Hepatic Encephalopathy

▎药明康德内容团队编辑Lipocine公司今日宣布其潜在“first-in-class”疗法LPCN 1148用于治疗肝硬化患者的2期临床研究顶线结果。分析显示，试验达成主要终点，Lipocine计划与美国FDA会面，讨论该药物上市的开发路径。这项2期概念验证研究是一项随机安慰剂对照研究，对象是肝移植候补名单上的肝硬化男性患者，这些患者具有肌肉减少症共病。该研究的主要终点是第24周时L3-骨骼肌指数（SMI）的变化，L3-SMI是用以估计全身骨骼肌质量的指标，患者在基线以及第12、24、36和52周时接受SMI的分析。关键次要终点包括肝性脑病发生率以及LPCN 1148的安全性/耐受性。▲患者在基线与第24、52周的L3-SMI结果（图片来源：参考资料[1]）所有接受LPCN 1148治疗的参与者（共15人）均顺利完成了24周的治疗，而在接受安慰剂的14名参与者中，有10人完成了24周的治疗。分析结果显示该试验达到主要终点，患者在第24周观察到SMI增加一直维持到52周。在改用LPCN 1148后安慰剂组患者的SMI增加。此外，LPCN 1148治疗期间，患者发生明显肝性脑病（OHE）事件较少，且首次复发OHE事件的时间亦较长。▲患者发生OHE事件统计结果（图片来源：参考资料[1]）安全性方面，LPCN 1148耐受性良好，不良事件发生率和严重程度与安慰剂相似，且LPCN 1148组受试者住院天数较少。LPCN 1148是一种在研口服疗法，包含十二烷酸睾酮（testosterone dodecanoate），这是一种独特的雄激素受体激动剂。LPCN 1148开发用以治疗肝硬化和相关共病，包括肌肉减少症和OHE，为潜在"first-in-class"疗法。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Lipocine Announces Positive Week 52 Results from LPCN 1148 Phase 2 Study in Patients with Cirrhosis. Retrieved March 28, 2024 from https://www.prnewswire.com/news-releases/lipocine-announces-positive-week-52-results-from-lpcn-1148-phase-2-study-in-patients-with-cirrhosis-302101966.html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。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

Met primary and Hepatic Encephalopathy (HE) endpoints in Phase 2 study Increase in Skeletal Muscle Index (SMI) observed at Week 24 was maintained through 52 weeks Participants on placebo increased SMI when switched to LPCN 1148 Fewer Overt Hepatic Encephalopathy (OHE) events and time to first recurrent OHE event was longer while on LPCN 1148 therapy LPCN 1148 was well-tolerated, with AE rates and severities similar to placebo. Participants on LPCN 1148 were hospitalized for fewer days SALT LAKE CITY, March 28, 2024 /PRNewswire/ -- Lipocine Inc. (NASDAQ: LPCN), a biopharmaceutical company today announced positive topline results from a Phase 2 clinical study of LPCN 1148. LPCN 1148 is an oral candidate under development for the clinical management of cirrhosis, specifically prevention of OHE recurrence and treatment of sarcopenia. LPCN 1148 is targeted to be a "First in Class" product candidate with a novel mechanism of action (MOA). Lipocine plans to meet with the FDA to discuss a development path to NDA filing. "We are encouraged with the positive results from our Phase 2 study. These results demonstrate that LPCN 1148 treatment benefits patients with cirrhosis who are sarcopenic and have experienced other serious decompensation events such as OHE," said Dr. Mahesh Patel, President and CEO of Lipocine Inc. "Cirrhosis management is a significant unmet medical need with a strong pharmaco-economic rationale. We believe LPCN 1148 both ameliorates sarcopenia and decreases the recurrence of OHE. If approved, this treatment is a compelling opportunity with the potential to be the standard of care as a mono or adjunct therapy in managing advanced cirrhosis." This Phase 2 proof of concept study was a randomized placebo-controlled study in sarcopenic male patients with cirrhosis on the liver transplant waitlist. In Stage 1, 29 patients were randomized 1:1 to receive either LPCN 1148 or matching placebo for 24 weeks. At Week 24, the open-label extension Stage 2 of the study commenced. During Stage 2, 8 participants who were on placebo in Stage 1 converted to LPCN 1148, and 11 participants who started the study on LPCN 1148 continued treatment with LPCN 1148. The study's primary endpoint was a change in L3-SMI at week 24. L3-SMI estimates whole body skeletal muscle mass. SMI was analyzed at baseline, and Weeks 12, 24, 