Inventiva, Inc.

The first patient was randomized in China in the NATiV3 Phase III clinical trial, triggering a milestone payment of $3 million from CTTQ to Inventiva. With this milestone payment Inventiva expects to have met the operational and financial conditions precedent to draw the second €25 million tranche of the EIB loan.1 China’s National Medical Products Administration has granted “Breakthrough Therapy Designation” to lanifibranor for the treatment of NASH. Lanifibranor is believed to be the first drug candidate to receive such designation from both the FDA and the NMPA. As of December 20, 2023, a total of 793 patients have been randomized in NATiV3 of which 657 in the main cohort and 136 in the exploratory cohort. 607 patients are currently in the screening process. The last patient first visit in the NATiV3 Phase III clinical trial is now expected in the first quarter of 2024, and the target number of randomized patients in the main cohort is expected to be reached in the second quarter of 2024. Analysis of the baseline characteristics of all patients randomized in the main cohort suggests a patient profile aligned with those of patients randomized in the NATIVE Phase II clinical trial. Lanifibranor continues to show a favorable tolerability profile as confirmed by the third Data Monitoring Committee2 of November 2023. Topline results of the proof-of-concept Phase II clinical trial, LEGEND, evaluating lanifibranor in combination with empagliflozin are expected in the first quarter of 2024. Inventiva (Euronext Paris and Nasdaq: IVA) (the “Company”), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of non-alcoholic steatohepatitis (“NASH”) and other diseases with significant unmet medical needs, today announced that the first patient has been randomized in China in the global NATiV3 Phase III clinical trial and provided an update on its clinical development program. Following the randomization of the first patient in China, Inventiva is eligible to receive a $3 million milestone payment from Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (“CTTQ”). This would be the second of the two short-term milestone payments following the $2 million milestone payment from CTTQ received on July 19, 2023, under the license and collaboration agreement with CTTQ. Upon the anticipated receipt in January 2024 of this $3 million milestone, Inventiva is expected to have met all financial and operational conditions precedent required to draw the second €25 million tranche under the finance contract with the European Investment Bank (“EIB”) dated May 16, 2022 (the "Finance Contract"). The Company expects to draw this second tranche in early 2024, following the issuance of warrants to the EIB as provided in the Finance Contract. Lanifibranor was granted Breakthrough Therapy Designation for NASH by China’s National Medical Products Administration (NMPA). Similar to the U.S. Food and Drug Administration’s (FDA) Breakthrough Therapy Designation, this designation is intended to accelerate the development and review of drugs for serious or life-threatening conditions. The NMPA granted “Breakthrough Therapy Designation” based on the results of Inventiva's Phase IIb NATIVE clinical trial. Inventiva believes that lanifibranor is the first drug candidate to receive “Breakthrough Therapy Designation” from both the FDA and the NMPA for the treatment of NASH. Frederic Cren, CEO and co-founder of Inventiva said: ”While we are not reaching the first visit of the last patient by the end of 2023 as previously projected, the