MENLO PARK, Calif.--(BUSINESS WIRE)--OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced preliminary safety and pharmacokinetic (PK) data from the single ascending dose (SAD) portion of an ongoing Phase 1 trial of TLC-6740, a liver-targeted, mitochondrial protonophore.

加州门洛帕克-（商业线）-OrsoBio，Inc.，一家开发严重代谢紊乱治疗方法的临床阶段生物制药公司，今天宣布了单次递增剂量（SAD）部分的初步安全性和药代动力学（PK）数据正在进行的TLC-6740 1期临床试验，TLC-6740是一种肝脏靶向的线粒体质子载体。

This study is exploring the safety and efficacy of TLC-6740 as an oral, first-in-class treatment for obesity and obesity-associated diseases, including diabetes and nonalcoholic steatohepatitis (NASH)..

本研究正在探索TLC-6740作为肥胖和肥胖相关疾病（包括糖尿病和非酒精性脂肪性肝炎（NASH））的口服，一流治疗的安全性和有效性。。

Increasing cellular energy expenditure by mitochondrial uncoupling is a validated approach to weight loss, however, toxicity due to systemic uncoupling (e.g., increased body temperature) has restricted its clinical use. To circumvent these potential toxicities, TLC-6740 was developed to be actively taken up by hepatocytes (liver cells), thereby avoiding high plasma exposures.

通过线粒体解偶联增加细胞能量消耗是体重减轻的有效方法，然而，由于全身解偶联（例如，体温升高）引起的毒性限制了其临床应用。为了避免这些潜在的毒性，TLC-6740被开发为由肝细胞（肝细胞）主动摄取，从而避免高血浆暴露。

In addition, by targeting the liver—a key organ governing whole body energy metabolism—TLC-6740 has multiple potential metabolic benefits, including weight loss and improvements in NASH, insulin resistance, lipids, and cardiovascular risk..

此外，通过靶向肝脏-控制全身能量代谢的关键器官-TLC-6740具有多种潜在的代谢益处，包括体重减轻和NASH改善，胰岛素抵抗，血脂和心血管风险。。

“Preliminary results from this Phase 1 study are very promising and support the safety of liver-targeted mitochondrial uncoupling with TLC-6740,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “Modeling of plasma and liver concentrations upon multiple dosing suggests that high systemic exposures of TLC-6740 will be avoided, providing large safety margins compared with thermogenic exposures in preclinical studies, while efficacious exposures will be achieved at low doses.

OrsoBio首席医疗官Rob Myers博士说：“这项1期研究的初步结果非常有希望，并支持肝脏靶向线粒体与TLC-6740解偶联的安全性。“多次给药时血浆和肝脏浓度的建模表明，TLC-6740的高全身暴露将被避免，与临床前研究中的产热暴露相比提供了大的安全裕度，而在低剂量下将实现有效暴露。

We look forward to confirming these findings in the multiple ascending dose (MAD) cohorts of this study, and to generating additional data to support the potential of TLC-6740 to treat obesity and its comorbidities.”.

我们期待在本研究的多次递增剂量（MAD）队列中证实这些发现，并产生额外的数据来支持TLC-6740治疗肥胖及其合并症的潜力“。

OrsoBio will present preliminary results from its first-in-human study of TLC-6740 at ObesityWeek®, an international conference for obesity researchers and clinicians, in Dallas, Texas, October 14-17, 2023.

OrsoBio将于2023年10月14日至17日在德克萨斯州达拉斯举行的肥胖研究人员和临床医生国际会议ObesityWeek®上首次进行人体TLC-6740研究。

Abstract #418: Preliminary Human Safety and PK of the Liver-Targeted Mitochondrial Protonophore TLC-6740

摘要＃418：肝脏靶向线粒体质子载体TLC-6740的初步人体安全性和PK

Poster Session: Tuesday, October 17, 2023 (11:45 a.m. - 1:15 p.m.)

海报会议：2023年10月17日星期二（上午11:45至下午1:15）

The randomized, double-blind Phase 1 trial (NCT05822544) is designed to evaluate the safety, tolerability, PK, and pharmacodynamics of single and multiple ascending doses of TLC-6740 for up to 10 days in healthy subjects. In cohorts treated with single doses of TLC-6740 (3, 6, 15, 30, 60, and 120 mg), only mild and non-serious adverse events (AEs) were reported.

随机，双盲1期试验（NCT05822544）旨在评估健康受试者中单次和多次递增剂量TLC-6740长达10天的安全性，耐受性，PK和药效学。在用单剂量TLC-6740（3,6,15,30,60和120mg）治疗的队列中，仅报告了轻度和非严重不良事件（AE）。

No AEs were considered related to treatment and there were no clinically significant laboratory abnormalities or changes in vital signs (e.g., temperature) or ECG parameters, supporting the safety and tolerability of TLC-6740. The PK profile of TLC-6740 includes a prolonged half-life (17 to 46 hours), supporting once-daily, oral dosing.