36, and 52. Key secondary endpoints included rates of hepatic encephalopathy and the safety/tolerability of LPCN 1148. Results All LPCN 1148-treated participants completed Week 24 (n=15), and 10 of 14 placebo participants completed Week 24. During the initial 24 weeks, all LPCN 1148-treated participants had at least one evaluable post-baseline CT scan and are therefore part of the modified intent to treat (mITT) analysis; 10 placebo-treated participants had an evaluable post-baseline CT. As prespecified, L3-SMI analysis was performed on the mITT population (n=25), with the last evaluable post-baseline observation carried forward (LOCF). Of those participants on placebo in Stage 1, 6 out of 8 who went on to receive LPCN 1148 starting at Week 24 had evaluable CT scans in Stage 2. Primary endpoint Participants who received LPCN 1148 during Stage 1 had a significant (p<0.01) increase in L3-SMI of 4.1 cm2/m2 (8.8%) at Week 24, the primary analysis timepoint, and this increase was maintained through the additional 28 weeks of the study (Week 52, 4.1 cm2/m2, 8.7%). Placebo participants who began receiving LPCN 1148 saw a marked increase in SMI as early as 12 weeks after therapy initiation (Week 36, 7.4 cm2/m2, 15.1%), and this increase was maintained through Week 52 (8.1 cm2/m2, 16.7%). Table 1: Change in L3-SMI at Week 24 and Week 52 Data are least squares mean (standard error), LOCF. # For Placebo participants converted to LPCN 1148, baseline is considered Week 24 data. ANCOVA model with treatment and overall baseline L3-SMI as covariates. * p<0.01 vs baseline. † p<0.01 LPCN 1148 vs placebo at Week 24. ‡ Change from baseline in SMI at Week 24 was the study's primary endpoint. Hepatic Encephalopathy Recurrent OHE is defined as an event of OHE in a participant with a medical history of HE. Most (22/29, 76%) study participants had experienced HE prior to this study, and there were similar numbers of these participants in each study arm in both Stage 1 and Stage 2. Nearly all (21/22, 95%) participants with a history of HE were on therapy for HE at baseline and during the study (lactulose and/or rifaximin). During Stage 1, LPCN 1148 treatment resulted in significantly (p<0.05) fewer cases of recurrent OHE (1 vs 6), a potential FDA-approvable endpoint. During the open-label Stage 2, there were two cases of OHE, one in a participant who was receiving LPCN 1148 since Day 1, and one who began receiving LPCN 1148 at Week 24. The average time to first OHE recurrence was longer with LPCN 1148 treatment, at 183 days compared to 35 days for placebo. Safety set; includes all participants who received study drug in a given stage. Overt HE (OHE) is defined as an event of HE with CTCAE severity ≥ grade 2. Safety In this 52-week study, LPCN 1148 was well-tolerated with AE rates and severities similar to those observed in Stage 1 with placebo. Participants experienced fewer serious or severe adverse events when switched from placebo to LPCN 1148. Participants on LPCN 1148 were hospitalized for fewer total days with shorter hospital stays. There were two deaths reported in placebo-treated participants and one in LPCN 1148-treated participants during the study. The company plans to share additional results pertaining to other secondary endpoints at upcoming scientific conferences. Dr. Arun J. Sanyal, MD, Director, Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University, commented, "I am delighted to see the durability of the results noted in this important trial to improve sarcopenia in a very sick population of patients