ARID1B

Topline Phase 1 dose escalation data for FHD-286 in combination with decitabine, in relapsed and/or refractory AML patients, anticipated in the fourth quarter of 2024 Dosing of first patient in a Phase 1 trial for FHD-909, a potential first-in-class SMARCA2 selective inhibitor, anticipated in the second half of 2024; primary target population in SMARCA4 mutated NSCLC IND-enabling studies for Selective CBP degrader program on track to begin by year-end 2024 Successful $110 million financing strengthens balance sheet with cash, cash equivalents and short-term investments of $285.2 million as of June 30, 2024 and extends expected cash runway into 2027 CAMBRIDGE, Mass., Aug. 08, 2024 (GLOBE NEWSWIRE) -- Foghorn® Therapeutics Inc. (Nasdaq: FHTX), a clinical-stage biotechnology company pioneering a new class of medicines that treat serious diseases by correcting abnormal gene expression, today provided a financial and corporate update in conjunction with the Company’s 10-Q filing for the quarter ended June 30, 2024. With an initial focus in oncology, Foghorn’s Gene Traffic Control® Platform and resulting broad pipeline have the potential to transform the lives of people suffering from a wide spectrum of diseases. “We anticipate topline data from our Phase 1 combination trial with FHD-286 in patients with relapsed and/or refractory AML in the fourth quarter of 2024. We believe FHD-286 has the potential to be a first-in-class, mutation-agnostic differentiation therapeutic,” said Adrian Gottschalk, President and Chief Executive Officer of Foghorn. “Additionally, the IND for FHD-909 cleared in May and we anticipate FHD-909 to be the first SMARCA2 selective inhibitor to enter the clinic. Dosing of the first patient in our Phase 1 trial, with primary target population in SMARCA4 mutated NSCLC, is planned for the second half of the year. We are also on track to initiate IND-enabling studies in the fourth quarter of 2024 for our Selective CBP degrader program targeting tumors harboring EP300 mutations including bladder, gastric and endometrial cancers.” Mr. Gottschalk continued, “The biological foundation for the development of therapeutics targeting the chromatin regulatory system in oncology and other disease areas continues to get stronger. In April, we were pleased to present preclinical data at AACR reinforcing the potential of our platform to deliver innovative medicines across cancers by selectively drugging historically very challenging targets. The conviction in our pipeline was further strengthened by our recent successful financing with new and long-term investors, which extended our expected cash runway into 2027 and through key inflection points, strongly positioning us for continued advancement.” Corporate Updates Strengthened Balance Sheet to Advance Pipeline. In May, Foghorn successfully closed an approximately $110 million registered direct offering to advance the Company’s pipeline. The offering included new investors BVF Partners, Deerfield Management and other leading healthcare specialist investors as well as current investors, including founding investor Flagship Pioneering. Presented at AACR Annual Meeting. In April, Foghorn presented preclinical data highlighting pipeline progress on the advancement of multiple potential first-in-class medicines, including the first presentation of preclinical data for FHD-909, at the 2024 American Association for Cancer Research (AACR) Annual Meeting. Hosted Chromatin Regulation Summit. In April, Foghorn hosted the first Future of Disease and Chromatin Regulation Summit at the Foghorn corporate headquarters in Cambridge, Massachusetts. The live event featured presentations and panel discussions with world-renowned industry and academic key opinion leaders on therapeutic opportunities in chromatin regulatory biology. Strengthened Executive Leadership. In April, Foghorn appointed Kristian Humer as Chief Financial Officer. Mr. Humer joined Foghorn with over 14 years of diversified financial strategy and business development experience in the life science industry and more than 20 years of experience in the financial industry. Key Recent Program Updates and Upcoming Milestones FHD-286. FHD-286 is a potent, first-in-class, selective inhibitor of the SMARCA2 (BRM) and SMARCA4 (BRG1) subunits of the BAF chromatin remodeling complex where dependency on SMARCA2/SMARCA4 is well-established