Gemfibrozil

Positive recommendation based on resmetirom’s favorable profile including positive results from the pivotal Phase 3 MAESTRO-NASH trialEuropean Commission decision expected in August 2025; if approved, resmetirom will be the first medication for people living with MASH in the E.U. CONSHOHOCKEN, Pa., June 20, 2025 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL), a biopharmaceutical company focused on delivering novel therapeutics for metabolic dysfunction-associated steatohepatitis (MASH), today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of resmetirom (Rezdiffra) for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis. The European Commission decision is anticipated in August. Bill Sibold, Chief Executive Officer of Madrigal, stated, “Madrigal is singularly focused on leading the fight against MASH globally. Resmetirom was the first medication to achieve fibrosis improvement and MASH resolution in a Phase 3 trial, the first medication to receive FDA-approval for MASH, and today’s positive CHMP opinion represents another historic first for the global MASH community. MASH is the fastest-growing indication for liver transplantation in Europe, and we believe resmetirom has the potential to address the urgent unmet need for a foundational, liver-directed therapy to treat patients with this serious disease.” MASH is a leading cause of liver-related mortality and an increasing burden on healthcare systems globally. Resmetirom is a once-daily, oral, liver-directed THR-β agonist designed to target key underlying causes of MASH. The CHMP opinion was based on resmetirom’s favorable profile including the positive results from the pivotal Phase 3 MAESTRO-NASH trial, which achieved both fibrosis reduction and MASH resolution primary endpoints. Jörn M. Schattenberg, M.D., Professor of Medicine and Director of the Department of Medicine at the University Medical Center Homburg and University of the Saarland in Germany, stated, “I’m encouraged by the CHMP’s positive opinion recommending approval of resmetirom. After years of clinical research and growing appreciation of the burden of MASH on patients and health systems across Europe, we are finally on the cusp of having an approved therapy that targets the underlying disease. Importantly, resmetirom is already included in European clinical practice guidelines, which provide a framework for identifying and monitoring patients with noninvasive tests. If approved, I believe the medication has the potential to transform care for my patients with MASH.” The U.S. Food and Drug Administration (FDA) granted accelerated approval in March 2024 for Rezdiffra in conjunction with diet and exercise for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials. About MASHMetabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a serious liver disease that can progress to cirrhosis, liver failure, liver cancer, need for liver transplantation, and premature mortality. MASH is the leading cause of liver transplantation in women and the second leading cause of all liver transplantation in the U.S., and the fastest-growing indication for liver transplantation in Europe. Once patients progress to MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically: these patients have a 10-17 times higher risk of liver-related mortality as compared to patients without fibrosis. Those who progress to cirrhosis face a 42 times higher risk of liver-related mortality, underscoring the need to treat MASH before complications of cirrhosis develop. MASH is also an independent driver of cardiovascular disease, the