with decompensated cirrhosis. The stability of improvement in sarcopenia and encephalopathy provide proof of concept that sarcopenia correction with LPCN 1148 may provide benefit to patients with decompensated cirrhosis and reduce the risk of breakthrough encephalopathy. These provide a strong rationale for further studies on the overall benefits and risks of LPCN 1148 in this population where there is a major unmet need to improve sarcopenia." Dr. Jennifer Lai, MD, MBA, UCSF Professor of Medicine, transplant hepatologist, and study principal investigator, added, "The rapid and sustained increases in muscle mass seen in this study with LPCN 1148 are very exciting, especially as there are currently no FDA-approved pharmacotherapeutics for sarcopenia in cirrhosis. The observed trends towards improved clinical outcomes including hepatic encephalopathy support what we know about the importance of increasing and maintaining muscle mass in patients with cirrhosis." About Cirrhosis Cirrhosis is an end stage liver disease of varying etiologies such as alcoholic liver disease, chronic viral hepatitis, nonalcoholic fatty liver disease and primary cholangitis. Complications of cirrhosis include decompensation events such as hepatic encephalopathy due to systemic ammonia buildup, variceal bleeding, and ascites, which require frequent hospitalizations. In addition, many patients exhibit sarcopenia (low muscle mass). Over 382,000 patients have been diagnosed with decompensated liver cirrhosis in the US, with few options for managing their disease other than liver transplant. Poor quality of life is common while waiting for a liver transplant. Although there is a limited supply of donor livers, transplant is the only cure for end-stage cirrhosis. About HE HE is a frequent complication and one of the most debilitating manifestations of liver disease, severely affecting the lives of patients and their caregivers. For patients with decompensated liver cirrhosis and sarcopenia, clinical outcomes tend to be worse - both sarcopenia and myosteatosis are associated with an increased risk of HE. OHE is an episodic neurological disorder with a high recurrence rate. Up to 50% of patients with cirrhosis will experience an OHE episode in their lifetime. Patients can exhibit global neurological, psychiatric, and musculoskeletal deficits. HE has a complex pathophysiology that includes impairment of ammonia clearance and increased inflammatory cytokine and HE recurrence is common, despite use of standard-of-care therapies. Options for prevention/treatment are limited, resulting in significant enduring unmet medical need as the 1-year survival for patients with OHE is ~50%. Furthermore, cognitive impairment associated with cirrhosis results in utilization of more health care resources. About LPCN 1148 LPCN 1148 comprises testosterone dodecanoate, a unique androgen receptor agonist. It is targeted as a differentiated intervention option with a novel multimodal MOA to elicit potential benefits in management of cirrhosis and associated comorbidities of cirrhosis. About the Phase 2 study This multi-center study enrolled and dosed a total of 29 patients across 8 centers in the United States. The primary objective was to evaluate the efficacy of 24 weeks of LPCN 1148 treatment in men with cirrhosis and sarcopenia. The secondary objective was to evaluate the safety and tolerability of LPCN 1148. Following Week 24, the open-label stage of the study began (Stage 2), wherein all participants received LPCN 1148 (no placebo in Stage 