preclinically with multiple tumor types, including acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), non-small cell lung cancer (NSCLC) and prostate cancer. AML Phase 1 trial. The ongoing Phase 1 dose escalation trial is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FHD-286 in combination with decitabine or low-dose cytarabine in patients with relapsed and/or refractory AML who have failed multiple previous courses of therapy. FHD-286 previously demonstrated a promising mutation-agnostic differentiation effect in a single-agent dose escalation trial. Topline clinical data are anticipated in the fourth quarter. We anticipate this will include topline safety, tolerability, initial efficacy and PK/PD data. Overcoming Tyrosine Kinase Inhibitor Resistance. Data published in Cancer Cell in August 2023, together with additional preclinical studies conducted by Foghorn, suggest that FHD-286 may play an important role in overcoming resistance in EGFR/KRAS tumors. Preclinical data profiling the ability of FHD-286 to amplify and/or restore tumor sensitivity will be presented with FHD-286 Phase 1 dose escalation data. FHD-909. FHD-909 is a first-in-class oral SMARCA2 (BRM) selective inhibitor that has demonstrated in preclinical studies to have high selectivity over its closely related paralog SMARCA4 (BRG1), two proteins that are the catalytic engines across all forms of the BAF complex. SMARCA4 mutations are common across tumor types, including approximately 10% of NSCLC, and result in tumors being dependent on SMARCA2 activity for their survival. Selectively blocking SMARCA2 activity is a promising synthetic lethal strategy intended to induce tumor death while sparing healthy cells. In December 2021, Foghorn announced a strategic collaboration with Lilly to create novel oncology medicines. The collaboration includes a U.S. 50/50 co-development and co-commercialization agreement for Foghorn’s Selective SMARCA2 oncology program, which includes a selective inhibitor and a selective degrader, and an additional undisclosed oncology target. In addition, the collaboration includes three discovery programs using Foghorn’s proprietary Gene Traffic Control platform.In April 2024, Foghorn and Lilly presented new preclinical data as a poster presentation at the AACR Annual Meeting and during a pipeline update call demonstrating at tolerable doses high SMARCA2 selectivity and dose-dependent single agent activity in SMARCA4 mutated cancers.In May 2024, the investigational new drug (IND) application was approved by the Food and Drug Administration. The primary target patient population is SMARCA4 mutated NSCLC.Dosing of the first patient in the Phase 1 trial for FHD-909 is planned to begin in the second half of 2024. Selective CBP degrader program and Selective EP300 degrader program. Foghorn is advancing two separate programs targeting either CBP or EP300, paralog histone acetyltransferases with a synthetic lethal relationship in tumor cells. Attempts to selectively drug CBP or EP300 have been challenging due to the high level of similarity between the two proteins. Additionally, dual inhibition of CBP/EP300 has been historically limited by hematopoietic toxicity. Selective CBP degrader program. In April, Foghorn presented new pharmacodynamic and pharmacokinetic preclinical data at the 2024 AACR Annual Meeting and during a pipeline update call highlighting: Deep and sustained CBP degradation significantly inhibited tumor growth in mouse xenograft solid tumor models.Robust monotherapy preclinical anti-tumor activity that was not associated with significant body weight loss, thrombocytopenia or anemia.Identification of potent and selective CBP protein degraders with first-in-class potential to address tumors harboring EP300 mutations in many types of cancer, including bladder, gastric and endometrial cancers.IND-enabling studies on track to initiate by the fourth quarter of 2024. Selective EP300 degrader program. In April, Foghorn presented new pharmacodynamic and pharmacokinetic preclinical data at the 2024 AACR Annual Meeting and during a pipeline update call highlighting: Well-tolerated in vivo with no observed decrease in platelet levels, with no effects on megakaryocyte viability at pharmacologically relevant concentrations in ex vivo studies.Identification of potent and selective EP300 degraders with anti-tumor activity in prostate and