UGT1A1

– Topline Data from 52-week Phase 3 Study Expected in Late 2025 – CAMBRIDGE, Mass., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, today announced that enrollment is complete for the Phase 3 RISE UP study. This global, double-blind, randomized, placebo-controlled trial is evaluating the efficacy and safety of mitapivat, an oral, small molecule PK activator, in sickle cell disease patients who are 16 years of age or older. Agios expects to report topline results from this 52-week Phase 3 study in late 2025. Sickle cell disease is an inherited, lifelong blood disorder caused by mutations in hemoglobin, the major protein that carries oxygen in red blood cells. In sickle cell disease, red blood cells are sickle-shaped due to a gene mutation that affects the hemoglobin molecule. When red blood cells sickle, they do not bend or move easily and can block blood flow to the rest of the body, resulting in chronic hemolytic anemia, pain, poor quality of life, organ damage and early mortality. In sickle cell disease there is an increased energy demand of adenosine triphosphate (ATP) to support red blood cell function and increased 2,3-diphosphoglycerate (2,3-DPG) concentrations that increase the likelihood of red blood cell sickling. Mitapivat is designed to optimize the glycolytic pathway, which has a dual effect of increasing ATP levels and decreasing 2,3-DPG concentrations in red blood cells. “There is a critical need for novel regimens that elevate the standard of care for patients suffering from sickle cell disease, a burdensome and debilitating disease,” said Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios. “We sincerely thank the patients, study investigators and patient advocates for their instrumental support and partnership in helping us complete enrollment of the Phase 3 RISE UP study. With enrollment now complete, we look forward to completing the trial and sharing topline results with the community in late 2025.” The Phase 3 RISE UP study enrolled more than 200 patients worldwide. The trial’s primary endpoints are hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 24 through Week 52 compared with baseline, and annualized rate of sickle cell pain crises. These are important clinical endpoints in sickle cell disease because anemia and pain episodes are the hallmark symptoms of the disease that severely impact a patient’s quality of life. The positive results from the double-blind period of the RISE UP Phase 2 study, which were presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2023, supported Agios’ further exploration of mitapivat’s risk-benefit profile in sickle cell disease in the Phase 3 study. About Phase 2/3 RISE UP StudyThe RISE UP Phase 2 and 3 studies are evaluating the efficacy and safety of mitapivat in sickle cell disease patients who are 16 years of age or older, have had between two and 10 sickle cell pain crises in the past 12 months, and have hemoglobin within the range of 5.5 to 10.5 g/dL during screening. The Phase 2 and Phase 3 studies are conducted under a single operationally seamless Phase 2/3 protocol. The two studies enrolled different participants and achieved operational efficiency through leveraging