2). Baseline characteristics, including age, disease etiology baseline L3-SMI, and other comorbidities were generally well-balanced between groups. Overall, the average baseline Model for End-Stage Liver Disease (MELD) score was 16.8, and 97% of patients had previously experienced at least one clinical decompensation event. Sarcopenia, or low muscle mass, was assessed by computed tomography (CT) scan; total skeletal muscle area at the third lumbar vertebra was measured by CT scan and normalized by participant height (L3-SMI, L3-skeletal muscle index). Patients had study visits every four weeks, with CTs performed at Weeks 12, 24, 36, and 52. Patients with a variety of cirrhosis etiologies were eligible. During the study there were no restrictions on standard of care medications, procedures, or other interventions. Further details on the study design, including inclusion and exclusion criteria, can be found on Clinicaltrials.gov (NCT04874350). About Lipocine Lipocine is a biopharmaceutical company leveraging its proprietary technology platform to augment therapeutics through effective oral delivery to develop products for CNS disorders. Lipocine has drug candidates in development as well as drug candidates for which we are exploring partnering. Our drug candidates represent enablement of differentiated, patient friendly oral delivery options for favorable benefit to risk pro target large addressable markets with significant unmet medical needs. Lipocine's clinical development candidates include: LPCN 1154, oral brexanolone, for the potential treatment of postpartum depression, LPCN 2101 for the potential treatment of epilepsy and LPCN 1148, an oral prodrug of bioidentical testosterone targeted for the management of symptoms associated with liver cirrhosis. Lipocine is exploring partnering opportunities for LPCN 1107, our candidate for prevention of preterm birth, LPCN 1148, for the management of decompensated cirrhosis, and LPCN 1144, our candidate for treatment of non-cirrhotic NASH. TLANDO, a novel oral prodrug of testosterone containing testosterone undecanoate developed by Lipocine, is approved by the FDA for conditions associated with a deficiency of endogenous testosterone, also known as hypogonadism, in adult males. For more information, please visit . Forward-Looking Statements This release contains "forward-looking statements" that are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and include statements that are not historical facts regarding our product development efforts, our product candidates and related clinical trials, our strategic plans for developing products to treat CNS disorders, our ability to monetize non-core product candidates, including through entering into partnering arrangements, the application of our proprietary platform in developing new treatments for CNS disorders, the timing and completion of regulatory reviews, outcomes of clinical trials of our product candidates, the potential uses and benefits of our product candidates, the potential uses and benefits of LPCN 1148, and the timing of and our ability to make any NDA filing relating to LPCN 1148. Investors are cautioned that all such forward-looking statements involve risks and uncertainties, including, without limitation, the risks that we may not be successful in developing product candidates to treat CNS disorders, we may not be able to enter into partnerships or other strategic relationships to monetize our non-core assets, the FDA will not approve any of our products, risks related to our products, expected