improvements in the randomization, screening numbers and screen failure rate give us confidence that we can reach this milestone in the first quarter of 2024. The recommendation of our third Data Monitoring Committee (DMC) in November 20242 to continue the trial without modification to the protocol is further confirmation of the good safety profile of lanifibranor. Furthermore, we have high hopes that the results of the LEGEND trial will show benefit of the combination of lanifibranor with empagliflozin in patients with NASH.” As of December 20, 2023, 468 clinical sites have been activated in 24 countries, including China, and a total of 793 patients have been randomized, of which 657 in the main cohort and 136 in the exploratory cohort. 607 patients are in the screening process and, based on the recent screen failure rate of approximately 80%, Inventiva expects 121 additional patients to be randomized in the main cohort in the next 10 weeks. Since July, with limited contribution from the sites in China, the newly opened sites and a third party clinical network in Mexico, between 250 to 300 patients are screened and approximately 50 patients are randomized in the main cohort each month, and the monthly enrolment rate is averaging 0.14 patient/site/month in the main cohort. Therefore, if the current screen failure rate for the main cohort and the number of patients entering the screening process are maintained, Inventiva now expects the first visit of the last patient to be in the first quarter of 2024 and to complete randomization in the second quarter of 2024. Topline results for the Phase III NATiV3 clinical trial are now expected to be published in the first half of 2026 versus the second half of 2025, as previously communicated. If the results of the trial confirm sufficient clinical benefit and a continued good safety profile, Inventiva plans to submit an application for accelerated approval in the United States and conditional approval in the European Union for the marketing of lanifibranor. In addition, CTTQ would also be in capacity to submit an application for a marketing authorization in Greater China. Approximately 70% of the patients randomized in the main and exploratory cohorts are from the United States, ~20% from Europe and ~10% from Latin America and the rest of the world. At baseline, 13% of patients randomized in the main cohort are receiving a stable dose GLP1 receptor agonists and 8% are receiving stable SGLT2 inhibitors. The baseline characteristics of the patients enrolled so far in the main cohort are in line with expectations and the patient population in the NATIVE Phase IIb clinical trial. The main difference in patient characteristics observed thus far is that there is a higher percentage of patients with type 2 diabetes (T2D) in the main cohort of the NATiV3 Phase III trial compared to the NATIVE Phase IIb trial (55% vs 42%, respectively). The effect size of lanifibranor therapy over placebo in the Phase IIb clinical trial on the composite endpoint “NASH resolution and fibrosis improvement” (which corresponds to the primary efficacy endpoint in the NATiV3 Phase III clinical trial), was higher in patients with T2D than in patients without diabetes: 21% and 26% for lanifibranor 800 and 1200 mg/day, respectively, in patients with T2D compared to 7% and 22%, respectively, in patients without T2D. Given the higher risk of hepatic and extrahepatic morbidity in patients with T2D and NASH3, the higher effect size observed in patients with NASH and T2D treated with lanifibranor in the Phase IIb