the same sites, vendors and other resources. The Phase 2 study included a 12-week randomized, placebo-controlled period in which participants were randomized in a 1:1:1 ratio to receive 50 mg mitapivat twice daily, 100 mg mitapivat twice daily or matched placebo. The primary endpoints were hemoglobin response, defined as ≥1.0 g/dL increase in average hemoglobin concentration from Week 10 through Week 12 compared to baseline, and safety. The Phase 3 study includes a 52-week randomized, placebo-controlled period in which participants will be randomized in a 2:1 ratio to receive 100 mg of mitapivat twice daily or matched placebo. The primary endpoints are hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 24 through Week 52 compared with baseline, and annualized rate of sickle cell pain crises. Participants who complete the double-blind period of the Phase 2 or Phase 3 studies will have the option to move into a 216-week open-label extension period to receive mitapivat. About PYRUKYND® (mitapivat)PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States, and for the treatment of PK deficiency in adult patients in the European Union. IMPORTANT SAFETY INFORMATIONAcute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath. Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. Drug Interactions: Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage.Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index.UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment. Please see full Prescribing Information and Summary of Product Characteristics for PYRUKYND. About AgiosAgios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency, myelodysplastic syndrome (MDS)-associated anemia and phenylketonuria (PKU). In addition to its clinical pipeline, Agios is advancing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. For more information, please visit the company’s website at www.agios.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of PYRUKYND® (mitapivat); Agios’ plans, strategies and expectations for its preclinical, clinical and commercial advancement of its drug development, including PYRUKYND®; Agios’ strategic vision and goals, including its key milestones for 2024 and 2025; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to establish and maintain key collaborations; uncertainty regarding any milestone or royalty payments related to the sale of its oncology business or its in-licensing of TMPRSS6 siRNA, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios’ cash and cash equivalents; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Contacts: Investor ContactChris Taylor, VP, Investor Relations and Corporate CommunicationsAgios PharmaceuticalsIR@agios.com Media ContactEamonn Nolan, Senior Director, Corporate CommunicationsAgios PharmaceuticalsMedia@agios.com