hematological malignancies, including prostate cancer, multiple myeloma and diffuse large B cell lymphoma (DLBCL). Selective ARID1B degrader program. ARID1A is the most mutated subunit in the BAF Complex and amongst the most mutated proteins in oncology. These mutations lead to a dependency on ARID1B, in several types of cancer, including ovarian, endometrial, colorectal and bladder. Attempts to selectively drug ARID1B have been challenging because of the high degree of similarity between ARID1A and ARID1B and the fact that ARID1B has no enzymatic activity to target. In April, Foghorn presented data at the AACR Annual Meeting demonstrating potent and selective small molecule binders to ARID1B. The Company is in the process of converting these selective binders into heterobifunctional degraders. Second Quarter 2024 Financial Highlights Collaboration Revenues. Collaboration revenue was $6.9 million for the three months ended June 30, 2024, compared to $5.6 million for the three months ended June 30, 2023. The increase year-over-year was primarily driven by the continued advancement of programs under the Lilly Collaboration Agreement. Research and Development Expenses. Research and development expenses were $23.8 million for the three months ended June 30, 2024, compared to $29.2 million for the three months ended June 30, 2023. This decrease was primarily due to lower personnel-related costs and lower development program spend following the shutdown of two clinical studies (FHD-286 in metastatic uveal melanoma and FHD-609 (BRD9 degrader) in synovial sarcoma). General and Administrative Expenses. General and administrative expenses were $7.3 million for the three months ended June 30, 2024, compared to $8.4 million for the three months ended June 30, 2023. This decrease was primarily due to lower personnel-related costs. Net Loss. Net loss was $23.0 million for the three months ended June 30, 2024, compared to a net loss of $29.5 million for the three months ended June 30, 2023. Cash, Cash Equivalents and Marketable Securities. As of June 30, 2024, the Company had $285.2 million in cash, cash equivalents and marketable securities, providing expected cash runway into 2027. About FHD-286 FHD-286 is a highly potent, first-in-class, selective, allosteric, and orally available small-molecule, enzymatic inhibitor of SMARCA2 (BRM) and SMARCA4 (BRG1), two highly similar proteins that are the ATPases, or the catalytic engines, of the BAF complex, one of the key regulators within the chromatin regulatory system. In preclinical studies, FHD-286 has shown anti-tumor activity across a broad range of malignancies including both hematologic and solid tumors. About AMLAdult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow and the most common type of acute leukemia in adults. AML is a diverse disease associated with multiple genetic mutations. It is diagnosed in about 20,000 people every year in the United States. About FHD-909FHD-909 (LY4050784) is a potent, first-in-class, allosteric and orally available small molecule that selectively inhibits the ATPase activity of SMARCA2 (BRM) over its closely related paralog SMARCA4 (BRG1), two proteins that are the catalytic engines across all forms of the BAF complex, one of the key regulators of the chromatin regulatory system. In preclinical studies, tumors with mutations in SMARCA4 rely on SMARCA2 for BAF function. FHD-909 has shown significant anti-tumor activity across multiple SMARCA4-mutant lung tumor models. About Foghorn TherapeuticsFoghorn® Therapeutics is discovering and developing a novel class of medicines targeting genetically determined dependencies within the chromatin regulatory system. Through its proprietary scalable Gene Traffic Control® platform, Foghorn is systematically studying, identifying and validating potential drug targets within the chromatin regulatory system. The Company is developing multiple product candidates in oncology. Visit our website at www.foghorntx.com for more information on the Company, and follow us on X (formerly Twitter) and LinkedIn. Forward-Looking StatementsThis press release contains “forward-looking statements.” Forward-looking statements include statements regarding the Company’s clinical trials, including its ongoing Phase 1 study of FHD-286 in combination with decitabine in relapsed and/or refractory AML patients and the planned Phase 1 trial of