trial is an important result for this specific patient population if confirmed in the larger clinical trial. As of December 20, 2023, 136 patients are randomised in the exploratory cohort including approximately 30% of patients with fibrosis stage F4. Inventiva believes that this subgroup of patients will provide valuable data on lanifibranor efficacy and safety. Lanifibranor continues to show a favorable tolerability profile as confirmed by the third Data Monitoring Committee (DMC) that took place late November 20232. This safety assessment was based on the review of safety data from more than 500 patients, including patients that have been treated with lanifibranor for more than 72 weeks. Enrolment in the proof of concept, LEGEND Phase II clinical trial evaluating lanifibranor in combination with the SGLT2 inhibitor empagliflozin in patients with NASH has been stopped, and data collection and cleaning is ongoing. The first topline results on primary and secondary endpoints are expected for the end of the first quarter of 2024. The primary efficacy endpoint of the trial is a change in Hemoglobin A1c (“HbA1c”) at the end of the 24-week treatment compared to baseline. Secondary endpoints include changes in liver enzymes, glycaemic and lipids parameters, and inflammatory markers. The trial has been designed to provide valuable information on body weight evolution in patients with NASH and T2D when treated with lanifibranor and empagliflozin, and on the reduction of hepatic steatosis using magnetic resonance imaging (MRI). Lanifibranor, Inventiva’s lead product candidate, is an orally-available small molecule that acts to induce antifibrotic, anti-inflammatory and beneficial vascular and metabolic changes in the body by activating all three peroxisome proliferator-activated receptor (“PPAR”) isoforms, which are well-characterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that is designed to target all three PPAR isoforms in a moderately potent manner, with a well-balanced activation of PPARα and PPARδ, and a partial activation of PPARγ. While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only pan-PPAR agonist in clinical development for the treatment of NASH. Inventiva believes that lanifibranor’s moderate and balanced pan-PPAR binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and pre-clinical studies to date. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor for the treatment of NASH. NATiV3 is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the long-term efficacy and safety of lanifibranor (800mg/daily and 1200mg/daily) in adult patients with biopsy-proven non-cirrhotic NASH and F2/F3 stage of liver fibrosis. The trial takes place in 24 countries and in more than 400 clinical sites and to recruit approximately 900 patients to be treated over a 72-week period. The effect of lanifibranor will be assessed on several histological endpoints, including NASH resolution and improvement of fibrosis of at least one stage. An exploratory cohort is anticipated to enrol approximately 200 patients with NASH and fibrosis screen-failed on histology for the main NATiV3 clinical trial. Inventiva anticipates that this exploratory cohort may allow the generation of additional data using non-invasive tests and contribute to the regulatory safety database requirement to support the planned submission for potential accelerated approval to the Food and Drug Administration (FDA) and potential conditional approval to the European Medicines Agency (EMA) of lanifibranor for the treatment of NASH. Topline results