October 19, 2024 5:09 pm ET – Novel Investigational Combination Regimen is Advancing to Phase 3 and has the Potential to Become the First Weekly Oral HIV Treatment – Foster City, Calif., & Rahway, N.J. [October 19, 2024] – (BUSINESS WIRE) Gilead Sciences, Inc. (Nasdaq: GILD) and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced new results from a Phase 2 clinical study evaluating the investigational combination of islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, and lenacapavir, a first-in-class HIV-1 capsid inhibitor. These late-breaking data were presented during an oral session at ID Week 2024 , taking place in Los Angeles, and virtually, from October 16-19. At 48 weeks, the novel investigational combination maintained a high rate (n=49; 94.2%) of viral suppression (HIV-1 RNA <50 copies/mL) in virologically suppressed adults, a secondary endpoint of the study. Zero participants had a viral load of ≥50 copies/mL at Week 48. Week 24 results, including the study’s primary endpoint, were previously presented at the 31st Conference on Retroviruses and Opportunistic Infections (CROI). “The future of HIV treatment is person-centered, with long-acting options tailored to help meet the needs and preferences of people affected by HIV,” said Jared Baeten, MD, PhD, Senior Vice President, Virology Therapeutic Area Head, Gilead Sciences. “There is no ‘one size fits all’ approach. The complexities of HIV care require putting people first in the development of biomedical innovations as we keep striving to offer options for all those living with HIV. These data presented at IDWeek demonstrate our commitment to continuous scientific discovery aimed at further transforming the HIV treatment landscape.” In this open-label, active-controlled study ( NCT05052996 ), virologically suppressed adults (n=104) on Biktarvy ® (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablets, B/F/TAF) were randomly allocated in a 1:1 ratio to receive either oral islatravir 2 mg and lenacapavir 300 mg once a week (n=52) or to continue daily oral Biktarvy (n=52). The median age of participants was 40 years (20-76). Eighteen percent of participants were assigned female at birth, 50% were non-white, and 29% were Latine. The proportion of individuals with HIV-1 RNA <50 c/mL at Week 48 by FDA snapshot algorithm (a secondary endpoint), showed that participants who switched to treatment with once-weekly islatravir and lenacapavir (ISL + LEN) or continued Biktarvy maintained comparable high rates of HIV suppression at Week 48 (94.2% v. 92.3%, respectively). No participants treated with either ISL + LEN or Biktarvy had a viral load of ≥ 50 copies/mL at Week 48 (another secondary endpoint). Treatment-related-adverse events (TRAEs), as attributed by study investigator, were experienced by 19.2% of participants (n=10/52) in the ISL + LEN group and the most common were dry mouth (n=2/52; 3.8%) and nausea (n=2/52; 3.8%). TRAEs were reported by 5.8% of participants in the Biktarvy group (n=3/52). No grade 3 or 4 TRAEs related to the study drug were reported in either treatment group. Two participants (n=2/52; 3.8%) discontinued ISL + LEN due to adverse events unrelated to the drug. At Week 48 no significant differences were seen between treatment groups in mean change from baseline in CD4+ T-cell counts or absolute lymphocyte counts. No participants discontinued due to a decrease in CD4+ T-cell or lymphocyte counts. “Daily single-tablet regimens have helped to transform HIV care but can be challenging for some people to maintain. Novel HIV treatment options that