FHD-909, pre-clinical product candidates, expected timing of clinical data, expected cash runway, expected timing of regulatory filings, and research efforts and other statements identified by words such as “could,” “may,” “might,” “will,” “likely,” “anticipates,” “intends,” “plans,” “seeks,” “believes,” “estimates,” “expects,” “continues,” “projects” and similar references to future periods. Forward-looking statements are based on our current expectations and assumptions regarding capital market conditions, our business, the economy and other future conditions. Because forward-looking statements relate to the future, by their nature, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. As a result, actual results may differ materially from those contemplated by the forward-looking statements. Important factors that could cause actual results to differ materially from those in the forward-looking statements include regional, national or global political, economic, business, competitive, market and regulatory conditions, including risks relating to our clinical trials and other factors set forth under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the Securities and Exchange Commission. Any forward-looking statement made in this press release speaks only as of the date on which it is made. Condensed Consolidated Balance Sheets(In thousands) June 30, 2024 December 31, 2023Cash, cash equivalents and marketable securities$285,177 $234,057 All other assets 43,408 51,859 Total assets$328,585 $285,916 Deferred revenue, total$290,726 $302,665 All other liabilities 52,181 60,441 Total liabilities$342,907 $363,106 Total stockholders’ deficit$(14,322) $(77,190)Total liabilities and stockholders’ deficit$328,585 $285,916 Condensed Consolidated Statements of Operations(In thousands, except share and per share amounts) Three Months Ended June 30, 2024 2023 Collaboration revenue$6,888 $5,599 Operating expenses: Research and development 23,797 29,248 General and administrative 7,325 8,401 Impairment of long-lived assets 2,398 — Total operating expenses$33,520 $37,649 Loss from operations$(26,632) $(32,050)Total other income, net$3,653 $3,505 Provision for income taxes$— $(942)Net loss$(22,979) $(29,487)Net loss per share attributable to common stockholders—basic and diluted (0.45) (0.70)Weighted average common shares outstanding—basic and diluted 51,580,310 41,825,555 Contacts:Karin Hellsvik, Foghorn Therapeutics Inc. (Investors & Media)khellsvik@foghorntx.com Adam Silverstein, ScientPR (Media)adam@scientpr.com Peter Kelleher, LifeSci Advisors (Investors)pkelleher@lifesciadvisors.com

学术前沿 单细胞结合空间转录组的研究思路和案例分享 ——遗传发育研究领域（上） 引言 Introduction 单细胞转录组测序是在单个细胞水平进行高通量转录组测序的一项技术，其能有效解决细胞异质性以及之前bulk RNA-seq被掩盖的种种问题。随着该技术在分辨率和通量方面的不断优化，研究者从异质性样本中分析细胞类型特异性基因调控网络的能力也相对提高，但是在细胞的空间位置水平尚有欠缺。空间转录组技术于2020年被《自然》杂志评为年度技术，可以解析时间和空间维度上单个细胞的基因表达模式，以及细胞类群的空间位置关系及生物学特征。其原理是将空间条形码寡核苷酸引物固定在载玻片上，然后将组织贴于载玻片实现组织内转录组序列的捕获与检测。随着10X Genomics的空间Visium技术的登场和不断更新加强，单细胞联合空间转录组的研究如火如荼的开展，遍布了遗传、发育、肿瘤、免疫等多个生物科研和医学热门领域。 研究目的 1.不同发育时期组织样本中细胞类群的差异变化； 2.发育畸形或疾病进展异常器官与正常发育器官中细胞群类的差异变化。 样本选择 1.各种发育器官按照发育时间段取组织样本： 比如在Chang Liu等[1]在斑马鱼发育的研究中（图一），选择了3.3hpf（受精后3.3小时）, 5.25hpf, 10hpf, 12hpf, 18hpf, 24hpf六个时间段的组织样本分别做了空间转录组和单细胞转录组检测。Yanxin Li等[2]在揭示了人类大脑发育的区域特征中选取了6-23孕周的人类多个大脑区域开展研究（图二）。 图一 图二 2.   异常或疾病器官vs正常器官: 由于临床上正常发育的器官获得难度较大，因此正常发育与异常发育器官的对比更多在动物模型或类器官模型中，在这里动物模型建模又可分为基因敲除型建模和疾病表型建模，比如Bruna Paulsen等[3]在研究自闭症（ASD）中枢神经发育机制中通过在类器官模型中分别敲除SUV420H1，ARID1B和CHD8单个基因，来识别由这三个ASD风险基因单倍体不足引起的细胞类型特异性发育异常。Huiya Li等[4]在研究急性缺血诱导脑损伤的研究中选取的样本为缺血再灌注3h,12h,72h的模型小鼠及sham组小鼠（下图）。 研究方法 1.主要研究方法：主要应用在发现探索阶段的方法,一般包括单细胞转录组、空间转录组、多重IHC、FISH、RNAscope等； 2.其他辅助方法：辅助研究方法应用在机制验证方面，会根据验证模型的不同水平，比如细胞水平、动物模型、人源组织、数据库等等，对应各种生物检测分析方法并没有固定的思路。 分析思路 1.单细胞图谱+空间图谱绘制：细胞类型的空间分布特征，亚群的图谱分类； 2.细胞/基因功能空间动态变化、空间细胞分化规律（拟时序）、各个亚群细胞中的变化； 3.关键靶点疾病机制研究和对外界刺激的反应机制：比如，病理或发育状态下，细胞和基因功能空间动态变化所引起差异以及上下游的调控机制； 4.实验验证靶点和机制：细胞水平、类器官水平、动物模型水平做敲除干预治疗等验证。 文献分享 案例1 《人卵巢衰老的时空转录组学变化及FOXP1的调控作用》 发表期刊：NATURE AGING，影响因子：16.6 样本类型：8种卵巢细胞在衰老过程中的不同切片； 技术组合：单细胞RNA转录组、空间转录组、免疫荧光、多重IHC、其他等等； 研究背景：卵巢具有生殖功能和激素分泌功能，在女性生殖寿命中起着至关重要的作用，卵巢老化已逐渐成为更年期女性的主要健康问题。人类卵巢在皮层和髓质上表现出广泛的变异，卵子发生的过程始于皮层，而卵巢的髓质区域经历了戏剧性的重组。因此，对空间原型的理解对于全面理解卵巢的衰老动力学是必要的。 技术路线： 主要结果： 1.   人卵巢细胞的单细胞序列分析和空间定位：通过单细胞组学及空间组学反卷积算法对卵巢组织的细胞类群区分；分析出卵巢老化转录程序中整体差异基因、信号通路及某些细胞亚群特异性的差异变化（Fig.1）。 2.   对卵巢衰老过程中卵母细胞、GC细胞、T&C细胞进一步亚群鉴定（Fig.2仅例举GC细胞），并进一步探索几类细胞中亚群中分化轨迹或发育机制。 3.   通过联合分析各类细胞亚群交并集的数据，最终发现FOXP1是体外卵巢细胞衰老的核心转录调控因子，且GC细胞中敲除FOXP1加速卵巢衰老（Fig.3)。 