EP300 x CREBBP

New research sheds light on the significance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting the activity of coregulator proteins. New research from the University of Eastern Finland sheds light on the significance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting the activity of coregulator proteins. Glucocorticoids regulate vital biological processes by affecting gene encoding through a DNA-binding transcription factor, namely the glucocorticoid receptor. The activity of the glucocorticoid receptor is made extensive use of in medicine because glucocorticoids have a strong anti-inflammatory effect. For this reason, synthetic glucocorticoids are one of the most prescribed drugs in the world. They are used to treat inflammatory diseases, such as rheumatoid arthritis, and as adjuvant therapy for cancer patients to alleviate the side effects of cancer therapy. In blood cancer, glucocorticoids are important drugs that limit the growth of cancer cells. However, recent studies have shown that the glucocorticoid receptor also has an oncogenic, or cancer-promoting, effect in cancers like breast and prostate cancer. In prostate cancer, the glucocorticoid receptor can replace the activity of the androgen receptor, which is main oncogenic factor in this cancer, when its activity is inhibited by drug therapy. Thus, glucocorticoids help prostate cancer develop resistance to drug therapy. "Due to these drug resistance and cancer-promoting effects, it is important to study how the glucocorticoid receptor functions on the cellular and molecular level in cancer," Academy Research Fellow, Docent Ville Paakinaho of the University of Eastern Finland notes. The Paakinaho Lab has published two recent genome-wide deep sequencing studies on the subject. The first, published in Nucleic Acids Research, explored how the glucocorticoid receptor replaces the androgen receptor on the molecular level. "This study showed that the glucocorticoid receptor can only use regulatory regions that are already active in prostate cancer cells," says Doctoral Researcher Laura Helminen of the University of Eastern Finland. In other words, glucocorticoid receptor-mediated drug resistance emerges through these regulatory regions, and by affecting the activity of these areas, the harmful effects of glucocorticoids in prostate cancer could be prevented. Bioinformatics analyses indicated the pioneer transcription factor FOXA1 as one possible target. FOXA1 is known to have cancer-promoting properties, which is why the researchers assumed that inhibiting its activity would limit the development of glucocorticoid receptor-mediated drug-resistant prostate cancer. Surprisingly however, the effect was exactly the opposite: inhibiting the activity of FOXA1 further increased the activity of the glucocorticoid receptor -- and the development of drug resistance. This is because FOXA1 was found to be involved in the silencing of the glucocorticoid receptor gene, and this is what increased its activity when FOXA1 was inhibited. "Research often reveals the unexpected, and that's part of its charm," Paakinaho says. The activity of the glucocorticoid receptor in regulatory regions can, however, be influenced in drug-resistant prostate cancer through an alternative pathway. Coregulator proteins were identified as an alternative target through which the glucocorticoid receptor affects the regulation of gene expression. These proteins include EP300 and CREBBP. Several pharmaceutical companies are developing small-molecule inhibitors targeting these proteins, and some are already being studied in patients. In another study by the Paakinaho Lab, the researchers explored ways to inhibit glucocorticoid receptor-mediated effects by inhibiting coregulator proteins. These findings were reported in Cellular and Molecular Life Sciences. "Silencing the EP300 and CREBBP proteins with a small-molecule inhibitor clearly prevented the activity of the glucocorticoid receptor in prostate cancer cells," Project Researcher Jasmin Huttunen of the University of Eastern Finland says. This allowed the growth of drug-resistant prostate cancer cells to be inhibited. Furthermore, the researchers found that silencing EP300 and CREBBP also effectively inhibited the activity of the androgen receptor especially in prostate cancer cells that have an amplification of the androgen receptor gene. This amplification is found in up to half of patients with advanced prostate cancer. Surprisingly, the EP300 and CREBBP inhibitor also inhibited the activity of FOXA1, while still preserving its ability to silence the expression of the glucocorticoid receptor gene. By using the EP300 and CREBBP inhibitor, it was possible to block the activity of FOXA1 without the development of glucocorticoid receptor-mediated drug resistance. Ultimately, inhibiting the activity of both the androgen and the glucocorticoid receptor was found to be primarily due to the limitation of FOXA1 activity. The study suggests that treatment targeting coregulator proteins could also be effective in untreated prostate cancer. The studies were funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland.