allow for less frequent oral dosing have the potential to help support adherence, and address stigma faced by some individuals taking daily oral therapy,” said Dr. Elizabeth Rhee, Vice President, Global Clinical Development, Merck Research Laboratories. “We are pleased to see these encouraging 48-week data for this once-weekly oral combination regimen and advance to phase 3 clinical trials in collaboration with Gilead.” Along with these most recent study results, the potent antiviral activities, and pharmacokinetic profiles of islatravir and lenacapavir support their continued development as an investigational once-weekly oral combination regimen for use in people with HIV who are virologically suppressed. This investigational combination of weekly oral ISL 2 mg + LEN 300 mg is being further evaluated as a fixed-dose combination regimen in two Phase 3 studies ( NCT06630286 and NCT06630299 ) in virologically suppressed people with HIV. Islatravir in combination with lenacapavir is investigational and not approved anywhere globally. The safety and efficacy of the combination of islatravir and lenacapavir have not been established. Lenacapavir is being studied in multiple ongoing early and late-stage development programs and has the potential to offer a diverse set of person-centric options for treatment that could uniquely fit into the lives of people with HIV. The use of lenacapavir for HIV treatment in virologically suppressed individuals is investigational and not approved anywhere globally. Please see below for the U.S. Indication and Important Safety Information, including Boxed Warning , for Biktarvy. There is currently no cure for HIV or AIDS. About Islatravir (MK-8591) and Merck’s HIV Research Islatravir (MK-8591) is Merck’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) under evaluation in multiple ongoing early and late-stage clinical studies in combination with other antiretrovirals for the treatment of HIV-1. Studies with islatravir are designed to offer different dosing options as potential daily and once-weekly treatments. For an overview of Merck’s HIV treatment and prevention clinical development program, please click here . About Lenacapavir The multi-stage mechanism of action of lenacapavir, is distinguishable from other currently approved classes of antiviral agents. While most antivirals act on just one stage of viral replication, lenacapavir is designed to inhibit HIV at multiple stages of its lifecycle. Lenacapavir is being evaluated as a potential long-acting option in multiple ongoing and planned early and late-stage clinical studies in Gilead’s HIV prevention and treatment research program. The goal is to offer both long-acting oral and injectable options with various dosing frequencies in combination with other antiretroviral agents for treatment or as a single agent for prevention. This approach aims to help address the individual needs and preferences of people with HIV and people who could benefit from pre-exposure prophylaxis (PrEP). The use of lenacapavir for HIV prevention is investigational and the safety and efficacy of lenacapavir for this use has not been established. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Merck’s Commitment to HIV For more than 35 years, Merck has been committed to scientific research and discovery in HIV leading to scientific breakthroughs that have helped change HIV treatment. Our work has been pioneering in the development of new options across multiple drug classes to help those impacted by HIV. Today, we are developing a series of antiviral options designed to help people manage HIV and protect people from HIV, with the goal of reducing the growing burden of infection worldwide. We want to ensure people are not defined by HIV and our work focuses on transformational innovations, collaborations with others in the global HIV community, and access initiatives aimed at the goal of helping to end the HIV epidemic for everyone. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer, and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, Calif. About Gilead Sciences in HIV For 35 years, Gilead has been a leading innovator in the field of HIV, driving advances in treatment, prevention and cure research. Gilead researchers have developed 12 HIV medications , including the first single-tablet regimen to treat HIV, the first antiretroviral for pre-exposure prophylaxis (PrEP) to help reduce new HIV infections, and the first long-acting injectable HIV treatment medication administered twice-yearly. Our advances in medical research have helped to transform HIV into a treatable, preventable, chronic condition for millions of people. Gilead is committed to continued scientific innovation to provide solutions for the evolving needs of people affected by HIV around the world. Through partnerships , collaborations, and charitable giving, the company also aims to improve education, expand access and address barriers to care, with the goal of ending the HIV epidemic for everyone, everywhere. Gilead is recognized as one of the leading funders of HIV-related programs in a report released by Funders Concerned About AIDS. IMPORTANT U.S. SAFETY INFORMATION AND INDICATION FOR THE USE OF BIKTARVY Biktarvy is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 14 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known or suspected substitutions associated with resistance to bictegravir or tenofovir. BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of BIKTARVY. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue BIKTARVY. If appropriate, anti-hepatitis B therapy may be warranted. Contraindications Coadministration: Do not use BIKTARVY with dofetilide or rifampin. Warnings and precautions Drug interactions: See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during BIKTARVY therapy and monitor for adverse reactions. Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported. New onset or worsening renal impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)–containing products. Do not initiate BIKTARVY in patients with estimated creatinine clearance (CrCl) <30 mL/min except in virologically suppressed adults <15 mL/min who are receiving chronic hemodialysis. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue BIKTARVY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Renal monitoring: Prior to or when initiating BIKTARVY and during therapy, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, assess serum phosphorus. Lactic acidosis and severe hepatomegaly with steatosis: Fatal cases have been reported with the use of nucleoside analogs, including FTC and TDF. Discontinue BIKTARVY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations. Adverse reactions Most common adverse reactions (incidence ≥5%; all grades) in clinical studies through week 144 were diarrhea (6%), nausea (6%), and headache (5%). Drug interactions Prescribing information: Consult the full prescribing information for BIKTARVY for more information on Contraindications, Warnings, and potentially significant drug interactions, including clinical comments. Enzymes/transporters: Drugs that induce P-gp or induce both CYP3A and UGT1A1 can substantially decrease the concentration of components of BIKTARVY. Drugs that inhibit P-gp, BCRP, or inhibit both CYP3A and UGT1A1 may significantly increase the concentrations of components of BIKTARVY. BIKTARVY can increase the concentration of drugs that are substrates of OCT2 or MATE1. Drugs affecting renal function: Coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC and tenofovir and the risk of adverse reactions. Dosage and administration Dosage: Adult and pediatric patients weighing ≥25 kg: 1 tablet containing 50 mg bictegravir (BIC), 200 mg emtricitabine (FTC), and 25 mg tenofovir alafenamide (TAF) taken once daily with or without food. Pediatric patients weighing ≥14 kg to <25 kg: 1 tablet containing 30 mg BIC, 120 mg FTC, and 15 mg TAF taken once daily with or without food. For children unable to swallow a whole tablet, the tablet can be split and each part taken separately as long as all parts are ingested within approximately 10 minutes. Renal impairment: For patients weighing ≥25 kg, not recommended in patients with CrCl 15 to <30 mL/min, or <15 mL/min who are not receiving chronic hemodialysis, or <15 mL/min who are receiving chronic hemodialysis and have no antiretroviral treatment history. For patients weighing ≥14 kg to <25 kg, not recommended in patients with CrCl <30 mL/min. Hepatic impairment: Not recommended in patients with severe hepatic impairment. Prior to or when initiating: Test patients for HBV infection. Prior to or when initiating, and during treatment: As clinically appropriate, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, assess serum phosphorus. Pregnancy and lactation Pregnancy: BIKTARVY is recommended in pregnant individuals who are virologically suppressed on a stable ARV regimen with no known substitutions associated with resistance to any of the individual components of BIKTARVY. Lower plasma exposures of BIKTARVY were observed during pregnancy; therefore, viral load should be monitored closely during pregnancy. An Antiretroviral Pregnancy Registry (APR) has been established. Available data from the APR for BIC, FTC, or TAF show no difference in the rates of birth defects compared with a US reference population. Lactation: Individuals infected with HIV-1 should be informed of the potential risks of breastfeeding. Gilead Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials or studies, including those involving lenacapavir; uncertainties