leading cause of mortality for patients. As MASH disease awareness improves and disease prevalence increases, the number of diagnosed patients with MASH with moderate to advanced fibrosis or compensated MASH cirrhosis (F2-F4c) is expected to grow. About RezdiffraRezdiffra is a once-daily, oral, liver-directed THR-β agonist designed to target key underlying causes of MASH. It is the first approved medication for the treatment of MASH in the U.S. In the pivotal Phase 3 MAESTRO-NASH biopsy trial, Rezdiffra achieved both fibrosis improvement and MASH resolution primary endpoints, and 91% of patients treated with Rezdiffra 100 mg experienced improvement or stabilization of liver stiffness. In the U.S., Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials. Rezdiffra is not approved in Europe for the treatment of patients with MASH with moderate to advanced liver fibrosis and not approved in any geography for the treatment of patients with cirrhosis. The ongoing, fully enrolled MAESTRO-NASH OUTCOMES trial is evaluating progression to liver decompensation events in patients with compensated MASH cirrhosis treated with Rezdiffra versus placebo. What is Rezdiffra?Rezdiffra is a prescribed medicine used along with diet and exercise to treat adults with nonalcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), but not with cirrhosis of the liver. It is not known if Rezdiffra is safe and effective in children (under 18 years old).This indication is approved based on improvement of NASH and liver scarring (fibrosis). There are ongoing studies to confirm the clinical benefit of Rezdiffra. Before you take Rezdiffra, tell your healthcare provider about all of your medical conditions, including if you: have any liver problems other than NASH.have gallbladder problems or have been told you have gallbladder problems, including gallstones.are pregnant or plan to become pregnant. It is not known if Rezdiffra will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if Rezdiffra passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Rezdiffra. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Rezdiffra and other medicines may affect each other, causing side effects. Rezdiffra may affect the way other medicines work, and other medicines may affect how Rezdiffra works.Especially tell your healthcare provider if you take medicines that contain gemfibrozil to help lower your triglycerides, or cyclosporine to suppress your immune system, because Rezdiffra is not recommended in patients taking these medicines.Tell your healthcare provider if you are taking medicines such as clopidogrel to thin your blood or statin medicines to help lower your cholesterol.Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. What are the possible side effects of Rezdiffra?Rezdiffra may cause serious side effects, including: liver injury (hepatotoxicity). Stop taking Rezdiffra and call your healthcare provider right away if you develop the following signs or symptoms of hepatotoxicity: tiredness, nausea, vomiting, fever, rash, your skin or the white part of your eyes turns yellow (jaundice), pain or tenderness in the upper middle or upper right area of your stomach (abdomen).gallbladder problems. Gallbladder problems such as gallstones, inflammation of the gallbladder, or inflammation of the pancreas from gallstones can occur with NASH and may occur if you take Rezdiffra. Call your healthcare provider right away if you develop any signs or symptoms of these conditions including nausea, vomiting, fever, or pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back and the pain may happen with or without vomiting. The most common side effects of Rezdiffra include: diarrhea, nausea, itching, stomach (abdominal) pain, vomiting, dizziness, constipation. These are not all the possible side effects of Rezdiffra. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Madrigal at 1-800-905-0324. Please see the full Prescribing Information, including Patient Information, for Rezdiffra. About Madrigal Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) is a biopharmaceutical company focused on delivering novel therapeutics for metabolic dysfunction-associated steatohepatitis (MASH), a liver disease with high unmet medical need. Madrigal’s medication, Rezdiffra (resmetirom), is a once-daily, oral, liver-directed THR-β agonist designed to target key underlying causes of MASH. Rezdiffra is the first and only medication approved by the FDA for the treatment of MASH with moderate to advanced fibrosis (consistent with stages F2 to F3). An ongoing Phase 3 outcomes trial is evaluating Rezdiffra for the treatment of compensated MASH cirrhosis (consistent with stage F4c). For more information, visit www.madrigalpharma.com. Forward-Looking StatementsThis press release includes “forward-looking statements” made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended, including statements related to the expected timing for a decision for marketing authorization by the European Commission and resmetirom’s role as a potential foundational therapy for the treatment of MASH in Europe. Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to: the assumptions underlying the forward-looking statements; risks of obtaining and maintaining regulatory approvals, including, but not limited to, potential regulatory delays or rejections; the challenges with the commercial launch of a new product, particularly for a company that did not have commercial experience prior to 2024; our history of operating losses and the possibility that we may never achieve or maintain profitability; risks associated with meeting the objectives of Madrigal’s clinical trials, including, but not limited to Madrigal’s ability to achieve enrollment objectives concerning patient numbers (including an adequate safety database), outcomes objectives and/or timing objectives for Madrigal’s trials; any delays or failures in enrollment, and the occurrence of adverse safety events; risks related to the effects of Rezdiffra’s (resmetirom’s) mechanism of action; market demand for and acceptance of Rezdiffra; the potential inability to raise sufficient capital to fund ongoing operations as currently planned or to obtain financing on acceptable terms; our ability to service indebtedness and otherwise comply with debt covenants; outcomes or trends from competitive trials; future topline data timing or results; our ability to prevent and/or mitigate cyber-attacks; the uncertainties inherent in clinical testing; uncertainties concerning analyses or assessments outside of a controlled clinical trial; and changes in laws and regulations applicable to our business and our ability to comply with such laws and regulations. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made. Madrigal undertakes no obligation to update any forward-looking statements to reflect new information, events, or circumstances after the date they are made, or to reflect the occurrence of unanticipated events. Please refer to Madrigal’s submissions filed with the U.S. Securities and Exchange Commission(“SEC”), for more detailed information regarding these risks and uncertainties and other factors that may cause actual results to differ materially from those expressed or implied. Madrigal specifically discusses these risks and uncertainties in greater detail in the sections appearing in Part I, Item 1A of its Annual Report on Form 10-K for the year ended December 31, 2024, filed with the SEC on February 26, 2025, and as updated from time to time by Madrigal’s other filings with the SEC. Investor ContactTina Ventura, IR@madrigalpharma.com Media ContactChristopher Frates, media@madrigalpharma.com