4.   动物模型实验中发现槲皮素保护中年小鼠的卵巢储备（Fig.4）。 Fig.1 单细胞和空间转录组的整体景观图 Fig.2 GC细胞亚群时空变化 Fig.3 联合分析找到靶向基因FOXP1 Fig.4 动物模型验证机制 案例2 《单细胞RNA测序揭示了胚胎阶段人类肺近端-远端模式的发育程序》 发表期刊：Nature Genetics，影响因子：30.6 样本类型：受精后4-8周人胚胎肺，6周人胚胎肺组织切片； 技术组合：单细胞RNA转录组、空间转录组、免疫荧光、单分子荧光原位杂交（smiFISH）等等； 研究背景：肺发育是一个由内在分子机制和微环境协调的连续分支形态发生过程。在此过程中，肺内胚层祖细胞分化为近端气道上皮细胞类型，如纤毛细胞、基底细胞和分泌细胞，以及远端肺泡细胞类型。本研究目的是通过单细胞RNA测序(scRNA-seq)和空间转录组谱分析绘制了人肺胚期器官发生过程的细胞变化图谱，描绘胚期肺上皮细胞和其他细胞的空间邻近关系，揭示胚期人肺近端-远端细胞谱系命运发育进程的内在（转录调控）和外部（微环境）的调控机制。 技术路线： 主要结果： 1.单细胞和原位探针杂交发现人肺器官发生起始时，肺组织中已经包含三个胚层来源的6种主要细胞类型（Fig.1）。 2.整合数据库信息后发现了肺上皮在胚期已经发生了近端-远端命运特化，并发现了一系列调控近端-远端特化新的转录因子如THRB和SOX6，并从动物实验中验证（Fig.2）。 3.近端-远端命运特化除了转录因子外，在空间转录组的层面对细胞互作微环境变化中发现并鉴定了一群表达BDNF的特殊间质细胞促进上皮细胞分化（Fig.3）。 4.发现平滑肌细胞中AMSC和VMSC均起源于一群早期的间质细胞，在4-5周出现了谱系命运特化，分别由新的转录因子如FOXF1和EBF1调控决定（Fig.4）。 Fig.1 主要的肺细胞类型出现在人类胚胎肺发育的起始阶段 Fig.2 TFs调节早期上皮近端-远端模式 Fig.3 多种基质细胞类型表现出近端和远端的空间异质性 Fig.4 ASMC和VSMC的发展轨迹推断 参考文献： [1]. 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Autism genes converge on asynchronous development of shared neuron classes. Nature. 2022 Feb;602(7896):268-273. doi: 10.1038/s41586-021-04358-6. Epub 2022 Feb 2. PMID: 35110736; PMCID: PMC8852827. [4]. Li H, Liu P, Zhang B, Yuan Z, Guo M, Zou X, Qian Y, Deng S, Zhu L, Cao X, Tao T, Xia S, Bao X, Xu Y. Acute ischemia induces spatially and transcriptionally distinct microglial subclusters. Genome Med. 2023 Dec 11;15(1):109. doi: 10.1186/s13073-023-01257-5. PMID: 38082331; PMCID: PMC10712107. [5]. Wu M, Tang W, Chen Y, Xue L, Dai J, Li Y, Zhu X, Wu C, Xiong J, Zhang J, Wu T, Zhou S, Chen D, Sun C, Yu J, Li H, Guo Y, Huang Y, Zhu Q, Wei S, Zhou Z, Wu M, Li Y, Xiang T, Qiao H, Wang S. Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1. Nat Aging. 2024 Apr;4(4):527-545. doi: 10.1038/s43587-024-00607-1. Epub 2024 Apr 9. PMID: 38594460; PMCID: PMC11031396. [6]. Cao S, Feng H, Yi H, Pan M, Lin L, Zhang YS, Feng Z, Liang W, Cai B, Li Q, Xiong Z, Shen Q, Ke M, Zhao X, Chen H, He Q, Min M, Cai Q, Liu H, Wang J, Pei D, Chen J, Ma Y. Single-cell RNA sequencing reveals the developmental program underlying proximal-distal patterning of the human lung at the embryonic stage. Cell Res. 2023 Jun;33(6):421-433. doi: 10.1038/s41422-023-00802-6. Epub 2023 Apr 21. PMID: 37085732; PMCID: PMC10119843. 本文由 科研学术部 提供

Dose escalation in FHD-286 combination trial in AML continues to progress with clinical data expected in the second half of 2024; potential to be a first-in-class oral broad-based differentiation therapeutic in AML IND filing submitted for FHD-909, a first-in-class oral BRM (SMARCA2) selective inhibitor; Phase 1 trial planned to begin in the second half of 2024 with primary target population in BRG1 mutated non-small cell lung cancer; first BRM selective inhibitor to enter the clinic IND-enabling studies for Selective CBP degrader program on track to begin by year-end 2024 Data presented at AACR support monotherapy activity and first-in-class potential for historically challenging targets including FHD-909, Selective CBP degrader and Selective EP300 degrader programs Cash, cash equivalents, and marketable securities of $206.7 million, as of March 31, 2024, providing cash runway into the first half of 2026 CAMBRIDGE, Mass., May 06, 2024 (GLOBE NEWSWIRE) -- Foghorn® Therapeutics Inc. (Nasdaq: FHTX), a clinical-stage biotechnology company pioneering a new class of medicines that treat serious diseases by correcting abnormal gene expression, today provided a financial and corporate update in conjunction with the Company’s 10-Q filing for the quarter ended March 31, 2024. With an initial focus in oncology, Foghorn’s Gene Traffic Control® Platform and resulting broad pipeline have the potential to transform the lives of people suffering from a wide spectrum of diseases. “We are excited about the progress and strength of data presented this quarter which includes robust preclinical anti-tumor monotherapy activity at tolerable doses for multiple pipeline programs. We believe these data demonstrate the potential of our platform to generate novel medicines against very challenging targets, as well as our leadership in the development of therapeutics in chromatin biology," said Adrian Gottschalk, President and Chief Executive Officer of Foghorn. Mr. Gottschalk added, “In the second half of the year, we expect initial data from our FHD-286 combination study in AML. The IND for FHD-909 