relating to regulatory applications and related filing and approval timelines, including potential applications for indications currently under evaluation; the possibility that Gilead may make a strategic decision to discontinue development of these programs and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). U.S. full Prescribing Information for Biktarvy, including BOXED WARNING , is available at www.gilead.com . Biktarvy, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. All other marks are the property of their respective owners. For more information about Gilead, please visit the company’s website at www.gilead.com , follow Gilead on X ( @Gilead Sciences ) and LinkedIn , or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. 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近期，英汐智能的研究人员回顾了对 MAT2A 靶点的最新研究进展，重点关注其在 TME 中代谢依赖和基因表达调节中的作用，进一步概述了 MAT2A 抑制剂的当前状况。 1. MAT2A 细胞转录和代谢调节功能 MAT2A 催化 MET（蛋氨酸） 和腺苷合成S -腺苷甲硫氨酸 (SAM)，这是蛋氨酸循环中的限速步骤（图 1）。因此，MAT2A 控制 MET 和 SAM 的细胞水平，这两个细胞代谢和稳态的关键效应器。MET 是一种从食物、肠道微生物和自噬中获得的必需氨基酸，它在蛋氨酸循环中被分解代谢和回收。MET 主要作为生长和发育所需的蛋白质合成的引发分子。相反，SAM 是通过甲基化对 DNA、RNA、蛋白质和代谢物进行通用翻译后修饰的主要甲基供体。MET 代谢以及 MET 和 SAM 的细胞平衡受到从 MET 循环中间体延伸出来的多种途径的复杂调节（图 1）。例如，从 SAM 生产多胺时会产生副产物甲硫腺苷 (MTA)。在 MET 回收途径中，MTA 通过 MTAP 以回收 MET，也称为 MTA 循环。相比之下，转硫途径（在此过程中 MET 的硫转移至丝氨酸以生成半胱氨酸和谷胱甘肽）对于控制细胞氧化还原平衡至关重要。此外，通过叶酸循环，MET 平衡还与一碳 (1C) 代谢相关，将 1C 单位整合到一系列重要的细胞过程中，包括嘌呤和嘧啶的生物合成，从而提供了细胞增殖。因此，MAT2A 催化活性的微妙调节对于维持细胞稳态至关重要。 图1. 蛋氨酸（MET）和一碳代谢循环 2. MAT2A 本身的致癌特性 通过控制通用甲基供体 SAM 和 MET 代谢物库的水平，MAT2A 在致癌的转录和代谢谱中发挥着关键作用。MAT2A 的失调不仅会导致异常的翻译后甲基化模式，从而影响基因表达和基因组稳定性，还会扰乱 MET 代谢，从而导致代谢变化，从而驱动恶性转化。 最早报道的 MAT2A 诱导增殖优势的联系之一是在肝癌中发现的，其中从肝脏特异性 MAT1A 到肝外 MAT2A 表达的转变以及 SAM:SAH 比率和 DNA 甲基化谱的变化被确定为驱动癌细胞生长。多组学分析发现，MAT2A 介导的 MTA 和 SAM 水平升高与肝细胞癌 (HCC) 中的 T 细胞功能障碍和耗竭密切相关。作者表明，MAT2A 缺失可抑制小鼠的 T 细胞功能障碍和 HCC 生长，证明通过 MAT2A 抑制重新编程肿瘤 MET 代谢是改善 HCC 免疫力的一种可能的治疗策略（图 2）。 在白血病和结直肠癌细胞中证实了 MAT2A 驱动的过度增殖。在结直肠癌中，多胺生物合成的增加被证明可以反式激活MAT2A表达并促进肿瘤生长。 在胃癌中，MAT2A 水平升高导致 MET 循环活性增加，通过 RIP1 启动子区域的表观遗传修饰调节肿瘤相关巨噬细胞 (TAM) 的表型。MAT2A 介导的 RIP1 启动子的 H3K4me3 修饰诱导促肿瘤 M2 TAM 极化，从而促进肿瘤进展。在宫颈癌中，MAT2A 介导的 AMPK 介导的程序性细胞死亡蛋白 6 (PDCD6) 的稳定性促进了葡萄糖剥夺下的肿瘤发生。高水平的 MAT2A 表达与乳腺癌的较差生存率相关，并且 MAT2A 细胞质定位的增加与侵袭性增加相关。MAT2A 还被发现驱动表观遗传调节，导致侵袭性高级别神经胶质瘤的 MET 代谢依赖性和白血病的致病性转化。此外，还发现肿瘤起始细胞在 MAT2A 表达和酶活性上调的驱动下具有高度升高的 MET 循环活性。 相比之下，MAT2A 表达在肾细胞癌 (RCC) 细胞系和肿瘤中下调，并且 MAT2A 在 RCC 中充当肿瘤抑制因子。这一观察结果可归因于 RCC 亚型高度不同的代谢特征以及 RCC 中 MAT2A 和血红素加氧酶 1 (HO-1) 基因表达的负相关性。HO-1 在肾细胞癌患者中通常过度表达，并促进肾癌细胞的存活。鉴于 MAT2A 可以抑制HO1表达，RCC 细胞对 HO-1 的依赖性可能超过高 MAT2A 水平的促生存刺激，从而促进其他肿瘤类型的癌变。这些观察结果表明靶向 MAT2A 可以对抗癌细胞的转录和代谢依赖。 3. MAT2A 和 MTAP 缺陷的合成致死 MTAP 在 MET 回收途径中催化 MTA 转化为 MET（图 1）。 MTAP位于染色体基因座 9p21.3 上，该基因座还包含多个重要的肿瘤抑制基因，包括CDKN2A （p16.INK4a 和 p14.ARF）和CDKN2B （p15.INK4B），编码两种共同激活 p53 的细胞周期蛋白依赖性激酶抑制剂信号传导并负调节细胞周期进程。CDKN2A 是继 p53 之后第二个最常见的癌症失活基因，9p21.3 的缺失突变与许多癌症的不良预后相关。鉴于 MTAP 序列与CDKN2A基因座非常接近，约 15% 的实体瘤中观察到MTAP缺失，其患病率范围为胶质母细胞瘤中的 58%、胰腺癌中的 40% 和成人 T 细胞白血病中的 14%，在结直肠癌中为 2%。  图2 .在甲硫腺苷磷酸化酶 (MTAP) 缺陷的细胞中抑制MAT2A会产生一种合成致死效应 在几个独立的筛选中发现，MTAP 功能的丧失与 MAT2A 抑制具有合成致死，合成致死的原因集中在 MTAP 缺陷细胞对精氨酸甲基转移酶 5 (PRMT5) 的依赖性。PRMT5 使用 SAM 作为甲基供体，将包括组蛋白在内的一系列蛋白质中的精氨酸残基甲基化，从而调节染色质可及性和基因表达。PRMT5 活性和表达增加会促进肿瘤发生，并与不良生存结果相关。重要的是，PRMT5 活性受甲基代谢物池调节：MTA（由 MTAP 回收）和 SAM（由 MET 的 MAT2A 产生）竞争性地结合到 PRMT5 的底物结合口袋，尽管具有不同的亲和力，并且，同时SAM 是 PRMT5 辅助因子，激活 PRMT5 酶活性，MTA 抑制 PRMT5。