product benefits not being realized, clinical and regulatory expectations and plans not being realized, new regulatory developments and requirements, risks related to the FDA approval process including the receipt of regulatory approvals and our ability to utilize a streamlined approval pathway for LPCN 1154, the results and timing of clinical trials, patient acceptance of Lipocine's products, the manufacturing and commercialization of Lipocine's products, and other risks detailed in Lipocine's filings with the SEC, including, without limitation, its Form 10-K and other reports on Forms 8-K and 10-Q, all of which can be obtained on the SEC website at . Lipocine assumes no obligation to update or revise publicly any forward-looking statements contained in this release, except as required by law. Company Codes: NASDAQ-SMALL:LPCN

*仅供医学专业人士阅读参考急性肝衰竭是一种死亡率很高的疾病，常见病因包括过量对乙酰氨基酚导致的中毒、肝缺血、病毒性和自身免疫性肝炎，以及处方药、草药和膳食补充剂引起的药物性肝损伤[1]。 目前，肝移植仍然是肝衰竭的唯一有效治疗方法，但由于供体短缺，肝细胞移植也被建议作为肝移植的替代策略。但是，肝细胞移植的临床应用存在一些技术障碍，例如原代人肝细胞短缺和质量控制困难，使用多能干细胞分化和成纤维细胞转分化得到肝细胞存在功能缺陷，并且由于重编程等基因操作可能存在体内移植的安全性问题。 此前，中国科学院分子细胞科学卓越创新中心（生物化学与细胞生物学研究所）惠利健团队在不进行基因操作的情况下将原代人肝细胞去分化为双表型状态，构建出可增殖人肝细胞（ProliHHs），ProliHHs具有肝细胞和祖细胞特征，可以扩增至少10000倍，在3D类器官系统中能够重新分化为接近原代人肝细胞的成熟状态。在ProliHH类器官中，肝脏基因的表达和相应的肝功能均得到显著改善[2,3]。 在最近的《细胞·干细胞》杂志上，惠利健团队再次发表最新研究成果[4]，他们实现了批量制备海藻酸钠微胶囊包裹的ProliHH类器官（eLO）。 在80%肝切术后肝衰竭小鼠模型中，eLO显著提高了小鼠存活率，并提供正常的肝功能，从而改善高氨血症和低血糖。此外，eLO治疗还保护了肠道屏障，减少血清内毒素和炎症反应，从而促进了肝脏再生。在过量对乙酰氨基酚诱导的肝衰竭小鼠模型中，eLO也证实了治疗效果。eLO对小鼠没有造成不良影响，并且始终保持非致瘤性。 基于此前开发的去分化培养系统，研究人员得以大规模扩增ProliHH，并经重新培养获得成熟的3D肝脏类器官，再使用海藻酸钠封装，eLO大小均匀，平均直径为435±48μm，可以至少维持一周不出现明显的形态变化。eLO与封装前具有相近的转录组、代谢活性和糖原储存能力，eLO对细胞死亡的抵抗能力更强。eLO生成和实验设计 为了验证eLO在体内的功能，研究人员首先构建了肝切除手术诱导的肝衰竭小鼠模型，切除了肝脏的左叶、中叶和右前叶，这些小鼠会出现肝功能不足、解毒减少、凝血受损、电解质平衡改变、氨浓度升高，导致炎症水平升高和多器官衰竭，最终死亡。 研究显示，1-10%肝质量的肝细胞能够支撑应对急性肝衰竭，研究人员选择了5%，即5x106的eLO，在肝切除手术后6小时腹膜内移植给小鼠。移植了空的微胶囊的对照组小鼠在第4天时的死亡率达到94%，而eLO组未超过40%。减少移植eLO的量后，小鼠的生存率有所下降，表明治疗效果可能是剂量依赖性的。移植了空的微胶囊（EMC）、间充质干细胞微胶囊（MSC）、小鼠原代肝细胞微胶囊（ePMH）和eLO的小鼠的生存率变化 接受eLO治疗后，小鼠的肝衰竭显著减弱，脂肪变性和微血管异常都显著减少，伴随肝细胞细胞内容物的逐渐积累。肝脏类器官在体内保持稳定，结构完整，直到第7天，eLO的活性都保持在80%以上，第14天时，也有36%。 另一组经对乙酰氨基酚诱导的肝衰竭小鼠也接受了类似的治疗，在治疗前小鼠已经出现肝脏结构受损并呈空泡化，eLO移植同样显著提高了小鼠的生存率，肝脏得到部分修复。 eLO治疗后的高生存率和一致的治疗效果为分析eLO在治疗肝衰竭中的潜在作用提供了独特的机会，这在以前是难以实现的。 手术诱导的肝衰竭与高氨血症和低血糖有关，氨是诱发肝性脑病的神经毒素，而eLO移植使得对氨的内源性解毒能力得到改善，并恢复了糖原储存，这意味着eLO为肝功能提供支持，从而改善肝衰竭相关高氨血症和低血糖。 在移植后第2天，eLO组的肝脏已经逐渐恢复粉红色，并且明显增大，第14天时，肝/体重比恢复至4.7%，转录组接近正常肝脏，肝脏再生大大增强，转录组学分析显示，eLO组小鼠参与细胞周期和细胞增殖的基因明显上调。eLO组肝脏再生 据报道，高浓度的内毒素会引发强烈的炎症反应，阻止细胞周期进程，是肝脏再生的阻碍，研究人员发现，移植了空的微胶囊的对照组小鼠确实内毒素水平显著升高，而eLO组则保持在低水平，对血清细胞因子阵列的测定也证实了两组的全身炎症水平差异。当人为增加eLO组小鼠的内毒素水平时，eLO的治疗效果显著减弱。 由于肝切除术会导致肠粘膜受损和内毒素泄露，eLO组内毒素水平的减少可能代表着肠粘膜得到修复，这一点也在实验中得到了证实。因此，eLO不仅提供了肝功能支持，还保护了肠屏障。 最后，在eLO的安全性方面，研究人员发现，eLO没有急性毒性，不会造成小鼠行为活动、食物摄入量和粪便特征的显著变化，移植后60天，肝脏、肾脏、睾丸、肠、心脏、脾脏和肺没有形态学或组织学变化，6个月时，肝脏结构完整，肝脏/体重比例正常，谷丙转氨酶和谷草转氨酶水平与60天时相比未发生变化。ProliHHs在基因组水平上高度稳定，未出现肿瘤。 综上所述，这项研究实现了大规模制备eLO，在两种肝衰竭小鼠模型中证明了eLO腹腔移植的有效性和eLO发挥作用的机制，并且证实了eLO的安全性，为正在进行的eLO临床研究奠定了坚实的基础。 参考文献：[1] Stravitz R T, Lee W M. Acute liver failure[J]. The Lancet, 2019, 394(10201): 869-881.[2] Zhang K, Zhang L, Liu W, et al. In vitro expansion of primary human hepatocytes with efficient liver repopulation capacity[J]. Cell stem cell, 2018, 23(6): 806-819. e4.[3] Feng S, Wu J, Qiu W L, et al. Large-scale generation of functional and transplantable hepatocytes and cholangiocytes from human endoderm stem cells[J]. Cell Reports, 2020, 33(10).[4] Yuan X, Wu J, Sun Z, et al. Preclinical efficacy and safety of encapsulated proliferating human hepatocyte organoids in treating liver failure[J]. Cell Stem Cell, 2024.本文作者丨应雨妍