was recently submitted and would be the first selective BRM inhibitor to enter the clinic, with a Phase 1 trial planned to begin in the second half of this year. Earlier this year, we also shared data from our Selective CBP degrader program demonstrating tumor growth inhibition in solid tumors without thrombocytopenia or anemia that have been observed with dual CBP/EP300 inhibition. Our Selective EP300 degrader program also demonstrated promising preclinical efficacy with no thrombocytopenia, which is often seen in dual approaches. Our cash balance remains strong, and with multiple programs advancing, we are expected to deliver near- and mid-term value for both patients and shareholders.” Corporate Updates Presented at AACR Annual Meeting. In April 2024, Foghorn presented preclinical data highlighting pipeline progress from multiple potential first-in-class medicines, including the first presentation of preclinical data for FHD-909, at the 2024 American Association for Cancer Research (AACR) Annual Meeting held April 5-10, 2024. Hosted Chromatin Regulation Summit. In April 2024, Foghorn hosted the first Future of Disease and Chromatin Regulation Summit at the Foghorn corporate headquarters in Cambridge, Massachusetts. The live event featured presentations and panel discussions with world-renowned industry and academic key opinion leaders on therapeutic opportunities in chromatin regulatory biology. Strengthened Financial Leadership. In April 2024, Foghorn appointed Kristian Humer as Chief Financial Officer. Mr. Humer joins Foghorn with over 14 years of diversified financial strategy and business development experience in the life science industry and more than 20 years of experience in the financial industry. Key Recent Program Updates and Upcoming Milestones FHD-286. FHD-286 is a potent, selective inhibitor of the BRG1 (SMARCA4) and BRM (SMARCA2) subunits of the BAF chromatin remodeling complex where dependency on BRG1/BRM is well-established preclinically with multiple tumor types, including acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), non-small cell lung cancer (NSCLC) and prostate cancer. AML Update. Foghorn initiated a Phase 1 trial of FHD-286 in combination with decitabine or low-dose cytarabine (LDAC) in relapsed and/or refractory AML patients, with the first patient dosed during the third quarter of 2023. Dose escalation is ongoing with initial clinical data expected in the second half of 2024 . Tyrosine Kinase Inhibitor Resistance. Data published in Cancer Cell in August 2023, along with Foghorn’s work, suggest that FHD-286 may play an important role in overcoming and delaying resistance in EGFR/KRAS tumors. Preclinical data is expected in the second quarter of 2024. FHD-909. FHD-909 is a first-in-class oral BRM (SMARCA2) selective inhibitor that has been demonstrated in preclinical studies to have high selectivity over its closely related paralog BRG1 (SMARCA4), two proteins that are the catalytic engines across all forms of the BAF complex. BRG1 mutations are common across tumor types, including approximately 10% of NSCLC, and result in tumors being dependent on BRM activity for their survival. Selectively blocking BRM activity is a promising synthetic lethal strategy intended to induce tumor death while sparing healthy cells. In December 2021, Foghorn announced a strategic collaboration with Lilly to create novel oncology medicines. The collaboration includes a US 50/50 co-development and co-commercialization agreement for Foghorn’s Selective BRM oncology program and an additional undisclosed oncology target. In addition, the collaboration includes three discovery programs using Foghorn’s proprietary Gene Traffic Control platform. In the first quarter of 2024, Lilly selected FHD-909 for clinical development and in April the investigational new drug (IND) application was submitted. The primary target patient population is BRG1-mutated NSCLC. In April 2024, Foghorn and Lilly presented new preclinical data as a poster presentation at the AACR Annual Meeting demonstrating, at tolerable doses, high BRM selectivity and dose-dependent single agent activity in BRG1-mutated cancers. Dosing of first patient in Phase 1 trial for FHD-909 in BRG1-mutated NSCLC is expected in the second half of 2024. Selective CBP Degrader Program and Selective EP300 Degrader Program. Foghorn is advancing two separate programs targeting