在 MTAP 缺陷的肿瘤中，细胞内 MTA 与 SAM 竞争结合 PRMT5，从而抑制 PRMT5 活性。为了维持生存，MTAP 缺失的癌细胞依靠 MAT2A 提供 SAM 来维持 PRMT5 的持续功能。因此，MTAP 缺陷细胞容易受到 MAT2A 抑制引起的 SAM 水平降低的影响，从而在 MTAP 缺失与 MAT2A 和 PRMT5 功能之间产生综合致死性。MTAP 缺陷细胞中 MTA 的瘤内积累，加上 MAT2A 生成的 SAM 的丧失，消除了 PRMT5 活性，进而扰乱剪接，抑制 DNA 修复，并导致有丝分裂缺陷和基因组不稳定。这种合成致死效应激发了 MAT2A 和 PRMT5 抑制剂的临床开发，几种新化合物正处于治疗 MTAP 缺陷癌症的临床测试的不同阶段。 4. MAT2A 抑制剂研发进展 哺乳动物细胞表达三种 MAT 基因。MAT1A 和 MAT2A 是具有催化和调节作用的基因同源物，而 MAT2B 与 MAT1A 和 MAT2A 仅具有 7% 的氨基酸序列同一性，并稳定 MAT2A 以实现有效催化。MAT1A 主要在肝脏中表达，在肝脏代谢膳食 MET 中发挥着至关重要的作用；相比之下，MAT2A和MAT2B主要在肝外组织中表达，而MAT2A在肝脏中的表达仅限于胎儿肝脏或肝损伤或恶变后。活性 MAT2A 是一种功能性同二聚体，具有两个对称的活性位点，形成催化 SAM 形成的界面，催化需要二聚化。MAT2B 通过距活性位点约 20 Å 的 C 末端与 MAT2A 二聚体结合，形成化学计量比为：MAT2A:MAT2B= 2:1。 第一代 MAT2A 抑制剂是竞争性 MET 底物类似物，其治疗开发的效力和特异性均低于标准水平。 虽然随着 FIDAS 药物（二苯乙烯衍生物）的开发，MAT2A 抑制效力可以提高至低微摩尔浓度，但它们对 MAT2A 的选择性仍然很差。第一个 MAT2A 变构小分子抑制剂PF-9366于 2017 年报道。PF-9366 与 MAT2B 竞争 MAT2A 结合，虽然它能有效抑制细胞 SAM 的产生，但还驱动MAT2A基因和蛋白质表达的适应性上调，以补偿 MAT2A 功能抑制，因此无法抑制细胞增殖。 表 1. MAT2A 抑制剂概况 2021年，一系列吡唑-嘧啶衍生物被报道为有效的MAT2A抑制剂，占据酶的变构袋，从而抑制SAM从其活性位点释放。其中一种化合物AG-270 (S095033)显示出优异的效力和良好的药物样特性，并使 MTAP-null 癌细胞对紫杉烷类药物（通常用于治疗晚期或转移性疾病的抗肿瘤药物）敏感。此外， AG-270抑制 MAT2A 会诱导 DNA 损伤并降低 MTAP 缺陷细胞中的 DNA 修复活性，表明 MAT2A 抑制可提高针对 DNA 损伤反应的癌症药物的功效。 AG-270已进入针对 MTAP 缺失的晚期实体瘤或淋巴瘤的 I 期临床试验（NCT03435250），但该试验于 2023 年 10 月终止，可能是因为 AG-270 通过抑制 UGT1A1 增加胆红素，限制了剂量的进一步增加，这种脱靶副作用随后在SCR-7952中被消除。  另一项 I/II 期临床试验 (NCT04794699) 正在评估 MAT2A 抑制剂 IDE-397 （GSK-4362676 或 GSK-676）在对标准治疗无反应或对标准治疗无反应的晚期 MTAP 缺失实体瘤中的作用。 IDE-397治疗使一名膀胱癌患者完全缓解，另一名非小细胞肺癌 (NSCLC) 患者的肿瘤缩小了 33%（数据未发表）。该试验正在进行中，预计试验完成后将对试验结果进行同行评审评估。 IDE397和 PRMT5 抑制剂 AMG193正在晚期 MTAP 缺陷肿瘤患者中进行 I/II 期评估 (NCT05975073)。AMG193 是第二代协同 PRMT5 抑制剂，针对 MTAP 缺失肿瘤中普遍存在的 MTA 结合酶。第一代PRMT5抑制剂具有SAM竞争性，并且由于靶向毒性而具有非常窄的治疗窗，这限制了它们的发展。 基于结构的药物设计已经产生了AGI-41998和AGI-43192作为 MAT2A 抑制剂，分别具有良好的脑渗透性和有效性。使用基于片段的设计优化 MAT2A 抑制剂的核心结构和取代基产生的 AZ-28作为一种有前途的新型口服生物可利用的 MAT2A 抑制剂。尽管化合物AZ-28在 HCT116 MTAP 缺陷肿瘤的小鼠异种移植模型中表现出优异的体外效力，并导致肿瘤完全停滞，但其体内功效受到高清除率的限制需要高剂量皮下给药。 正在开发的两种新颖有前景的 MAT2A 抑制剂是化合物 28 以及 INS化合物 8。该设计与PF9366 、 AG-270和AZ-28形成对比，其共晶结构表明两个对称定位的抑制剂分子占据位于 MAT2A 二聚体表面的变构袋。因此，INS化合物8是第一个用单分子占据MAT2A变构袋、抑制MAT2B结合的MAT2A抑制剂。与之前的 MAT2A 抑制剂相比，这可以显著增强 INS化合物 8的亲和力并降低有效剂量。 5. MAT2A 对衰老和肌肉萎缩的影响 鉴于 MAT2A 信号传导因其在衰老和肌肉萎缩中的作用而受到重视，MAT2A 抑制策略也可能有利于非致癌疾病适应症。Kitada 及其同事的简明总结讨论了多项临床前研究，其中减少 MET 摄入量、药理学 MAT2A 抑制和 MAT2A 信号传导缺陷延长了酵母、果蝇、蠕虫、小鼠和大鼠的寿命。在这些临床前研究中，MET 限制通过诱导自噬、硫酸氢产生和自由基抑制来减少氧化应激，部分延长了寿命和代谢健康。相比之下，增加 MET 摄入量也与高同型半胱氨酸血症、体重减轻和胆固醇水平升高有关，这表明需要在“黄金”的摄入范围内才能实现其有益效果。 最近，Rajabian 及其同事进行的一项具有里程碑意义的研究发现，MAT2A 抑制可以恢复新陈代谢并改善衰老的骨骼肌功能。尽管 MET 分解代谢与衰老相关的肌肉病理学之间的联系是已知的，但将 MET 分解代谢与成肌细胞中这些很大程度上由代谢驱动的变化联系起来的直接生物学机制仅被部分了解。报道称，MAT2A 活性增加会产生高水平的铵，从而加剧成肌细胞衰老标志物。老化的成肌细胞在急性损伤后表现出胰岛素敏感性、葡萄糖摄取和肌肉再生降低。MAT2A 抑制通过增加 Akt2 信号传导、丙酮酸激酶活性和糖酵解来逆转这种恶化，从而提高早衰小鼠模型的肌肉力量。因此，老年人类和小鼠衰老成肌细胞依赖 MET 作为替代能源，这使得 MAT2A 抑制成为逆转这种年龄诱导的代谢转变的有利策略。这项研究的局限性是使用 FIDAS 来抑制 MAT2A，MAT2A 也可能针对其他与生长相关的细胞途径（c-Myc、CyclinD1 等）。使用靶向 MAT2A 特异性抑制剂（表 1 ）转化这些发现，并将这些研究扩展到非人类灵长类动物，为人体测试提供依据，将是该研究领域下一步的重要步骤。 6. 总结 总而言之，MAT2A 是一个有前途的药物靶点，可以立即改善 MTAP 缺陷肿瘤的生存结果。随着对生物标志物和 MTAP 抑制剂的持续研究，MAT2A 抑制也可以作为一种治疗策略来探索，以对抗 MTAP 熟练细胞中的 MET 代谢依赖。此外，它也可能成为一种延长健康寿命的抗衰老疗法。 参考:https://www.sciencedirect.com/science/article/pii/S1359644624003143#b0175 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