Activity of CFT7455 Improves Activity in H929 MM Cells Compared to Pomalidomide* © 2022 C4 Therapeutics, Inc. 8 *Pomalidomide is an approved IKZF1/3 degrader while CC-220, CC-92480 and CFT7455 are all investigational compounds. C4 Therapeutics data on file. Binding Affinity (FP) Degradation Kinetics MM Cell Viability Catalytic activity enhancement resulted in >1000-fold improvement in potency vs. Pomalidomide Key Takeaway:
In comparison to CC-92480, CFT7455 achieves equivalent efficacy at 1/100th of the dose In the NCI-H929 xenograft model, 100 μg/kg/day of CFT7455 resulted in durable tumor regressions CFT7455 Demonstrates Superior Efficacy in NCI-H929 MM Xenograft Model QD Dosing No Drug Administered CFT7455 vs. Comparators CFT7455 Results in Durable Complete Regression © 2022 C4 Therapeutics, Inc. 9 Key Takeaways:
CFT7455 is Highly Efficacious in a Model of Systemic Multiple Myeloma CFT7455 vs Comparators in a Model of Systemic MM © 2022 C4 Therapeutics, Inc. 10 Day 14 *Mouse missing in CFT7455 100 µg/kg group due to changes unrelated to treatment or disease
CFT7455 and CC-92480* Tumor and Plasma Concentrations Degradation Kinetics for CFT7455, CC-92480 and Pomalidomide *CC-92480 was created in-house based on compound described in: Hansen JD, et al. J Med Chem. 2020;63(13):6648-6676. Single Dose PK/PD in H929 Xenografts Differentiates CFT7455 from CC-92480 © 2022 C4 Therapeutics, Inc. 11
Pharmacokinetic (PK) Profile of a Novel IKZF1/3 Degrader, CFT7455, Enables Significant Potency Advantage over Other IKZF1/3 Degraders in Models of Multiple Myeloma (MM) and the Results of the Initial Treatment Cohort from a First-in-Human (FIH) Phase 1/2 Study of CFT7455 in MM Sagar Lonial, MD, FACP1, Shambavi Richard, MD2, Jeffrey V. Matous, MD3, Andrew J. Yee, MD4, Urvi A. Shah, MD5, Neha Mehta-Shah, MD, MSCI6, Thomas Martin, MD7, Eli Muchtar, MD8, Sikander Ailawadhi, MD9, Paul G. Richardson, MD10, Manisha Bhutani, MD11, Samantha Perino, B.S.12, Jason Kirby, MSc12, Roman V. Agafonov, PhD12, Prasoon Chaturvedi, PhD12, Bradley Class, MSc12, Matthew Schnaderbeck, PhD12, Michael R. Palmer, PhD12, Cathleen Gorman, MSc.12, Oliver Schoenborn-Kellenberger, MSc12, Amanda Hoerres, PharmD12, Stewart L. Fisher, PhD12, Roy M. Pollock, PhD12, Adam Crystal, MD, PhD12, Michelle Mahler, MD12 and Jesus G. Berdeja, MD13
CFT7455 Phase 1/2 Trial Design Phase 1 Dose Escalation R/R Multiple Myeloma Monotherapy N =~30 Cohort B1: R/R Multiple Myeloma Monotherapy N =~15 Status: Enrolling Cohort C: Non-Hodgkin’s Lymphoma Monotherapy N =~15 Status: Enrolling Mantle Cell Lymphoma N=~20 Peripheral T-Cell Lymphoma N=~20 Cohort A: Monotherapy1 R/R Multiple Myeloma & Non-Hodgkin’s Lymphoma N=5 Status: Complete Phase 2 Expansion Cohort B2: R/R Multiple Myeloma Combination with Dexamethasone2 N =~15 R/R Multiple Myeloma Combo w/ Dexamethasone N =~30 28-day cycle / dose limiting toxicity (DLT) window Combination therapy cohorts will open once the selected CFT7455 dose level has been cleared for safety Note: 6–12 patient food effect enrichment cohort also included during escalation, not pictured in the schema © 2022 C4 Therapeutics, Inc. 13 Cohorts B1 & C Enrolling Patients to Determine Recommended Phase 2 Dose
Cohort A Enrolled Heavily Pre-Treated and Highly Refractory MM Patients © 2022 C4 Therapeutics, Inc. 14
Observed Steady State Exposures Suggest CFT7455 50 µg QD Achieves Efficacious Exposures Patient 4 received 50 µg for 8 days followed by 25 µg for 13 days followed by the regular 7-day rest period in Cycle 1; subsequent cycles continued at 25 µg 21 days on and 7 days off in a 28-day cycle. Data not available for Patient 5. Key Takeaways: The 50 µg dose achieved exposures which were active (and superior to pomalidomide) in pre-clinical models CFT7455 was rapidly absorbed, with a plasma half-life of approximately two days Accumulation of drug was observed up to four-fold by day 15 (360 hours) © 2022 C4 Therapeutics, Inc. 15 QD, every day
