HepaRegeniX GmbH

HepaRegeniX said Wednesday it has successfully closed a €15 million ($16.2 million) series C round to advance a new therapy designed to jumpstart the liver's regenerative powers. The financing was led by Vesalius Biocapital IV with participation from existing investors Novo Holdings, Boehringer Ingelheim Venture Fund, and High-Tech Gründerfonds.HRX-215 is a small molecule inhibitor of MKK4, designed to unlock the regenerative capacity of hepatocytes and boost liver regeneration in patients. According to HepaRegeniX, the therapy holds promise for people with liver metastases, primary liver tumours, and those undergoing liver transplantation."With the new funds, HepaRegeniX will advance with its clinical plans for a Phase Ib study in the US and an international Phase IIa study to enhance liver recovery and prevent liver failure," commented Elias Papatheodorou, who transitions from chair of the board to CEO.The company also announced the appointment of Linda Greenbaum as chief medical officer. "MKK4 is a key regulator of liver regeneration, and MKK4 inhibition has been shown to induce liver regeneration after a partial hepatectomy," she said. "With this mode of action, HRX-215 has an immense potential to improve outcomes for patients who are currently not able to undergo potentially curative surgical resections due to liver tumours."The funding comes on the heels of promising preclinical data and a Phase I trial. In a paper published in the journal Cell earlier this year, researchers said "we are convinced that the observed antisteatotic and antifibrotic activity provides a very good basis for further testing of HRX215 in chronic liver disease.""We envision that HRX215 harbours the potential to push the boundaries of oncological liver surgery," they said, adding "perioperative HRX215 treatment holds the promise to safely prevent PHLF [post-hepatectomy liver failure] after liver resections and will make more extensive resections possible, thus allowing a potential curative perspective for more patients with colorectal cancer liver metastases and also for patients suffering from primary liver carcinomas."HepaRegeniX raised a €9 million series A and €11 million series B in 2017 and 2020, respectively.

Funds to support Phase Ib clinical trial of HRX-215 in the US and an international multicenter Phase IIa clinical trial in liver regeneration Elias Papatheodorou moves from Chair of the Board to CEO of HepaRegeniX Dr. Linda Greenbaum joins HepaRegeniX as CMO TUEBINGEN, Germany, July 10, 2024 (GLOBE NEWSWIRE) -- HepaRegeniX GmbH, a clinical stage company developing a novel regenerative therapy for the treatment of acute and chronic liver diseases, today announced the closing of a Series C round led by Vesalius Biocapital IV with participation of existing investors Novo Holdings, Boehringer Ingelheim Venture Fund (BIVF), and High-Tech Gründerfonds (HTGF). The new funds of €15 million will be used to advance the clinical development of the Company’s clinical candidate HRX-215. As part of the financing, Fabienne Roussel, Partner at Vesalius Biocapital, joins the Non-Executive Board of Directors. Elias Papatheodorou will become Chief Executive Officer, moving from Chair of the Board. Elias Papatheodorou, Chair of the Board, said “We are thrilled to secure this significant financing, which underscores the confidence our investors have in our science and our capabilities to bring effective treatments to patients suffering from liver diseases. With the new funds, HepaRegeniX will advance with its clinical plans for a Phase Ib study in the US and an international Phase IIa study to enhance liver recovery and prevent liver failure.” HRX-215 is a small molecule inhibitor of Mitogen-Activated Protein (MAP) Kinase Kinase 4 (MKK4). Inhibition of MKK4 unlocks the regenerative capacity of hepatocytes and can strongly boost liver regeneration in patients. This is highly relevant for patients