PPARα

近日，Inventiva公司宣布，小分子泛PPAR激动剂lanifibranor联用SGLT2抑制剂恩格列净（empagliflozin）治疗代谢功能障碍相关性脂肪性肝炎（MASH）/非酒精性脂肪性肝炎（NASH）和控制不佳的2型糖尿病（T2D）患者的2期概念验证试验LEGEND取得了良好的中期分析结果，达到了主要疗效终点。 此次公布结果的LEGEND试验是一项多中心、随机、安慰剂对照的2期概念验证试验，治疗周期为24周。非肝硬化MASH/NASH的诊断基于既往组织学评估或非侵入性方法（包括影像学检查）的组合。按照方案的计划，63名随机患者中有一半完成24周的治疗期或过早停止治疗后进行中期分析。 中期分析结果显示，与安慰剂组相比，lanifibranor治疗组和lanifibranor联用恩格列净治疗组的糖化血红蛋白水平（HbA1c）水平显著下降，达到了主要疗效终点。 此外，几种肝损伤指标、葡萄糖和脂质代谢指标以及肝脂肪变性指标也具有统计学意义的改善。 在为期24周的研究中，接受lanifibranor联合恩格列净治疗的患者体重保持稳定，可能解决了在一些接受lanifibranor治疗的患者中观察到的体重增加和代谢方面的问题。此外，lanifibranor单药和lanifibranor联用恩格列净可显著降低患者腹部内脏脂肪（VAT）与皮下脂肪（SAT）的比率，这反映了促炎症内脏脂肪向代谢健康脂肪组织的转变。 安全性方面，患者接受lanifibranor 800 mg每天一次单药或联用恩格列净治疗24周的耐受性良好，无安全问题报告。 Lanifibranor是一种口服小分子泛PPAR激动剂，它对PPARα和PPARδ产生均衡的激活，并且能够部分激活PPARγ，诱导体内抗纤维化、抗炎症反应，和有益的血管和代谢变化。Inventiva认为lanifibranor适度且平衡的泛PPAR结合特征有助于实现在临床试验和临床前研究中观察到的良好耐受性特征。2020年10月，lanifibranor获得了美国FDA授予的突破性疗法认定，用于治疗NASH/MASH。 参考资料：[1] Inventiva announces positive results from the Phase II, LEGEND, Proof-of-Concept study combining lanifibranor with empagliflozin in patients with MASH/NASH and T2D. Retrieved March 19, 2024, from https://www.globenewswire.com/news-release/2024/03/18/2848135/0/en/Inventiva-announces-positive-results-from-the-Phase-II-LEGEND-Proof-of-Concept-study-combining-lanifibranor-with-empagliflozin-in-patients-with-MASH-NASH-and-T2D.html 内容来源于网络，如有侵权，请联系删除。

LEGEND achieved its primary efficacy endpoint by significantly lowering HbA1c level in both the lanifibranor arm and in the lanifibranor with empagliflozin arm compared to placebo. Statistical significance was also achieved on several markers of liver injury, markers of glucose and lipid metabolism, as well as hepatic steatosis. Patients treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24 weeks study, addressing the moderate, metabolically healthy, weight gain that has been observed in some patients treated with lanifibranor. Treatment with lanifibranor alone and in combination with empagliflozin decreased the ratio of visceral abdominal fat to subcutaneous fat, reflecting a shift from pro-inflammatory visceral fat towards metabolically healthy adipose tissue. The treatment with lanifibranor 800mg/once daily alone or in combination with empagliflozin for 24 weeks was well tolerated, with no safety concerns reported. Inventiva will host an investor webcast Tuesday, March 19th at 8am ET (details below). March 18, 2024 – Inventiva (Euronext Paris and Nasdaq: IVA), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), and other diseases with significant unmet medical needs, today announces positive results of its interim analysis of the Phase II, Proof-of-Concept clinical trial, LEGEND, evaluating lanifibranor in combination with empagliflozin in patients with MASH/NASH and poorly controlled Type 2 Diabetes (T2D). The LEGEND trial has been designed as a multi-center, randomized, 24-week treatment, placebo-controlled Phase II Proof-of-Concept trial to assess the safety and efficacy of lanifibranor in combination with the SGLT2 inhibitor empagliflozin for the treatment of patients with non-cirrhotic MASH/NASH and T2D. The trial is double-blind for the placebo arm and lanifibranor (800mg daily) arm, and open-label for the combination of lanifibranor (800mg daily) and empagliflozin (10 mg daily) arm. The diagnosis of non-cirrhotic MASH/NASH was based on historic histology evaluation or a combination of non-invasive methods including diagnostic methods including imaging. As planned per protocol, the interim analysis was done once half of the 63 planned randomized patients with MASH completed the 24-week treatment period or prematurely discontinued from treatment. The study achieved the primary efficacy endpoint with an absolute reduction in Hemoglobin A1c (HbA1c) of 1.14% and 1.59% in patients with MASH and T2D treated with lanifibranor (800mg daily) or in combination with empagliflozin (10mg daily) at week 24 compared to an increase of 0.26% observed in the placebo arm. The study also demonstrated a statistically significant reduction in hepatic steatosis measured by MRI-PDFF1, in patients treated with lanifibranor alone and in combination with empagliflozin, -47% and -38% respectively, compared to placebo (0%). 