CHICAGO--( BUSINESS WIRE )--Pathos AI, Inc. ( www.pathos.com ), a biotechnology company focused on revolutionizing precision medicine in cancer by harnessing the power of machine learning to transform drug development, announced today that it has entered into a worldwide license agreement to develop FT-7051, a small molecule CBP/p300 inhibitor program from Novo Nordisk as Pathos’ first clinical-stage asset in its pipeline. FT-7051 was developed by Forma Therapeutics, which was acquired by Novo Nordisk in 2022, and is currently in phase I development. FT-7051 (renamed P-300) was evaluated in prostate cancer and has potential for development in multiple tumor types. The molecule inhibits the CBP/p300 protein, which is involved in the activation of genes that promote cancer cell growth and proliferation. The development of this molecule reflects Pathos' commitment to precision medicine and biomarker-driven approaches in cancer treatment. “P-300 has shown promising phase I data and we are confident that leveraging our PathOS Platform™ will enhance an optimized path toward a broader patient population that could benefit from this therapeutic option,” explained Ryan Fukushima, Pathos CEO. “We are thrilled about this licensing agreement with Novo Nordisk and accelerating the development for this CBP/p300 inhibitor program.” The license will enable Pathos to continue the development of the drug and bring it to market as quickly and as safely as possible. Pathos has not yet shared specific plans for P-300 but will disclose more details during upcoming oncology conferences. About P-300 P-300 is an oral, small molecule inhibitor that has the potential to provide clinical benefit for patients with advanced prostate cancer, either alone or in combination with other treatments. P-300 works by inhibiting CREBBP/EP300 (also known as CBP/p300), which are proteins that activate genes that promote cancer cell growth and proliferation. Inhibiting these proteins impacts the expression of key cancer drivers, including the androgen receptor (AR) and its variants, making P-300 relevant not only to advanced prostate cancer, but also to other cancer indications as well, either alone or in combination with other treatments. About Pathos Pathos is a clinical-stage biotechnology company focused on re-engineering drug development, leveraging the power of AI technologies to bring precision medicines to market through partnership with biopharmaceutical companies. Pathos has raised $40 million to accelerate the development of precision medicines and to expand its platform, combining computational approaches across multimodal real-world data and patient-derived biological models. Additional information can be found at www.pathos.com

- Phase 1 dose escalation study of FHD-286, a BRG1/BRM inhibitor, in metastatic uveal melanoma continues to progress with initial safety and efficacy data expected in the first half of 2023 - Phase 1 dose escalation study of FHD-609, a selective degrader of BRD9, in synovial sarcoma continues to progress with initial safety and efficacy data expected mid-2023 - Advancing preclinical pipeline targeting key regulators of gene expression, including newly disclosed EP300 program, and selective BRM, ARID1B, CBP and other undisclosed programs, setting up the potential for six INDs over the next four years - Cash, cash equivalents and marketable securities of $345.8 million, as of December 31, 2022, provide cash runway into the second half of 2025 CAMBRIDGE, Mass., March 09, 2023 (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 corporate update including the Company’s 2023 strategic priorities and 2022 key achievements in conjunction with its 10-K filing for the year ending December 31, 2022. With an initial focus in oncology, Foghorn’s Gene Traffic Control® Platform and resulting broad pipeline has the potential to transform the lives of people suffering from a wide spectrum of diseases. “2022 was a productive year for Foghorn as we made significant progress advancing our robust preclinical and clinical pipeline,” said Adrian Gottschalk, President and Chief Executive Officer of Foghorn. “Specifically, we advanced more than 15 programs, which include selective inhibitors and degraders for some of the most challenging targets in oncology – BRM, CBP, EP300 and ARID1B. This year, we expect Phase 1 clinical data for our BRG1/BRM inhibitor FHD-286 in metastatic uveal melanoma in the first half of 2023 and aim to provide clarity on the path forward for FHD-286 in AML/MDS. We also expect to share clinical data for our BRD9 degrader FHD-609 mid-year. Our cash position remains strong and supports our R&D investments as we continue to advance our pipeline through late 2025.” 