Deep and Sustained Degradation of IKZF1/3 Observed in Cycle 1 of Single Agent CFT7455 Data not available for Patient 1 and Patient 3 due to compromised sample integrity PBMC, peripheral blood mononuclear cells Key Takeaways: IKZF3 degradation was deeper in human PBMCs at 50 and 25 μg/day than was projected based on observed pre-clinical IKZF3 degradation of ~70% at equivalent exposures © 2022 C4 Therapeutics, Inc. 16 Patient 2 Patient 4 Patient 5 50 μg dosing 50 μg dosing 25 μg dosing 25 μg dosing
Meaningful Decreases in dFLC Achieved with Single Agent CFT7455 at Lower Exposure and Dose Than Seen with Another Investigational IKZF1/3 Degrader Patient 4 had an increase in dFLC of 56%, however it is not plotted as exposure data is not available; Patient 5 sample was not obtained dFLC, difference between involved FLC and uninvolved FLC dFLC equation: [Abnormal light chainbaseline- normal light chainbaseline ]- [Abnormal light chain nadir- normal light chain nadir] /[Abnormal light chainbaseline- normal light chainbaseline] * 100 © 2022 C4 Therapeutics, Inc. 17 Key Takeaways: Meaningful reduction in differences in serum free light chain (at nadir) was observed at achieved steady state exposures Reductions in dFLC were observed in the 3 patients for whom data is available (all dosed at 50 μg) for plotting* Decreases in dFLC were observed at lower exposures in comparison to other clinical stage IKZF1/3 degraders CFT7455: 50 μg resulted in active exposures with reduction (>40%) in dFLC in 3 patients CC-92480: 100 μg (starting dose) + dexamethasone resulted in no reduction in dFLC1 1 From CC-92480 PD Poster at ASCO 2020 (Abstract 8531)
Responses to Single Agent CFT7455 * Patients were dose reduced from 50 μg to 25 μg Each bar represents one patient in the study. Right arrow cap indicates continued on study. dFLC, difference between iFLC and uninvolved FLC; SCR, Stringent Complete Response; CR, Complete Response; VGPR, Very Good Partial Response; PR, Partial Response; SD, Stable Disease; PD, Progressive Disease; NE, Non-evaluable; ND, Not done. © 2022 C4 Therapeutics, Inc. 18 Across the five patients treated, a best response of SD was observed. Three patients achieved SD and two patients had a best response of PD. Patient 2 achieved a decrease in dFLC of 78%. This patient did not achieve PR due to the presence of measurable radiographically stable plasmacytomas. Week
Patient 2 Vignette: Encouraging CFT7455 Singe Agent Activity in Heavily Pre-treated, High-risk MM Patient 60-year-old female enrolled 2 June 2021 into Cohort A Diagnosed with MM (IgG κ) Jan 2017 Heavily pretreated Per IMWG response criteria, patient achieved Stable Disease: Best response of 78.1% decrease in difference between light chains at nadir Best response of 26.5% percent radiographic reduction of plasmacytomas, from baseline CR, complete response; Dara, daratumumab; Dex, dexamethasone; dFLC, difference between involved minus uninvolved serum free light chains; EMD, extramedullary disease; IKZF1/3, Ikaros family zinc finger proteins 1 and 3; IMWG, International Myeloma Working Group; KPD, carfilzomib–pomalidomide–dexamethasone; MM, multiple myeloma; PD; progressive disease; Pom, pomalidomide; PR, partial response; Rev, Revlimid; RVD, Revlimid-velcade-dexamethasone; SD, stable disease; VGPR, very good partial response. © 2022 C4 Therapeutics, Inc. 19
Summary of Adverse Events No Serious Adverse Events © 2022 C4 Therapeutics, Inc. 20 *Thrombocytopenia includes the preferred term thrombocytopenia and platelet decreased
Patient 4 received 50 µg for 8 days, followed by 25 µg Patient 5 received 25 µg dose On-target Neutropenia Seen Across Patients; Most Severe at Day 21 Key Takeaways: Neutropenia tended to worsen following day 15 and recovery was incomplete during the 7-day drug holiday The mechanism is considered due to on-target effects of degrading IKZF1 resulting in the downstream decrease in PU.1 causing transient neutrophil maturation arrest1 Two DLTs were observed at the 50 μg per day dose, both consistent with on-target activity: Grade 4 neutropenia lasting more than 5 days A delay (more than 7 days) in initiating treatment in Cycle 2, in the setting of persistent Grade 3 neutropenia © 2022 C4 Therapeutics, Inc. 21 Neutrophil Change Over Time DLT, dose-limiting toxicity 1 Li S, et al. Blood Adv. 2018 Mar 13;2(5):492-504.