83% and 67% of patients treated with lanifibranor alone or in combination with empagliflozin respectively, showed a reduction greater or equal to 30% of their hepatic fat, compared to 0% in the placebo arm. In addition, the study demonstrated a statistically significant effect on several secondary and exploratory endpoints, including liver enzymes (alanine aminotransferase (“ALT”) and aspartate aminotransferase (“AST”)), insulin resistance (HOMA-IR), HDL, and adiponectin (see tables below). Markers of liver inflammation and fibrosis (corrected T1 relaxation time (cT1) assessed by LiverMultiScan®) were assessed for the first time with lanifibranor and showed a significant effect with lanifibranor alone and in combination with empagliflozin. The study also demonstrated that patients treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24 weeks study, addressing the moderate, metabolically healthy, weight gain that can be observed in some patients treated with lanifibranor alone. Furthermore, these results demonstrated a significant relative reduction in the VAT/SAT ratio (visceral and subcutaneous adipose tissue) in patients treated with lanifibranor alone or in combination with empagliflozin, -5% and -17% respectively, compared to an increase of 11% in patients under placebo. This result reflects a shift from pro-inflammatory visceral fat towards metabolically healthy adipose tissue. The treatment with lanifibranor 800mg/daily alone and in combination with empagliflozin 10mg/daily for 24 weeks appears to be well tolerated, with no safety concerns reported. Dr. Michael Cooreman, M.D., Chief Medical Officer of Inventiva: “The results of the LEGEND study announced today further illustrate the potential of lanifibranor to address the broad spectrum of the disease biology of MASH and T2D. These data complement the already published dataset of lanifibranor demonstrating fibrosis improvement and MASH resolution but also its role as a potent insulin sensitizer. With roughly 50% of the U.S. population estimated to have either prediabetes or diabetes, and the well-established correlation between MASH and T2D, lanifibranor has a unique mechanism of action to potentially address the medical need of patients with both MASH and T2D. We wish to thank the patients who participated in the study and the investigators of LEGEND.” Dr. Onno Holleboom, MD PhD, endocrinologist and associate professor at Amsterdam UMC, co-principal investigator of the LEGEND Phase II clinical trial: “It is a big step seeing these positive results of LEGEND demonstrating the impact of lanifibranor on steatosis, inflammation and fibrosis while stabilizing weight with empagliflozin in patients with poorly controlled T2D and MASH. The study was designed as a proof of concept and these results are significant and strengthen confidence in the potential of lanifibranor to address the specific metabolic unbalance in patients with T2D while also addressing steatosis and fibrosis, a hepatic consequence of insulin resistance.” Prof. Michelle Lai, M.D., Ph.D., Beth Israel Deaconess Medical Center and co-principal investigator of the LEGEND Phase II clinical trial, said: “These LEGEND results provide valuable insights on the complementary mechanisms of action of an SGLT2 inhibitor and the panPPAR agonist, lanifibranor. MASH is a multifaceted disease that we believe will benefit from combination therapies in order to properly address the full cardiometabolic spectrum of the disease. These