2023 Outlook and Key Milestones FHD-286. FHD-286 is a potent, selective inhibitor of the BRG1 and BRM subunits of the BAF chromatin remodeling complex, where dependency on BRG1/BRM is well-established pre-clinically with multiple tumor types, including uveal melanoma, acute myelogenous leukemia (AML) / myelodysplastic syndrome (MDS), non-small cell lung cancer (NSCLC) and prostate cancer. mUM Update. Phase 1 dose escalation of FHD-286 in metastatic uveal melanoma (mUM) continues to enroll patients per protocol. Initial Phase 1 safety and efficacy data are expected in the first half of 2023. AML/MDS Update. In August 2022, the U.S. Food and Drug Administration (FDA) placed a full clinical hold on the Phase 1 dose escalation study of FHD-286 in relapsed and/or refractory AML and MDS. The Company anticipates providing clarity on the development path for FHD-286 in AML/MDS in the first half of 2023. FHD-609 Update. FHD-609 is a potent and selective heterobifunctional protein degrader of BRD9, which is a component of the BAF chromatin remodeling complex and a protein synovial sarcoma cells rely on for survival. Patient enrollment is continuing in the Phase 1 dose escalation clinical study of FHD-609 in synovial sarcoma and SMARCB1-loss tumors, with initial safety and efficacy data expected in mid-2023. Newly Disclosed Selective EP300 Degrader. Foghorn disclosed a selective EP300 degrader targeting CBP mutant cancers and subsets of EP300 dependent malignancies. The Selective EP300 program has potential in various cancers which include bladder, NSCLC and various lymphomas and leukemias, and could provide a new therapeutic option for more than 100,000 people a year. Differentiated Pipeline Advancement. Foghorn continues to expand its platform and pipeline. The Company has the potential for six new molecular investigational new drug (IND) applications in the next four years. The Company continues to progress programs for multiple targets which include chromatin remodeling complexes, transcription factors, helicases and other chromatin related factors. These targets include Selective BRM, CBP, EP300 and ARID1B as well as other undisclosed targets, which combined could address more than 20 tumor types impacting more than 500,000 new people annually. Strategic Collaborations. Foghorn expects continued progress across its strategic collaborations with two leading pharmaceutical companies. In December 2021, Foghorn entered into a strategic collaboration with Loxo Oncology, and in 2023 the Company anticipates continued progress across the collaboration, including the co-development and co-commercialization agreement on the selective BRM program, an additional undisclosed oncology target and three additional discovery programs. In July 2020, Foghorn entered into a strategic collaboration with Merck. In 2023, Foghorn will continue to leverage its Gene Traffic Control platform to discover and develop novel therapeutics based on disruptors of an undisclosed transcription factor target. Strong Balance Sheet and Cash Runway. As of December 31, 2022, the Company had $345.8 million in cash, cash equivalents and marketable securities, providing cash runway into the second half of 2025. 2022 Key Achievements Selective CBP Program Announced. In October 2022, Foghorn disclosed a selective CBP degrader targeting EP300 mutant cancers. The Selective CBP program is aimed at degrading the CREB binding protein and has therapeutic potential in subsets of several cancers including bladder, colorectal, breast, gastric and lung. Using selective CBP degraders, the program aims to exploit the synthetic lethal relationship it shares with its paralog EP300 to identify and treat those patients with EP300 mutated cancers. If successful, the Selective CBP program has the potential to address more than 100,000 people per year across many cancer types. Advanced Top Synthetic Lethal Relationship Targets. BRM and ARID1B represent two of the top synthetic lethal targets in cancer, where the mutation occurs in BRG1 and ARID1A paralogues, respectively. We continued to make progress on our BRM selective program with Loxo Oncology. Additionally, we continued to advance our ARID1B program with validated selective chemical matter. Merck Collaboration Progress. In July 2022, a research milestone on the transcription factor target was achieved under the Merck collaboration triggering a $5 million milestone payment to Foghorn. Key Leadership Updates. In 2022, Foghorn announced Steven Bellon, Ph.D., former Senior Vice President of Drug Discovery, was promoted to Chief Scientific Officer. Dr. Bellon joined Foghorn Therapeutics in 2016 as head of drug discovery, bringing more than 20 years of drug discovery experience from multiple drug classes. During his tenure at Foghorn, Dr. Bellon has been instrumental in building Foghorn’s Gene Traffic Control® platform and advancing the Company’s broad therapeutic pipeline of more than 15 programs including protein degraders, enzymatic inhibitors and transcription factor disruptors. Board of Directors Updates. During 2022, Foghorn announced the election of B. Lynne Parshall, Esq., and Thomas J. Lynch Jr., M.D., to its Board of Directors. Ms. Parshall brings nearly three decades of experience in finance and operations in the biotechnology industry and served as the Senior Strategic Advisor for Ionis Pharmaceuticals. Dr. Lynch is currently the president and director of Fred Hutchinson Cancer Center, where he holds the Raisbeck Endowed Chair and sets the strategic direction of the center, oversees center-wide initiatives and represents the center’s interests to major partners and governmental bodies. Full Year 2022 Financial Highlights Collaboration Revenues. Collaboration revenues were $19.2 million for the year ended