E2F1

Impressive response results for CG Oncology’s oncolytic immunotherapy in a late-stage bladder cancer study lend credence as to how the biotech was able to execute one of the sector’s few successful public debuts this year. The company raised $380 million in an upsized offering in January, one of the biggest biotech IPOs since 2018, and the year’s largest so far. CG Oncology is also one of the few firms to be trading up from its debut price. For more analysis, see Vital Signs: Taking the temperature on a cooling IPO cycle.High response rateThe data, presented Friday at the American Urological Association (AUA) conference, are from the single-arm Phase III BOND-003 trial in patients with high-risk non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG) therapy. CG Oncology’s oncolytic virus, cretostimogene grenadenorepvec, led to an any-time complete response (CR) rate of 75.2% in 105 measurable patients, the study’s primary endpoint.  Of the 79 patients with a CR, none had to undergo bladder removal or showed nodal or metastatic progression, and 29 of these participants maintained the response for a year or longer. Median duration of response has not yet been reached. CG Oncology reported no Grade 3 or higher treatment-related adverse events (TRAEs) or deaths, while two patients had Grade 2 TRAEs associated with the oncolytic immunotherapy. About 62.5% of patients experienced a TRAE, with the most common being bladder spasm, pollakiuria, dysuria, micturition urgency, and haematuria.The results are important, CG Oncology chief executive Arthur Kuan told FirstWord, because many patients who fail on BCG have no other options except surgical removal of the bladder. Furthermore, because of a shortage of BCG – the standard-of-care treatment – it is currently not available to NMIBC patients with intermediate risk, or even to some high-risk patients.“There is a great need for a local, well-tolerated, and effective bladder-preserving option for patients with intermediate-risk as well as high-risk BCG-unresponsive NMIBC,” Kuan said. He added that CG Oncology will share by year-end when it expects to submit a regulatory application to the FDA for the treatment candidate.Shooting for firstWith no FDA-approved oncolytic viruses, cretostimogene stands to be a first-in-class immunotherapy. The treatment is designed to preferentially replicate in retinoblastoma (Rb) gene pathway-defective cells and trigger an anti-tumour immune response. It also features two modifications intended to boost its selectivity and potency. First, an E2F-1 promoter is added to act as a safety mechanism so the virus selectively replicates within and lyses Rb-defective tumour cells, avoiding healthy cells.Next, the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) is inserted. The cytokine is known to stimulate longer-term anti-tumour activity, and Kaun explained that “its addition to the viral construct may both prime the immune system and induce tumour-specific immunity.”

Data show activity across a wide range of human tumor cell lines Tumor regression observed in xenograft models of small cell lung cancer and ovarian cancer Research from the laboratory of Dr. Matthew Oser at the Dana Farber Cancer Institute identified the key role of the SAC complex in selective tumor cell killing by cyclin A/B inhibitors SAN FRANCISCO--(BUSINESS WIRE)-- Circle Pharma announced today that two poster presentations at the American Association for Cancer Research (AACR) Annual Meeting held April 14-19, in Orlando, Florida, highlight promising pre-clinical data of its first-in-class orally bioavailable macrocyclic cyclin A/B inhibitors targeting intractable cancers. Circle expects to advance its cyclin A/B inhibitor program into IND-enabling studies later this year and subsequently into clinical development for testing in a range of cancer types, including SCLC. The data presented by Circle Pharma shows activity across a wide range of human tumor cell lines and tumor regression in xenograft models of small cell lung carcinoma (SCLC) and ovarian cancer. Pre-clinical development of orally bioavailable macrocycles with dual cyclin A and B inhibitory activity drive synthetic lethality in multiple tumor types. The compounds are shown to be well-tolerated in mice with no observed body weight