either CBP or EP300, both of which are paralog histone acetyltransferases with a synthetic lethal relationship in tumor cells. Attempts to selectively drug CBP or EP300 have been historically challenging due to the high level of similarity between the two proteins. Additionally, dual inhibition of CBP/EP300 is limited by hematopoietic toxicity. Selective CBP Degrader Program. In April, Foghorn presented new pharmacodynamic and pharmacokinetic preclinical data at the 2024 AACR Annual Meeting highlighting: Deep and sustained CBP degradation significantly inhibited tumor growth in mouse xenograft solid tumor models. Robust monotherapy preclinical anti-tumor activity that was not associated with significant body weight loss, thrombocytopenia or anemia. Identification of potent and selective CBP protein degraders with first-in-class potential to address tumors harboring EP300 mutations in many types of cancer, including bladder, gastric and endometrial cancers. Long-acting CBP-selective protein degrader formulations with first-in-class potential for patients with tumors harboring EP300 mutations. IND-enabling studies on track to initiate by year-end 2024. Selective EP300 Degrader Program. In April, Foghorn presented new pharmacodynamic and pharmacokinetic preclinical data at the 2024 AACR Annual Meeting highlighting: No observed thrombocytopenia in vivo. Identification of potent and selective EP300 protein degraders with first-in-class potential to address tumors harboring CBP mutations and tumors with dependency on EP300 in several types of cancer, including prostate, multiple myeloma and diffuse large B cell lymphoma (DLBCL). Selective ARID1B Degrader Program. ARID1A is the most mutated subunit in the BAF Complex and amongst the most mutated proteins in oncology. These mutations lead to a dependency on ARID1B, in several types of cancer, including ovarian, endometrial, colorectal and bladder. Attempts to selectively drug ARID1B have been challenging because of the high degree of similarity between ARID1A and ARID1B and the fact that ARID1B has no enzymatic activity to target. In April, Foghorn presented data at the AACR Annual Meeting demonstrating potent and selective small molecule binders to ARID1B. The Company is in the process of converting these selective binders into heterobifunctional degraders. Drug Discovery Platform. Foghorn's synthesis of deep chromatin expertise, protein biochemistry and screening, and degrader expertise uniquely positions the Company to successfully drug historically challenging targets. Potential for five additional INDs in the next four years. Targets combined have the potential to address more than 20 tumor types impacting over 500,000 new patients annually. First Quarter 2024 Financial Highlights Collaboration Revenues. Collaboration revenue was $5.1 million for the three months ended March 31, 2024, compared to $5.3 million for the three months ended March 31, 2023. The decrease year-over-year was primarily driven by the termination of the Merck collaboration agreement. Research and Development Expenses. Research and development expenses were $25.5 million for the three months ended March 31, 2024, compared to $30.0 million for the three months ended March 31, 2023. This decrease was primarily due to lower personnel-related costs. General and Administrative Expenses. General and administrative expenses were $7.7 million for the three months ended March 31, 2024, compared to $8.6 million for the three months ended March 31, 2023. This decrease was primarily due to lower personnel-related costs. Net Loss. Net loss was $25.0 million for the three months ended March 31, 2024, compared to a net loss of $30.5 million for the three months ended March 31, 2023. Cash, Cash Equivalents and Marketable Securities. As of March 31, 2024, the Company had $206.7 million in cash, cash equivalents and marketable securities, which providing expected cash runway into the first half of 2026. About FHD-286 FHD-286 is a potent, selective, allosteric, and orally available small-molecule, enzymatic inhibitor of BRG1 (SMARCA4) and BRM (SMARCA2), two highly similar proteins that are the ATPases, or the catalytic engines, of the BAF complex, one of the key regulators within the chromatin regulatory system. In preclinical studies, FHD-286 has shown anti-tumor activity across a broad range of malignancies including both hematologic