December 31, 2022, compared to $1.3 million for the year ended December 31, 2021. The increase year-over-year was primarily driven by revenue recognized under the Lilly collaboration agreement, which was executed in December 2021. Research and Development Expenses. Research and development expenses were $105.6 million for the year ended December 31, 2022, compared to $80.3 million for the year ended December 31, 2021. This increase was primarily due to costs associated with continued investment in R&D personnel and the Phase 1 studies for both FHD-286 and FHD-609, which were initiated in 2021. General and Administrative Expenses. General and administrative expenses were $30.7 million for the year ended December 31, 2022, compared to $21.7 million for the year ended December 31, 2021. This increase was primarily due to an increase in investments to support the growing business which included increases in personnel-related costs and stock-based compensation expense. Net Loss. Net loss was $108.9 million for the year ended December 31, 2022, compared to a net loss of $101.3 million for the year ended December 31, 2021. Cash, cash equivalents and marketable securities. As of December 31, 2022, the Company had $345.8 million in cash, cash equivalents and marketable securities, providing cash runway into the second half of 2025. About FHD-286 FHD-286 is a highly potent, selective, allosteric and orally available, small-molecule, enzymatic inhibitor of BRG1 and BRM, two highly similar proteins that are the ATPases, or the catalytic engines across all forms of the BAF complex, one of the key regulators of 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. To learn more about these studies, please visit ClinicalTrials.gov. (Link here for metastatic uveal melanoma and here for AML and MDS). About Uveal Melanoma Uveal (intraocular) melanoma (UM) is a rare eye cancer that forms from cells that make melanin in the iris, ciliary body and choroid. It is the most common eye cancer in adults. It is diagnosed in about 2,000 adults every year in the United States and occurs most often in lightly pigmented individuals with a median age of 55 years. However, it can occur in all races and at any age. UM metastasizes in approximately 50% of cases, leading to very poor prognosis. 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-609 FHD-609 is a potent, selective, intravenously administered protein degrader of BRD9, a component of the ncBAF complex. Preclinical studies have demonstrated tumor growth inhibition in synovial sarcoma and SMARCB1-loss tumors, cancers genetically dependent on BRD9. To learn more about this study, please visit ClinicalTrials.gov. About Synovial Sarcoma Synovial sarcoma is a rare, often aggressive soft tissue sarcoma that originates from different types of soft tissue, including muscle or ligaments. Synovial sarcoma can occur at any age but is most common among adolescents and young adults. It represents around 5-10% of all soft tissue sarcomas, with ~800 new cases each year in the United States. Surgery remains the most effective treatment for synovial sarcoma, and there are limited therapeutic treatment options. About Foghorn Therapeutics Foghorn® Therapeutics Inc. 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 Twitter and LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements” regarding the Company’s clinical programs for FHD-286 and FHD-609, including its efforts to resolve the full clinical hold relating to FHD-286 in AML and MDS, the anticipated timing of release of clinical data, its collaborations with Lilly and Merck and its research pipeline, including the filing of INDs and its protein degrader efforts. Forward-looking statements include statements regarding the Company’s clinical trials, product candidates 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, 2021 and subsequent Quarterly Reports on Form 10-Q, 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) Dec. 31, 2022 Dec. 31, 2021 Cash, cash equivalents and marketable securities $ 345,798 $ 154,289 Collaboration receivable — 300,000 All other assets 59,085 65,485 Total assets $ 404,883 $ 519,774 Deferred revenue, total $ 336,820 $ 351,047 All other liabilities 67,951 71,856 Total liabilities 404,771 422,903 Total stockholders’ equity 112 96,871 Total liabilities and stockholders’ equity $ 404,883 $ 519,774 Condensed Consolidated Statements of Operations (In thousands, except share and per share amounts) Twelve Months Ended December 31, 2022 2021 Collaboration revenue $ 19,228 $ 1,319 Operating expenses: Research and development 105,618 80,325 General and administrative 30,747 21,728 Total operating expenses 136,365 102,053 Loss from operations (117,137 ) (100,734 ) Total other income, net 8,255 (586 ) Net loss $ (108,882 ) $ (101,320 ) Net loss per share attributable to common stockholders—basic and diluted $ (2.62 ) $ (2.73 ) Weighted average common shares outstanding—basic and diluted 41,591,433 37,171,147 Contact: Ben Strain, Foghorn Therapeutics Inc. (Media and Investors) bstrain@foghorntx.com Karin Hellsvik, Foghorn Therapeutics Inc. (Media) khellsvik@foghorntx.com Michael Lampe, ScientPR (Media) michael@scientpr.com Hans Vitzthum, LifeSci Advisors (Investors) hans@lifesciadvisors.com