loss, neutropenia, or depletion of bone marrow across all dose regimens. In vitro studies showed that target engagement in cells leads to displacement of E2F1 from Cyclin A:CDK2 and Myt1 from Cyclin B:CDK1, and the compounds induce DNA damage, G2/M arrest, and apoptosis. The presentation further showed that sensitivity in SCLC cell lines is correlated with RB dysfunction and E2F1 target gene expression. In addition, studies conducted by the laboratory of Matthew Oser at Dana Farber Cancer Institute (DFCI) validate that cyclin A/B inhibitors induce mitotic arrest and apoptosis in SCLC cell lines. The researchers deployed a genome wide CRISPR/Cas9 positive selection screen to identify that activation of the mitotic spindle assembly checkpoint (SAC) complex by the kinase MSP1 is a dominant mechanism for selective cancer cell killing by the cyclin A/B inhibitors. Dr. Oser’s laboratory at DFCI was sponsored by Circle Pharma. Program Presentation Details Cyclin A/B Abstract Number: 1559 Abstract Title: Mechanisms responsible for hypersensitivity of small cell lung cancers to novel cyclin A/B RxL macrocyclic peptide inhibitors Session Title: Experimental and Molecular Therapeutics Session Type: Poster Cyclin A/B Abstract Number: 1560 Abstract Title: Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types Session Title: Experimental and Molecular Therapeutics Session Type: Poster About Circle Pharma, Inc. Circle is a biopharmaceutical company advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop first-in-class macrocycle therapeutics for challenging targets to address unmet clinical needs. Circle’s macrocycle can address both intra- and extra-cellular therapeutic targets and is applicable across a wide range of serious diseases; the company is initially focusing its development efforts on intracellular protein-protein interactions that are key drivers in cancer but have remained elusive to other treatment modalities. Circle is headquartered in South San Francisco and has raised $160 million to date from leading life sciences investors including The Column Group, Nextech, Pfizer and Eli Lilly. To learn more about Circle Pharma please visit . View source version on businesswire.com: Contacts Circle Pharma Media Contact: Eleanor Lim 650.825.4099 info@circlepharma.com Source: Circle Pharma, Inc. View this news release online at:

– CFT7455 Demonstrated High Binding Affinity to Cereblon and Target Selectivity in Non-Hodgkin’s Lymphoma Cell Models, Producing Rapid and Deep Degradation of IKZF1/3 Proteins – – CFT7455 Resulted in Improved Efficacy and Potency in Tumor Xenograft Models Compared to Investigational and Approved IMiD Therapies – – CFT7455 Phase 1/2 Trial in Multiple Myeloma and Non-Hodgkin’s Lymphomas Initiated June 2021; Top-line Clinical Data Expected 2022 – WATERTOWN, Mass., June 21, 2021 (GLOBE NEWSWIRE) -- C4 Therapeutics (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company pioneering a new class of small-molecule medicines that selectively destroy disease-causing proteins through degradation, presented pre-clinical data for CFT7455, the Company’s lead program. CFT7455 is an orally bioavailable MonoDAC™ targeting IKZF1/3 for the treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL), including peripheral T-cell lymphoma (PTCL) and mantle cell lymphoma (MCL). These results, which support clinical evaluation of CFT7455 in non-Hodgkin’s lymphomas, were delivered as a poster presentation at the 16th Annual International Conference on Malignant Lymphoma (ICML). “We are pleased to share these pre-clinical data, which further validate the potential of our lead candidate, CFT7455, to generate deep and durable antitumor responses in non-Hodgkin’s lymphomas. IKZF1/3 proteins are essential transcription factors for B cell malignancies, including non-Hodgkin’s lymphomas, and we believe there is a compelling opportunity to explore the potential of optimized IKZF1/3 degradation as a much-needed therapeutic alternative,” said Adam Crystal, M.D., Ph.D., chief medical officer of C4 Therapeutics. “These results, which are consistent with recent pre-clinical data in multiple myeloma presented at the AACR Annual Meeting 2021, reinforce our belief that CFT7455 will provide significant clinical value in the treatment of hematologic malignancies