没有AE被认为与治疗有关，并且没有临床上显着的实验室异常或生命体征（例如温度）或ECG参数的变化，支持TLC-6740的安全性和耐受性。TLC-6740的PK曲线包括延长的半衰期（17至46小时），支持每日一次口服给药。

Due to liver targeting, plasma concentrations are projected to remain >80-fold below exposures associated with hyperthermia in preclinical studies, providing large safety margins for human use. The results also suggest that low doses of TLC-6740 will reach therapeutic exposures, supporting its potential efficacy for obesity and associated disorders..

由于肝脏靶向，预计血浆浓度将低于临床前研究中与热疗相关的暴露>80倍，为人类使用提供大的安全裕度。结果还表明，低剂量的TLC-6740将达到治疗暴露，支持其对肥胖和相关疾病的潜在功效。。

“With the growing burden of obesity and obesity-associated diseases, development of safe, effective oral therapies that are complementary to existing therapies, such as GLP-1 receptor agonists, will help address the tremendous unmet medical need for patients with severe metabolic disorders,” said Gerald Shulman, MD, PhD, MACP, MACE, FRCP, the George R.

“随着肥胖和肥胖相关疾病负担的日益增加，与现有疗法（如GLP-1受体激动剂）相辅相成的安全有效的口服疗法的开发将有助于解决严重代谢患者巨大的未满足的医疗需求Gerald Shulman博士，MACP博士，MACE，FRCP博士，George R。

Cowgill Professor of Medicine and Professor of Cellular and Molecular Physiology at Yale School of Medicine, Co-Director of the Yale Diabetes Research Center, and scientific advisor to OrsoBio. “These preliminary human data suggest that TLC-6740 has the potential to be a highly safe and effective mitochondrial protonophore based on the novel approach of liver targeting.”.

Cowgill医学教授，耶鲁大学医学院细胞与分子生理学教授，耶鲁糖尿病研究中心联合主任，OrsoBio科学顾问。“这些初步的人体数据表明TLC-6740基于肝脏靶向的新方法有可能成为高度安全有效的线粒体质子载体。”。

About TLC-6740

关于TLC-6740

TLC-6740 is a novel, oral, liver-targeted mitochondrial protonophore in development for the treatment of obesity and obesity-associated diseases, including diabetes and NASH. Based on active hepatic uptake and mitochondrial protonophore activity, TLC-6740 increases energy expenditure in hepatocytes, and is expected to have broad, systemic metabolic and cardiovascular benefits, including weight loss, and improved insulin sensitivity, NASH, and dyslipidemia.

TLC-6740是一种新型的口服肝靶向线粒体质子载体，用于治疗肥胖和肥胖相关疾病，包括糖尿病和NASH。基于活跃的肝脏摄取和线粒体质子载体活性，TLC-6740增加肝细胞的能量消耗，并且预期具有广泛的全身代谢和心血管益处，包括体重减轻，以及改善的胰岛素敏感性，NASH和血脂异常。

Preclinical data presented at AASLD’s The Liver Meeting® in 2022 showed that dysmetabolic rodents treated with TLC-6740 achieved dose-dependent reductions in body weight and improvements in glucose tolerance and liver and plasma triglycerides. Moreover, due to active hepatic uptake, plasma exposures of TLC-6740 are limited, serving to enhance its therapeutic safety.

2022年AASLD的肝脏会议上提供的临床前数据显示，用TLC-6740治疗的代谢紊乱的啮齿动物实现了体重的剂量依赖性降低以及葡萄糖耐量和肝脏和血浆甘油三酯的改善。此外，由于活跃的肝脏摄取，TLC-6740的血浆暴露是有限的，用于增强其治疗安全性。

The safety, tolerability, PK, and pharmacodynamic activity of multiple ascending doses of TLC-6740 for up to 10 days in healthy subjects are being evaluated in an ongoing Phase 1 study (NCT05822544)..

正在进行的1期研究（NCT05822544）中评估健康受试者多次递增剂量TLC-6740长达10天的安全性，耐受性，PK和药效学活性。。

About OrsoBio, Inc.

关于Orsobio，Inc。

OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat severe metabolic disorders, including obesity, type 2 diabetes, NASH, and severe dyslipidemias. The company was co-founded by Mani Subramanian, MD, PhD, former Therapeutic Area Head for Liver Diseases at Gilead Sciences, and Samsara BioCapital.

OrsoBio，Inc。是一家私营的临床阶段生物制药公司，致力于开发治疗严重代谢紊乱的疗法，包括肥胖，2型糖尿病，NASH和严重血脂异常。该公司由Gilead Sciences肝病治疗领域负责人Mani Subramanian博士和Samsara BioCapital共同创立。

OrsoBio currently has four programs in clinical and preclinical development with first-in-class compounds that address central pathways in energy metabolism. For more information, please visit www.orsobio.com..

OrsoBio目前在临床和临床前开发方面有四个项目，一流的化合物可以解决能量代谢的中心途径。欲了解更多信息，请访问www.orsobio.com。。