Alternative CFT7455 Dosing Schedule Expected to Increase Therapeutic Index 22 There is insufficient time for neutrophil recovery during the 21 day on, 7 day off schedule. A 14 day on, 14 day off schedule may limit neutropenia by permitting neutrophil maturation and recovery while effecting tumor apoptosis day 1-14 and limiting tumor recovery during break © 2022 C4 Therapeutics, Inc. Modeling Based on Initial Dosing Schedule 21 Days On, 7 Days Off Modeling Based on Planned Dosing Schedule 14 Days On, 14 Days Off Concentration at which stasis observed in H929 xenograft Concentration at which stasis observed in H929 xenograft
Pre-clinically, single agent CFT7455 demonstrates increased activity in vivo in comparison to CC-92480 CFT7455 has longer exposure compared to CC-92480, resulting in sustained IKZF1/3 degradation in pre-clinical models After 21 days of once-daily dosing, CFT7455 100 μg/kg/day resulted in durable tumor regressions for prolonged period after drug discontinuation Clinically, CFT7455 was well absorbed with a plasma T1/2 of approximately 2 days, accumulation of drug was observed up to 4-fold by day 15 and achieved exposures at 50 μg, which are equivalent to predicted efficacious exposures from nonclinical studies On-target neutropenia was observed, including 3 patients with Grade 4 neutropenia resulting in 2 DLTs Early pharmacodynamic data suggests substantial potency and deeper degradation of the primary targets, IKZF1 and IKZF3 than initially projected at 50 μg Preliminary evidence of single agent CFT7455 activity was observed in this initial cohort of heavily pretreated MM patients, including meaningful decreases in dFLC Summary 23 © 2022 C4 Therapeutics, Inc.
Cohorts B and C Enrolling At Starting Dose of 25 μg With Alternative Dosing Schedule Phase 1 Dose Escalation Phase 2 Expansion 28-day cycle / dose limiting toxicity (DLT) window Combination therapy cohorts will open once the selected CFT7455 dose level has been cleared for safety Note: 6–12 patient food effect enrichment cohort also included during escalation, not pictured in the schema © 2022 C4 Therapeutics, Inc. 24 Modeling suggests that alternative dosing regimens expected to increase therapeutic index by allowing time for adequate neutrophil maturation during the days off drug with limited impact on efficacy R/R Multiple Myeloma Monotherapy N =~30 Cohort B1: R/R Multiple Myeloma Monotherapy N =~15 Status: Enrolling Cohort C: Non-Hodgkin’s Lymphoma Monotherapy N =~15 Status: Enrolling Mantle Cell Lymphoma N=~20 Peripheral T-Cell Lymphoma N=~20 Cohort A: Monotherapy1 R/R Multiple Myeloma & Non-Hodgkin’s Lymphoma N=5 Status: Complete Cohort B2: R/R Multiple Myeloma Combination with Dexamethasone2 N =~15 R/R Multiple Myeloma Combo w/ Dexamethasone N =~30
Q&A Session