of NATiV3 are expected for the half 2026. For more information about NATiV3, visit clinicaltrials.gov. Inventiva is a clinical-stage biopharmaceutical company focused on the research and development of oral small molecule therapies for the treatment of patients with NASH, mucopolysaccharidoses (“MPS”) and other diseases with significant unmet medical need. The Company benefits from a strong expertise and experience in the domain of compounds targeting nuclear receptors, transcription factors and epigenetic modulation. Inventiva is currently advancing one clinical candidate, has a pipeline of two preclinical programs and continues to explore other development opportunities to add to its pipeline. Inventiva’s lead product candidate, lanifibranor, is currently in a pivotal Phase III clinical trial, NATiV3, for the treatment of adult patients with NASH, a common and progressive chronic liver disease for which there are currently no approved therapies. Inventiva’s pipeline also includes odiparcil, a drug candidate for the treatment of adult MPS VI patients. As part of Inventiva’s decision to focus clinical efforts on the development of lanifibranor, it suspended its clinical efforts relating to odiparcil and is reviewing available options with respect to its potential further development. Inventiva is also in the process of selecting an oncology development candidate for its Hippo signalling pathway program. The Company has a scientific team of approximately 90 people with deep expertise in the fields of biology, medicinal and computational chemistry, pharmacokinetics and pharmacology, and clinical development. It owns an extensive library of approximately 240,000 pharmacologically relevant molecules, approximately 60% of which are proprietary, as well as a wholly-owned research and development facility. 1 The disbursement of the second tranche of €25 million is subject to, among other conditions, (i) the Company issuing warrants to EIB in accordance with the terms and conditions of the warrant agreements entered into July 1, 2022 in connection with the EIB credit facility, (ii) the receipt by the Company from the date of the EIB credit facility of an aggregate amount of at least €70.0 million (as of today, the Company has received 68.5 million of euros, which includes the August 2023 financing, the Hepalys upfront payment of $10.0 million and the €18.0 million that was a condition for the disbursement of the first tranche of the EIB loan), paid either in exchange for Company shares, or through upfront or milestone payments; and (iii) operational conditions, including criteria based on patient enrolment and number of sites activated in the Company’s NATiV3 Phase III clinical trial of lanifibranor in patients with NASH a condition that the Company believes it has met in December 2023. 2 Inventiva-PR-3rd-DMC-NATiV3-EN-12-04-2023.pdf (inventivapharma.com) 3 Kenneth Cusi; Time to Include Nonalcoholic Steatohepatitis in the Management of Patients With Type 2 Diabetes. Diabetes Care 1 February 2020; 43 (2): 275–279. https://doi.org/10.2337/dci19-0064 The content above comes from the network. if any infringement, please contact us to modify.