as we advance the Phase 1/2 trial and prepare to share data in 2022.” Summary of Results C4T conducted in vitro studies which demonstrated that CFT7455 binds to cereblon with high affinity, inducing potent and deep degradation of IKZF1 in pre-clinical NHL models. Notable observations include: Cellular competition studies confirmed the high potency of CFT7455 as a cereblon binder (IC50 = 0.4 nM). Treatment of the KiJK cell line of anaplastic large cell lymphoma (ALCL) with CFT7455 for 6 hours led to an 89% reduction in IKZF1 protein levels. CFT7455 demonstrated potent antiproliferative activity across a panel of NHL cell lines with MYC, BCL2, and/or BCL6 translocations or rearrangements. This includes in vitro models of cutaneous T-cell lymphoma (CTCL), anaplastic large cell lymphoma (ALCL), mantle cell lymphoma (MCL), and high-grade B-cell lymphoma. In xenograft models of NHL, CFT7455 achieved improved in vivo potency and efficacy, including deeper and more durable tumor regressions in models of ALCL, diffuse large B-cell lymphoma (DLBCL) and MCL, when compared to approved and investigational IMiD therapies. Notable observations include: CFT7455 treatment (100 µg/kg/day, PO) led to durable tumor regression associated with deep IKZF1 degradation and IRF4 downregulation (7% and 25% remaining, respectively) in KiJK xenografts, where pomalidomide treatment was ineffective at a clinically relevant dose (3000 µg/kg/day). In the TMD8 DLBCL xenograft model, which proved insensitive to IMiD treatment, CFT7455 (100 µg/kg) promoted tumor regression. In the REC1 MCL xenograft model, doses of CFT7455 ≥ 10 µg/kg promoted tumor regression. Pharmacodynamic studies showed that CFT7455 (30 µg/kg) promoted degradation of IKZF1 and downregulation of cyclin D1 and E2F1. CFT7455 achieved dose-dependent efficacy in both ALK- (DL-40) and ALK+ (KiJK) xenograft models, from 3-100 µg/kg with regressions at doses ≥ 30 µg/kg. In addition, CFT7455 was shown to be between >30-100 times more potent than other IKZF1/3 degraders in development. Global proteomic studies showed only IKZF1/3 proteins were significantly degraded in DL-40 tumors with treatment of CFT7455, resulting in modulation of IFN-regulated genes. These results support continued development of CFT7455, which C4T is currently exploring for the treatment of relapsed or refractory multiple myeloma and non-Hodgkin’s lymphomas following the initiation of a Phase 1/2 clinical study in June 2021. C4T’s ICML poster presentation will be archived on the “Scientific Publications” page in the Investors section of the Company’s website, located at . About CFT7455 CFT7455 is an orally bioavailable MonoDAC™ (Monofunctional Degradation Activating Compound) designed to bind with high affinity to the E3 ligase adapter protein, cereblon, to target and degrade IKZF1/3 for the treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHLs), including peripheral T cell lymphoma (PTCL) and mantle cell lymphoma (MCL). In preclinical studies, CFT7455 has demonstrated potent and selective protein degradation with favorable pharmacological properties. The Company initiated a Phase 1/2 clinical trial for CFT7455 in June 2021. More information about this trial may be accessed at (identifier: NCT04756726). About C4 Therapeutics C4 Therapeutics (C4T) is a clinical-stage biopharmaceutical company focused on harnessing the body’s natural regulation of protein levels to develop novel therapeutic candidates to target and destroy disease-causing proteins for the treatment of cancer and other diseases. This targeted protein degradation approach offers advantages over traditional therapies, including the potential to treat a wider range of diseases, reduce drug resistance, achieve higher potency, and decrease side effects through greater selectivity. To learn more about C4 Therapeutics, visit . 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; 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 submissions and 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; our current resources and cash runway; regulatory developments or approvals in the United States and foreign countries; and upcoming events that C4T will participate in. 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 future 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