with liver metastases or primary liver tumors, as resection of the tumors is the only curative therapeutic approach. Liver regeneration is also key in liver transplant and especially in enabling left liver lobe living donor transplant. This strategy could significantly reduce waiting list for liver transplant candidates. Promising preclinical data have confirmed HRX-215’s capacity for liver regeneration, and HepaRegeniX has successfully completed a Phase I trial. These results have been published in the prestigious journal Cell. “Vesalius Biocapital is excited to support HepaRegeniX as it progresses into the next phase of clinical development for HRX-215. There is an immense need for a treatment that can induce liver regeneration in patients suffering from liver damage, liver tumors, as well as in transplant settings. HRX-215 has potential to help these patients and make a meaningful impact on their lives. I look forward to working with HepaRegeniX’ excellent leadership team to advance this promising treatment candidate,” commented Fabienne Roussel, Partner at Vesalius Biocapital IV. Importantly, to take HepaRegeniX through the next stages of clinical development and value creation, Dr. Linda Greenbaum is joining HepaRegeniX as Chief Medical Officer (CMO). She brings extensive expertise and experience in clinical development and translational medicine. She recently served as Executive Director, Translational Medicine at Novartis in the US. Before joining Novartis, she held the position of Director of Clinical Development at Janssen R&D and served on the faculty of Thomas Jefferson University and University of Pennsylvania where she led a research laboratory investigating liver regeneration and fibrosis. Dr. Greenbaum holds an MD from the Columbia University Vagelos College of Physicians and Surgeons. “I am honored to join HepaRegeniX at such a critical juncture in its development,” added Dr. Linda Greenbaum, Chief Medical Officer of HepaRegeniX. “MKK4 is a key regulator of liver regeneration, and MKK4 inhibition has been shown to induce liver regeneration after a partial hepatectomy. With this mode of action, HRX-215 has an immense potential to improve outcomes for patients who are currently not able to undergo potentially curative surgical resections due to liver tumors, and other patient groups affected by liver failure. I look forward to working with the talented team at HepaRegeniX to advance the clinical development of HRX-215 through Phase II trials and beyond, with the ultimate goal of improving outcomes for patients with liver diseases worldwide." Elias Papatheodorou concluded “It is a pleasure to welcome Dr. Linda Greenbaum to our leadership team. With her extensive knowledge and expertise, she will guide the future clinical development of HRX-215. With our new funding and the extension to our experienced leadership team, we hope to bring a much-need therapy to patients suffering from liver diseases.” info@heparegenix.com For media inquiries: MC Services AG Katja Arnold, Dr. Regina Lutz +49 89 210 228-0 UK: Shaun Brown M: +44 7867 515 918 heparegenix@mc-services.eu About HepaRegeniX GmbH – Since 2017, HepaRegeniX has successfully discovered and developed several drug candidates for the treatment of acute and chronic liver diseases based on a novel proprietary molecular target Mitogen-Activated Protein (MAP) Kinase Kinase 4 (MKK4). The first MKK4 inhibitor HRX-215 recently completed Phase 1 clinical testing. MKK4 is a key regulator of liver regeneration and suppression of MKK4 unlocks the regenerative capacity of hepatocytes even in severely diseased livers. This new and unique therapeutic concept was discovered by Prof. Lars Zender and his research group at the University Hospital Tuebingen, Germany. Investors in HepaRegeniX include Vesalius Biocapital IV, the Boehringer Ingelheim Venture Fund (BIVF), Novo Holdings A/S, Coparion, High-Tech Gründerfonds (HTGF) and Ascenion GmbH.