Hepalys Pharma, Inc. is a new company created by Catalys Pacific and in which Inventiva has a 30% ownership position. Under the exclusive licensing agreement, Inventiva will receive a $10 million upfront payment, and is eligible to receive up to $ 231 million in clinical, regulatory and commercial milestone payments in addition to tiered royalties from mid double digits to low twenties based on net sales of lanifibranor in Japan and South Korea. Pending regulatory approvals, Hepalys Pharma, Inc. is expected to initiate Phase I PKPD studies in Japanese patients and healthy volunteers and will be responsible for funding all studies of lanifibranor necessary to file for a new drug application in Japan and South Korea. In addition to the 30% of shares of Hepalys Pharma, Inc., Inventiva already owns, Inventiva has the option to acquire all outstanding shares of Hepalys Pharma, Inc., at a pre-agreed multiple of post-money valuation. In the event Hepalys receives an offer to sell the license or rights related to lanifibranor, Inventiva has a right of first refusal. Inventiva (Euronext Paris and Nasdaq: IVA), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of non-alcoholic steatohepatitis (NASH) and other diseases with significant unmet medical needs, and Hepalys Pharma, Inc., a company incorporated in Japan and incubated by Catalys Pacific, have entered into an exclusive licensing agreement (the “Agreement”) to develop and commercialize Inventiva’s proprietary drug candidate lanifibranor for the treatment of non-alcoholic steatohepatitis (NASH) in Japan and South Korea. Hepalys Pharma is a new company founded by Catalys Pacific, an investment firm specialized in creating and financing venture capital-backed biopharmaceutical companies to develop pharmaceutical products in Asia. Hepalys Pharma is backed by renowned investors including Catalys Pacific, Mitsubishi UFJ Capital, DBJ Capital, and MEDIPAL Innovation Fund. In parallel of the incorporation of Hepalys Pharma, Inventiva has exercised its right to own 30% of the company. Under the terms of this licensing agreement, Inventiva will receive a $10 million upfront payment from Hepalys Pharma and will be eligible to receive up to $231 million in milestone payments if certain clinical, regulatory and commercial conditions are met. Subject to regulatory approval, Inventiva has the right to receive tiered royalties from mid double digits to low twenties based on net sales of lanifibranor in Japan and South Korea. In addition, under the terms of this agreement, Inventiva has the option to acquire the outstanding shares of Hepalys Pharma at a pre-agreed multiple of post-money valuation under certain conditions, and has a right of first refusal if Hepalys Pharma, Inc. receives an offer to sell the license and rights related to lanifibranor. This agreement is expected to accelerate the time to market of lanifibranor in Japan and South Korea if regulatory approvals are obtained. Both countries are major markets, with up to 2.7%1 of and up to 5.2%2 of Japanese and South Koreans, respectively, suffering from NASH, including about 15% of South Korean patients with significant fibrosis. Hepalys Pharma, Inc. is expected to start the clinical development of lanifibranor by conducting two phase I studies in Japanese patients and healthy volunteers. It is anticipated that these studies would support, if positive, the initiation of a dedicated pivotal trial in Japanese and Korean patients with NASH, which is planned to start once the results of NATiV3, the pivotal phase III trial currently conducted by Inventiva, are available. Hepalys Pharma, Inc. will be responsible for conducting and financing all development trials in Japan and South Korea needed to file for a new drug application in these territories. Frederic Cren, CEO and cofounder of Inventiva, stated: “We are thrilled to further expand our global reach to Japan and South Korea through this exclusive