and solid tumors. About AML Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow and the most common type of acute leukemia in adults. AML is a diverse disease associated with multiple genetic mutations. It is diagnosed in about 20,000 people every year in the United States. About FHD-909 FHD-909 (a.k.a. LY4050784) is a potent, allosteric and orally available small molecule that selectively inhibits the ATPase activity of BRM (SMARCA2) over its closely related paralog BRG1 (SMARCA4), two proteins that are the catalytic engines across all forms of the BAF complex, one of the key regulators of the chromatin regulatory system. In preclinical studies, tumors with mutations in BRG1 rely on BRM for BAF function. FHD-909 has shown significant anti-tumor activity across multiple BRG1-mutant lung tumor models. About Foghorn Therapeutics Foghorn® Therapeutics is discovering and developing a novel class of medicines targeting genetically determined dependencies within the chromatin regulatory system. Through its proprietary scalable Gene Traffic Control® platform, Foghorn is systematically studying, identifying and validating potential drug targets within the chromatin regulatory system. The Company is developing multiple product candidates in oncology. Visit our website at for more information on the Company, and follow us on X (formerly Twitter) and LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements.” Forward-looking statements include statements regarding the Company’s clinical trials, including its ongoing Phase 1 study of FHD-286 in combination with decitabine or low-dose cytarabine (LDAC) in relapsed and/or refractory AML patients, pre-clinical product candidates, including the planned Phase 1 study of FHD-909, expected timing of clinical data, expected timing of regulatory filings, and research efforts and other statements identified by words such as “could,” “may,” “might,” “will,” “likely,” “anticipates,” “intends,” “plans,” “seeks,” “believes,” “estimates,” “expects,” “continues,” “projects” and similar references to future periods. Forward-looking statements are based on our current expectations and assumptions regarding capital market conditions, our business, the economy and other future conditions. Because forward-looking statements relate to the future, by their nature, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. As a result, actual results may differ materially from those contemplated by the forward-looking statements. Important factors that could cause actual results to differ materially from those in the forward-looking statements include regional, national or global political, economic, business, competitive, market and regulatory conditions, including risks relating to our clinical trials and other factors set forth under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the Securities and Exchange Commission. Any forward-looking statement made in this press release speaks only as of the date on which it is made. Condensed Consolidated Balance Sheets (In thousands) March 31, 2024 December 31, 2023 Cash, cash equivalents and marketable securities $ 206,661 $ 234,057 All other assets 48,343 51,859 Total assets $ 255,004 $ 285,916 Deferred revenue, total $ 297,615 $ 302,665 All other liabilities 54,875 60,441 Total liabilities $ 352,490 $ 363,106 Total stockholders’ equity (deficit) $ (97,486 ) $ (77,190 ) Total liabilities and stockholders’ equity $ 255,004 $ 285,916 Condensed Consolidated Statements of Operations (In thousands, except share and per share amounts) Three Months Ended March 31, 2024 2023 Collaboration revenue $ 5,050 $ 5,309 Operating expenses: Research and development 25,534 29,985 General and administrative 7,710 8,641 Total operating expenses $ 33,244 $ 38,626 Loss from operations $ (28,194 ) $ (33,317 ) Total other income, net $ 3,178 $ 3,389 Provision for income taxes $ — $ (560 ) Net loss $ (25,016 ) $ (30,488 ) Net loss per share attributable to common stockholders—basic and diluted (0.59 ) (0.73 ) Weighted average common shares outstanding—basic and diluted 42,428,813 41,811,087 Contacts: Greg Dearborn, Foghorn Therapeutics Inc. (Investors) gdearborn@foghorntx.com Karin Hellsvik, Foghorn Therapeutics Inc. (Investors & Media) khellsvik@foghorntx.com Adam Silverstein, ScientPR (Media) adam@scientpr.com Peter Kelleher, LifeSci Advisors (Investors) pkelleher@lifesciadvisors.com