药物–药物相互作用（DDI）可能会是致命的.....既往教训告诉我们，即使是经过严格研发、被寄予厚望的药物，也可能因为与其他药物的相互作用而导致严重的后果。1997年，某医药公司推出了一款名为西立伐他汀的他汀类药物，这款药物以其良好的降脂效果迅速赢得了市场的青睐，当年就开出了200多万的处方。然而，好景不长。随着西立伐他汀的广泛使用，全球范围内开始陆续出现因服用该药而产生横纹肌溶解所致的死亡报告。据统计，全球600多万患者中，有52例因药物相互作用而丧生。深入调查揭示，几乎所有横纹肌溶解病例都与另一种降胆固醇药物吉非罗齐的联合使用有关。为了追求更快的降脂效果，医生们将这两种药物同时开给患者，却未料到联合使用会导致西立伐他汀血药浓度激增五倍，最终引发致命反应。这场本为治疗疾病的医疗行为，因药物相互作用而变成了夺命的凶手。对此，该公司于2001年8月决定将西立伐他汀退出市场，这一决定既是对逝去生命的悼念，也是对医疗界的一次警示。当下，新冠药物的使用也日益广泛。然而，在使用新冠药物时，我们必须时刻牢记药物相互作用的风险，确保用药安全有效。01药物–药物相互作用是什么？药物-药物相互作用（Drug-Drug Interaction，简称 DDI）是指联合应用两种或两种以上药物时，由于药代动力学（PK）或药效学（PD）的相互影响，导致药物暴露量、药物疗效或不良反应风险发生改变[1]。常见的相互作用结果有协同和拮抗两种。药物协同作用能增加药物的疗效，加快患者的康复速度；而拮抗作用则降低药物疗效，减慢患者康复速度。合理的药物相互作用可以增强疗效或降低药物不良反应，反之可导致疗效降低或毒性增加，还可能发生一些异常反应，干扰治疗，加重病情，甚至死亡。02新冠药物使用中，当心DDI这个隐形杀手在新冠疫情刚开放管控政策初期，特效药市场需求激增，供不应求。其中就包括一款小分子新冠特效药奈玛特韦/利托那韦[2]，作用机制属于3CL蛋白酶抑制剂。为什么这款药由两种成分构成？奈玛特韦是这种药物组合中的主要抗病毒成分，角色定位是“战士”。它是一种针对SARS-CoV-2主要蛋白酶Mpro（也称为3C-样蛋白酶，3CLpro）的拟肽类抑制剂。通过抑制这种蛋白酶，奈玛特韦阻止病毒处理多蛋白前体，从而阻断病毒复制。然而，奈玛特韦单独使用时存在一个问题：它在体内的代谢速度较快，导致血浆水平可能不足以达到所需的治疗效果。为了解决这个问题，引入了利托那韦。利托那韦在这种药物组合中扮演辅助角色。它本身并不直接作用于新冠病毒，而是一种肝药酶CYP3A4的抑制剂。CYP3A4是人体内一种重要的药物代谢酶，负责代谢多种药物，包括奈玛特韦。利托那韦通过抑制CYP3A4的活性，减缓了奈玛特韦的代谢速度，从而延长了其在血液中的活性时间，提高了其在体内的药物浓度。奈玛特韦和利托那韦的组合，实现了1+1>2的协同作用。奈玛特韦负责抑制病毒的复制，而利托那韦则确保奈玛特韦在体内保持较高的浓度，增强了整体的抗病毒效果。但是，对于同时服用多种药物的患者来说，奈玛特韦和利托那韦的组合可能会带来一些风险。首先，由于利托那韦是CYP3A4酶的强效抑制剂，它会影响许多依赖该酶进行代谢的药物的清除率。奈玛特韦/利托那韦与这些药物合用时，这些药物的血药浓度可能会显著升高，从而导致毒性反应或不良反应的加剧。此外，奈玛特韦/利托那韦还可能与其他类型的药物产生相互作用。例如，与抗凝药物利伐沙班合用时，可能会增加出血风险；与某些降糖药合用时，可能会增加低血糖风险；与某些镇痛药合用时，可能会增强镇痛效果，导致呼吸抑制等严重不良反应。还有一些药物，会降低奈玛特韦和利托那韦的血药浓度，降低疗效。奈玛特韦/利托那韦说明书中明确罗列了禁止联用的药品：•镇痛剂：哌替啶、吡罗昔康、丙氧芬•抗癌药：Neratinib、Venetoclax•心血管类药物：胺碘酮、苄普地尔、决奈达隆、恩卡尼、氟卡尼、普罗帕酮、奎尼丁、雷诺嗪、辛伐/洛伐他汀•抗感染药物：夫西地酸、伏立康唑、利福布汀、利福平•抗组胺药：阿司咪唑、特非那定•抗精神病/精神安定药/镇静/催眠药：鲁拉西酮、氯氮平、匹莫齐特、喹硫平、氯拉卓酸、地西泮、舒乐安定氟西泮、口服咪达唑仑、三唑仑•麦角衍生物：二氢麦角胺、麦角新碱、麦角胺、甲基麦角新碱•PDE5抑制剂：西地/阿伐/伐地那非•其他：阿呋唑嗪、西沙必利、秋水仙碱、圣约翰草、卡马西平、苯巴比妥、苯妥英、鲁玛卡托/依伐卡托除上述药物外，仍有部分药物与奈玛特韦/利托那韦存在相互作用，合并用药需谨慎。在中国，已获批的新冠治疗药物中，除了奈玛特韦/利托那韦组合外，还包括先诺特韦/利托那韦以及阿泰特韦/利托那韦等药物含有利托那韦。那么，是不是所有新冠治疗药物都无一例外地包含了利托那韦，我们别无他选呢？03阿兹夫定，药物相互作用少除了这些包含利托那韦的药物外，还有其他选择，比如阿兹夫定片。阿兹夫定对CYP450酶系中的多个亚型无诱导或抑制作用，因此它能够与多种临床常见药物类型安全联用，包括降血糖药物、抗凝剂、非阿片类镇痛药、抗组胺药、抗菌药、抗高血压药、心血管药以及抑酸类药等。在与这些通过CYP450酶代谢的药物合并使用时，阿兹夫定不会改变它们的全身暴露量，既不会影响其疗效，也不会增加毒性风险。同时，阿兹夫定片是一种高效且独特的RdRp抑制剂，“标本兼治”抗病毒、提免疫[3,4]，为新冠治疗提供了另一种有力武器。具体来讲，阿兹夫定片通过其核苷三磷酸形式精准靶向病毒RdRp，发挥强大的抗病毒作用，这是“标”。“本”是指阿兹夫定及其代谢产物三磷酸盐在人体胸腺和外周血单核细胞中高度富集，这些活性成分在免疫器官进一步激活了关键的免疫细胞——CD4+和CD8+ T细胞，优先清除免疫器官内病毒，促进了宿主免疫系统对新冠病毒的选择性清除能力，强化了人体的免疫防线，实现了从内部对病毒的免疫调节与清除，缩短病程，最大可能避免新冠后遗症的发生。结语在现代医疗实践中，药物治疗是治疗众多疾病不可或缺的一环。然而，随着患者同时使用多种药物的现象日益普遍，药物–药物相互作用的问题也随之凸显。药物–药物相互作用是药物联合使用时可能发生的相互影响，可能导致药物疗效增强、减弱或出现新副作用，甚至危及生命。西立伐他汀与吉非罗齐的联合使用导致的悲剧就是一个典型例子。在新冠治疗中，包含利托那韦的组合药物与其他药物合用不当造成的DDI，不但会导致治疗失败，还可能使药物的毒副反应发生率增高。而阿兹夫定不影响CYP450酶的活性，产生DDI的概率较小，不失为优选药物，值得在临床实践中不断探索和完善其应用。参考文献：1.Sparkes T, Lemonovich TL; AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13510.2.Paxlovid说明书3.Yu, B.; Chang, J. Azvudine (FNC): a promising clinical candidate for COVID-19 treatment. Signal Transduction and Targeted Therapy 2020, 5 (1), 236.4.Zhang JL, et al. Signal Transduct Target Ther. 2021 Dec 6;6(1):414.END声明：此篇文章受众仅为医药、医疗等健康产业专业伙伴，仅供医学药学专业人士使用，不针对普通消费大众。