licensing agreement with Hepalys Pharma, Inc. We strongly believe that Hepalys Pharma, Inc. with its experienced team is the right partner to start and fund the clinical development of lanifibranor in Japan and South Korea. This agreement is a great opportunity for Inventiva to speed up the potential commercialization of its lead asset in these two major markets and diversify our milestones and royalties’ source of revenues if regulatory approvals are achieved. With the ongoing partnership in Greater China and this new agreement in Japan and Korea, Inventiva is eligible to receive up to an additional $519M of clinical, regulatory and commercial milestones. BT Slingsby, MD, PhD, MPH, Representative Director of Hepalys Pharma, Inc., stated: “We are delighted to enter into a licensing agreement with Inventiva. We purposely founded Hepalys Pharma, Inc. to conduct the clinical development and potential commercialization of lanifibranor, a drug candidate for the potential treatment of NASH in Japan and Korea. We are confident that, if successful in our clinical programs and if required regulatory approvals are obtained, lanifibranor could potentially become an effective treatment for patients with NASH in Japan and South Korea based on the efficacy demonstrated so far on fibrosis and NASH resolution, and on the cardiometabolic components of the disease. We are looking forward to starting the clinical development program of lanifibranor in Japan and South Korea.” About Hepalys Pharma, Inc. Hepalys Pharma, Inc. is a private venture-backed biopharmaceutical company focused on the development of novel therapeutics for liver disease, led by a world-class team and a transpacific clinical advisory board, committed to develop and commercialize lanifibranor and potentially other compounds for patients in Asian countries. Hepalys is headquartered in Tokyo, Japan. About Catalys Pacific Catalys Pacific is a life sciences venture capital firm whose mission is to provide healthcare solutions for patients worldwide through the creation of, and investment in biotech companies. Catalys Pacific is led by a global team versed in working closely with its partners in academia, biotech, venture capital and the pharmaceutical industry worldwide with an emphasis in Japan. The firm maintains offices in Tokyo, Japan and in San Francisco, California. About lanifibranor Lanifibranor, Inventiva’s lead product candidate, is an orally-available small molecule that acts to induce anti-fibrotic, anti-inflammatory and beneficial vascular and metabolic changes in the body by activating all three peroxisome proliferator-activated receptor (PPAR) isoforms, which are well-characterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that is designed to target all three PPAR isoforms in a moderately potent manner, with a well-balanced activation of PPARα and PPARδ, and a partial activation of PPARγ. While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only pan-PPAR agonist in clinical development for the treatment of NASH. Inventiva believes that lanifibranor’s moderate and balanced pan-PPAR binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and pre-clinical studies to date. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor for the treatment of NASH. About Inventiva Inventiva is a clinical-stage biopharmaceutical company focused on the research and development of oral small molecule therapies for the treatment of patients with NASH (also known as metabolic dysfunction-associated steatohepatitis (MASH)), mucopolysaccharidoses (“MPS”) and other diseases with significant unmet medical need. The Company benefits from a strong expertise and experience in the domain of compounds targeting nuclear receptors, transcription factors and epigenetic modulation. Inventiva is currently advancing one clinical candidate, has a pipeline of two preclinical programs and continues to explore other development opportunities to add to its pipeline. Inventiva’s lead product candidate, lanifibranor, is currently in a pivotal Phase III clinical trial, NATiV3, for the treatment of adult patients with NASH, a common and progressive chronic liver disease for which there are currently no approved therapies. Inventiva’s pipeline also includes odiparcil, a drug candidate for the treatment of adult MPS VI patients. As part of Inventiva’s decision to focus clinical efforts on the development of lanifibranor, it suspended its clinical efforts relating to odiparcil and is reviewing available options with respect to its potential further development. Inventiva is also in the process of selecting an oncology development candidate for its Hippo signaling pathway program. The Company has a scientific team of approximately 90 people with deep expertise in the fields of biology, medicinal and computational chemistry, pharmacokinetics and pharmacology, and clinical development. It owns an extensive library of approximately 240,000 pharmacologically relevant molecules, approximately 60% of which are proprietary, as well as a wholly-owned research and development facility. Inventiva is a public company listed on compartment B of the regulated market of Euronext Paris (ticker: IVA, ISIN: FR0013233012) and on the Nasdaq Global Market in the United States (ticker: IVA). www.inventivapharma.com 1Eguchi Y, Wong G, Lee EI, Akhtar O, Lopes R, Sumida Y. Epidemiology of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: A focused literature review. JGH Open. 2020 May 5;4(5):808-817. 2Park J, Lee EY, Li J, Jun MJ, Yoon E, Ahn SB, Liu C, Yang H, Rui F, Zou B, Henry L, Lee DH, Jun DW, Cheung RC, Nguyen MH. NASH/Liver Fibrosis Prevalence and Incidence of Nonliver Comorbidities among People with NAFLD and Incidence of NAFLD by Metabolic Comorbidities: Lessons from South Korea. Dig Dis. 2021;39(6):634-645. The content above comes from the network. if any infringement, please contact us to modify.

NASH（非酒精性脂肪肝炎）治疗领域又传来好消息。近日，89bio公布其用于治疗NASH的在研药物pegozafermin，在一项临床IIb试验中获得积极结果。Pegozafermin是一款成纤维细胞生长因子21（FGF21）类似物，拟开发用于治疗NASH与严重性高甘油三酯血症。 在公布的这项多中心、随机双盲、安慰剂为对照的IIb期临床试验中，共192例NASH患者纳入研究，结果显示，分别有27%与26%接受每两周一次44mg与每周一次30mg pegozafermin治疗的患者达成至少一个阶段的纤维化改善且NASH症状无恶化，是安慰剂组（7%）的3.5倍。此外，分别有26%与23%接受每两周一次44mg与每周一次30mg pegozafermin治疗的患者达成NASH症状清除且没有纤维化恶化，这是安慰剂组患者（2%）的12-14倍。 这些积极数据为NASH新药研发带来了一丝希望的曙光。事实上，自1980年NASH这一疾病被提出以来，针对NASH的药物研发已经开展了40多年，但鲜有成果。除了印度批准上市的PPARα/γ双重激动剂Saroglitazar，其他地区还没有一款NASH药物获批上市。 那么NASH药物研发为何这么难？如今又取得了哪些进展？ 致病机理扑朔迷离、试水公司屡变心碎玩家 NASH是一种由非酒精性脂肪肝（NAFLD）进展而来的严重慢性肝脏疾病。根据流行病学调查，全球的NAFLD患病率约为25%，其中10%-30%最终会发展为NASH。据全球肝脏研究所数据显示，预计到2030年，全球将有3.57亿人的生活受到NASH的影响，其中美国NASH患者人数约为1500万-3000万，中国约有5000万NASH患者。 据弗若斯特沙利文预测，到2025年全球NASH药物市场将达到107亿美元，并于2030年达到322亿美元，期间复合年增长率为41.8%和24.6%。 由于市场空间极为庞大，NASH药物素来是全球新药研发领域的热门方向，吸引了吉利德、诺华、辉瑞等一众MNC的布局，但都纷纷折戟。 2019年4月，吉利德旗下ASK1抑制剂Selonsertib因在III期临床试验中错过一级终点和未达到预定48周临床终点而终止临床试验；2019年6月，诺华宣布其FXR激动剂emricasan治疗NASH的IIb期研究未能达到主要终点，进而停止患者治疗；2020年10月，辉瑞因旗下ACC1/2双重抑制剂PF-05221304存在安全性风险，宣布砍掉该临床管线；2021年11月，BMS报告了一项NASH资产的中期失败，目前该资产已被搁置。2023年2月，默沙东宣布决定终止MK-3655（NGM313）治疗NASH的IIb期研究。 造成这一切的根本原因在于NASH的病因非常复杂，涉及多条通路，多个靶点，多种细胞交叉相互作用。其风险因素包括胰岛素抵抗、氧化应激、激素失调、慢性炎症、纤维化、免疫因素等。 