撰文丨王聪肝脏疾病是一个全球性的健康问题，每年导致200多万人死亡。近几十年来，肝脏疾病的死亡人数增加了50%，预计在未来20年内还将翻倍。虽然肝脏是一个可以自我再生的器官，但这种再生特性也有其局限性。特别是在慢性和急性肝脏疾病或手术切除大部分肝脏后，肝细胞无法再充分再生，从而导致致命的肝功能衰竭。肝移植是终末期肝病患者的唯一选择，然而，由于供体器官稀缺，只有10%的患者能够接受挽救生命的肝移植。早在2013年，Lars Zender 团队在 Cell 期刊发表论文【1】，通过体内RNAi筛选，发现MKK4是肝脏再生的主要调控因子，抑制MKK4能够显著提高肝细胞的再生能力。此外，他们成立了一家名为HepaRegeniX的公司，致力于开发用于肝脏疾病治疗的MKK4抑制剂。2024年3月14日，德国图宾根大学的 Lars Zender 团队联合美国梅奥医学中心及初创公司HepaRegeniX的研究人员合作，在 Cell 期刊发表了题为：First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure 的研究论文【2】。这项临床前和临床1期研究表明，研究团队开发的First-in-class（首创新药）HRX-215（MKK4抑制剂）能够抑制肝细胞中的MKK4蛋白，从而促进肝脏再生，这可能预示着肝癌手术和肝脏移植的新时代，甚至有可能显著改善急性和慢性肝病的治疗。由于之前没有任何药物能够增加受损肝脏的再生能力，因此HRX-215临床数据的发表的是肝脏再生领域的一个里程碑。在之前的研究中，Lars Zender 团队揭示了抑制MKK4能够提高肝脏能力的机制，MKK4是一种MAP2激酶，是应激活化蛋白激酶（SAPK）/丝裂原活化蛋白激酶（MAPK）信号网络的一部分。当细胞暴露于不同的应激刺激时，MKK4可以被激活。MKK4的下游底物JNK1也被MKK7激活，抑制MKK4可以解锁急性或慢性损伤肝脏中肝细胞的内源性再生能力，这主要通过MKK7和JNK1解除SAPK信号通路，转向由转录因子ATF2和ELK1介导的下游促再生转录程序。在这项最新研究中，研究团队首先验证了抑制MKK4的安全性，小鼠研究显示，长期抑制MKK4的表达，对各个器官及体重未产生任何毒性症状，也没有出现任何促进肿瘤的现象。这些数据支持了通过抑制MKK4来促进肝脏再生而不增加肝脏肿瘤风险的思路。研究团队基于MKK4蛋白结构开发了一款小分子抑制剂——HRX-215，在动物模型中进行的临床前研究表明，HRX-215（MKK4抑制剂）促进了小鼠和猪模型的肝脏再生能力，在肝病小鼠模型中显示出抗脂肪变性和抗纤维化作用，而猪在致死性的85%肝脏切除后，未接受治疗的6只猪只有1只存活，切除前使用HRX-215治疗的6只猪存活4只，切除后使用HRX-215治疗的6只猪存活5只。因此，HRX-215能够通过提高肝脏再生能力，从而实现以前不可能的肝脏手术。例如，在晚期肝癌患者中，往往无法切除所有癌变肝组织，因为这样大量切除会导致剩余肝脏衰竭。此外，HRX-215还能够为更多肝衰竭患者提供拯救生命的肝移植，因为在它的帮助下，可能只需要移植更小尺寸的肝脏组织。接下来，为了评估HRX215的安全性、耐受性和药代动力学，研究团队在48名健康志愿者中进行了一项安慰剂对照（治疗组36人，安慰剂组12人）的探索性1期人体临床研究。结果显示，治疗没有报告严重或危重不良事件，治疗组和安慰剂组之间轻度至中度不良反应率相当（治疗组36.1% vs. 安慰剂组41.7%）。全血细胞计数显示HRX215治疗组和安慰剂组之间没有显著差异。研究团队还通过液相色谱-串联质谱（LC-MS/MS）研究了HRX215的药代动力学，结果显示HRX215被快速吸收，并在达到最大浓度后呈双相消除。随着剂量的增加，药物暴露呈比例增加。当在进餐后给药时，HRX215的吸收延迟，但生物利用度显著提高。总体而言，这项1期临床研究观察到HRX215良好的药代动力学、安全性和耐受性，为未来的2期临床研究奠定了基础。该研究的领导者、Lars Zender 教授表示，HRX-215不仅是肝癌手术切除中急需的治疗选择，而且还能够帮助克服肝移植领域面临的器官短缺这一主要问题，在HRX-215帮助下，对于健康捐赠者而言，将他们的肝脏中较小的左半叶进行活体移植，对健康捐赠者的风险较小，但这部分肝脏太小，难以在移植后接管受体的肝脏功能。而在HRX-215的帮助下增强肝脏再生能力，从而让较小的肝脏左半叶移植成为可能。论文链接：https://doi.org/10.1016/j.cell.2013.03.026https://doi.org/10.1016/j.cell.2024.02.023