results of LEGEND suggest that lanifibranor in combination with empagliflozin could be an ideal combination for patients we care for in our clinic who suffer from T2D and MASH.” Given that the primary endpoint of LEGEND was met, and statistically significant results were achieved on several key additional markers, the Company has decided to stop the recruitment as defined per protocol. More details on these results are expected to be presented in upcoming scientific conferences and submitted for publication. Conference call Inventiva will host a conference call and webcast with slide presentation on Tuesday, March 19, 2024 at 8:00 am ET (New York time) 1:00 pm CET (Paris time). Introduced by Frederic Cren, Chairman, CEO and cofounder of Inventiva, this event will be as follow: Presentation of LEGEND Results - Michael Cooreman, M.D., CMO of Inventiva Metabolic and hepatic benefits of lanifibranor - Stephen Harrison, M.D., Pinnacle Clinical Research and principal investigator of the exploratory cohort of NATiV3, Phase III clinical trial Vascular benefits of lanifibranor - Sven Francque, M.D., University Hospital Antwerp, co-principal investigator of NATiV3, Phase III clinical trial Opportunity for lanifibranor - Frederic Cren, CEO and cofounder of Inventiva The conference call and the slides of the presentation will be webcast live at: https://edge.media-server.com/mmc/p/hyuvxf9a and will also be available on Inventiva’s website: Investor Presentations - Inventiva Pharma. In order to receive the conference access information necessary to participate to the conference call, it is required to register in advance using the following link: https://register.vevent.com/register/BI334d62953abb41cea27de99dc5da974c . Participants will need to use the conference access information provided in the e-mail received at the point of registering (dial-in number and access code). 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 ‑wellbalanced‑ 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 panPPAR‑ agonist in clinical development for the treatment of MASH/NASH. Inventiva believes that lanifibranor’s moderate and balanced panPPAR‑ binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and preclinical studies to date. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor‑ for the treatment of MASH/NASH. Inventiva is a clinical-stage biopharmaceutical company focused on the research and development of oral small molecule therapies for the treatment of patients with MASH/NASH, 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 MASH/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 a 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 The content above comes from the network. if any infringement, please contact us to modify.

▎药明康德内容团队编辑3月18日，微芯生物宣布，西格列他钠单药治疗非酒精性脂肪性肝炎（NASH）的2期临床研究（CGZ203研究）已完成数据清理并锁库，试验首要疗效终点达成，进一步的数据分析工作正在进行中。西格列他钠是微芯生物研发的过氧化物酶增殖体活化相关受体（PPAR）全激动剂，此前已经在中国获批用于运动饮食无法有效控制的2型糖尿病患者的临床治疗。NASH是代谢功能障碍相关脂肪性肝病（MAFLD）的晚期形式，是导致肝脏相关死亡的主要原因，患者进展为晚期肝病的风险（包括肝功能丧失和肝癌）也高于一般人群。近日（3月15日），Madrigal公司宣布resmetirom获美国FDA加速批准上市，成为获得FDA批准的首款NASH疗法，标志着该领域的一项重要里程碑。PPAR是能调节与脂质代谢、血糖稳态和胰岛素信号转导相关的多个过程的核素受体。根据微芯生物公开资料介绍，西格列他钠属于构型限制型过氧化物酶增殖体激活受体全激动剂，可适度平衡激活PPARα、γ和δ三个受体亚型，更有效地抑制由肥胖及炎症因子激活的CDK5对PPARγ的磷酸化，从而选择性地改变一系列与胰岛素增敏相关基因的表达。本次达到首要疗效终点的CGZ203研究是一项在NASH患者中开展治疗的无创性临床2期探索研究，入组患者为临床诊断的NASH并伴有肝纤维化患者，按照2:2:1的比例随机入组分别接受每天一次口服西格列他钠48mg、64mg和安慰剂治疗。试验的首要疗效终点为治疗18周后经磁共振质子密度脂肪分数（MRI-PDFF）评估的肝脏脂肪含量（LFC）相比基线变化的比例，同时观察评估试验期间患者的安全性。该研究由首都医科大学附属北京友谊医院牵头，在中国24家临床中心开展。初步结果显示，在试验设定的首要疗效终点上，相比安慰剂对照组，西格列他钠两个剂量组均具有统计学显著意义且剂量依赖的降低；在次要疗效终点如肝脂肪含量下降超过30%的患者比例、肝细胞损伤、炎症及纤维化等无创性指标上，西格列他钠两个剂量也具有统计学显著意义的或剂量依赖趋势性的改善。试验总体安全性良好。该研究的详细结果会在后续的学术会议上或以研究论文的形式公开发表。参考资料：[1] 西格列他钠单药治疗非酒精性脂肪性肝炎的II期临床试验（CGZ203研究）达成首要疗效终点. Retrieved Mar 18 , 2024, from https://mp.weixin.qq.com/s/UBpUvnAdeTk8QfD6syNqtQ本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。