除了发病机理复杂外，NASH药物研发还缺乏临床转化的动物肝纤维化模型，而且FDA还严格规定了NASH药物III期临床试验的替代终点，即必须采用肝组织穿刺病理学评价脂肪肝炎和纤维化程度的改善情况，不能用影像学、血清学评价作为上市审批的主要终点。种种因素使得NASH领域一度被认为是制药界的研发“黑洞”。 可以说，NASH药物的研发如同在一片迷雾中前行。不过，在这片迷雾中，研究者们还是找到了一丝方向。 NASH在病理生理学层面比较广为接受的成因是“二次打击”假说，即第一次“打击”是肝脏中脂类的过度沉积和其所带来的胰岛素抵抗，第二次“打击”是在第一次基础上多种细胞因子或炎症因子介导的脂肪酸过氧化所导致的炎症和氧化应激反应，最终导致NASH。 目前多数药物开发基于“二次打击”框架，针对这条路径上的不同环节进行药物靶点选择，主要集中于四类靶点：代谢类靶点，如改善胰岛素敏感性、抑制脂肪生成各种酶、改善线粒体对脂肪酸摄取等；炎症类靶点，如抑制炎性细胞招募、阻断炎性信号传导等；消化类靶点：如调节肝肠轴循环、改善胆汁酸循环等；纤维化类靶点：如减少肝脏中胶原沉积、增强纤维分解等。 新靶点带来新希望 现阶段，围绕NASH的研究主要集中在靶向代谢、炎症及纤维化等多个潜在靶点上。 FXR 法尼醇X受体（FXR）是近年来NASH研究的一个热门靶点。它是一种核受体，主要在肝脏、肠道、肾脏中表达。FXR靶基因包括多个胆汁酸代谢/转运相关基因、脂质代谢相关基因以及糖代谢相关基因等，在NAFLD/NASH发生、进展和消退中起关键作用。 目前全球已有十余款针对NASH的FXR激动剂进入临床开发，其中美国Intercept制药公司的奥贝胆酸（Obeticholic acid，OCA）进展最快。它是一款胆汁酸类似物，于2016年5月获FDA批准治疗原发性胆汁性胆管炎。2019年，Intercept基于III期REGENERATEA研究的第一次中期分析结果向FDA提交了奥贝胆酸拓展适应症用于NASH的申请。但由于组织学终点数据带来的获益仍具有不确定性，2020年，FDA给予该申请完整回复信（CRL），要求其补充更多数据。 2023年1月，基于REGENERATEA研究的第二次中期分析数据，Intercept再次提交奥贝胆酸用于NASH的适应症申请。Intercept曾在去年7月公布了REGENERATEA研究中第一个主要终点的第二次中期分析数据，结果显示，接受奥贝胆酸（25mg，每日1次）治疗18个月时有22.4%的患者实现了纤维化程度至少改善1级且未出现NASH恶化，而安慰剂组达到该指标的患者只有9.6%（p<0.0001）。目前，研究仍在继续，以搜集另一个主要终点全因死亡率和肝脏相关临床数据。FDA预计将在今年6月22日之前做出审评决定。 在NASH适应症上，国内研发进度较快的FXR激动剂有拓臻生物的TERN-101和雅创医药的HPG-1860。 THR 甲状腺激素(THs)对许多生理过程产生显著影响，例如生长、发育和新陈代谢。缺乏甲状腺激素会引发多种疾病。大多数TH效应由两种不同的甲状腺激素受体(THR)亚型介导，即THR-α和THR-β，其中THR-β亚型负责TH对肝脏的有益作用。 THR-β激动剂可通过促进脂肪酸的分解和改善线粒体功能来降低肝脏脂肪含量，改善肝功能。在NASH患者的肝脏中，THR-β活性水平降低，因此THR-β激动剂是治疗NASH的潜在治疗手段之一。 Resmetirom是THR-β激动剂的代表产品，由Madrigal公司研发，是目前研发进展最快的一款THR-β激动剂。Resmetirom在一项III期临床试验MAESTRO-NASH中已获得积极的安全性数据。MAESTRO-NASH是一项双盲、随机、安慰剂对照研究，其临床结果完全采用了肝活检的金标准。 在为期52周的连续肝活检研究中，950多例晚期肝纤维化（F2期和F3期）NASH患者接受了resmetirom治疗，与安慰剂相比，每日口服80 mg和100 mg剂量的resmetirom既达到了治疗一年后NASH缓解的主要终点，也达到了降低低密度脂蛋白胆固醇的次要终点。安全性方面两种剂量均耐受良好。 目前来看，resmetirom距离上市仅一步之遥。这是近年来NASH药物研发领域久违的好消息，在Madrigal公布这一临床数据后，公司股价飙升，单日暴涨268%。 PPAR 过氧化物酶体增殖物激活受体（PPAR）是一类由配体激活的核转录因子，包括PPARα、PPARβ/δ和PPARγ三种亚型。PPARα在肝脏中高表达，它的激活可降低甘油三酯水平并参与能量稳态调节；PPARβ/δ和PPARγ参与巨噬细胞的功能调控，激活后可使巨噬细胞由M1（促炎）表型向M2（抗炎）表型转化，从而减轻肝脏炎症。 针对NASH，PPARα/γ双重激动剂Saroglitazar已在印度获批上市，这是全球第一个获批用于治疗非肝硬化性NASH的药物。 其他进展较快的药物有Inventiva研发的PPAR α/γ/δ泛激动剂——Lanifibranor。目前，Lanifibranor已在II期临床研究中达到主要和次要终点，即NASH 缓解而纤维化不恶化，肝脏纤维化改善而NASH不恶化。这一积极结果支持Lanifibranor进入关键的III期临床研究。 FGF21 成纤维细胞生长因子21（FGF21）是一种内源性代谢激素，可调节能量消耗以及葡萄糖和脂质代谢，主要在肝脏、脂肪组织等中表达，在肝脏内起到调控生酮、糖异生、脂肪酸氧化等作用，在脂肪组织内起到调控血糖摄取、脂类代谢、PPAR-γ活性等作用。 目前，除了89bio公司的Pegozafermin外，FGF-21类似物还有Efruxifermin，这是一款由Akero公司开发，基于人体免疫球蛋白G1的Fc片段与FGF21融合多肽的长效FGF21类似物。在去年9月公布的一项IIb期临床试验中，efruxifermin 28mg和50mg剂量组均达到了改善肝脏纤维化的主要终点以及多个次要终点。 除了以上靶点外，在NASH领域还有GLP-1R、GCGR、FASN、ACC等靶点在研，还有不少联合用药的研究正在开展。作为一种慢性代谢性疾病，NASH的发病周期长、致病机理复杂、药物开发困难。尽管如此，NASH赛道的热度从未褪去。在经历了全球医药行业多年的投入以及一个个候选药物的黯然退场后，目前制药界已在释放积极信号，NASH新药研发很可能已经到了产生突破性进展的前夕。未来，这片蓝海市场的竞争程度无疑将更加激烈。 参考资料 1.89bio’s Phase 2b ENLIVEN Trial of Pegozafermin in Nonalcoholic Steatohepatitis (NASH) Achieved High Statistical Significance on Both Primary Histology Endpoints with Weekly (QW) and Every-Two-Week (Q2W) Dosing at 24 Weeks. 2.《非酒精性脂肪性肝炎(NASH)深度行研报告》，西南证券，2022-08-31. 3. FDA accepts intercept’s new drug application for the treatment of pre-cirrhotic liver fibrosis due to NASH. Retrieved January 19, 2023. 4.《FXR激动剂在非酒精性脂肪性肝炎治疗中的应用》，临床肝胆病杂志，2022-07-13. 5. Madrigal Announces Additional Positive Results from the Pivotal Phase 3 MAESTRO-NASH Clinical Trial of Resmetirom for the Treatment of NASH with Liver Fibrosis，Retrieved January 9th, 2023. 6. Akero treatment for NASH reduces liver scarring, achieves goals of mid-stage study. Retrieved September 13, 2022. 7.《NASH药物，百亿市场下一城》，西南证券，2022-10-09. 8.《NASH领域研发再获重磅进展，国内药企紧随海外龙头之后》，民生证券，2022-11-07.