Lysogene SA

Genespire patched together a €46.6 million (about $52 million) funding round to get its lead gene therapy into the clinic in a few years. The Milan-based biotech, which employs nine people, said Wednesday that the Series B will fuel its mission to create a lentiviral vector-based gene therapy for children with methylmalonic acidemia, a rare genetic disease marked by disruptions to the breakdown of certain fats and amino acids. Also known as MMA, it can lead to muscular weakness, seizures, developmental delays, organ damage and even death. Other gene therapy startups have attempted but then abandoned efforts to develop treatments for the disease, including AstraZeneca’s LogicBio and Selecta Biosciences . There are no disease-modifying drugs, and treatment is currently addressed by diet modifications or sometimes liver transplants. Genespire’s work is based on research out of the San Raffaele Telethon Institute for Gene Therapy. The four-year-old biotech recently recruited former Lysogene CEO Karen Aiach-Pignet as its new chief executive after Lysogene shut down. It’s “a new page for me at a time when there have been a lot of ups and downs in the gene therapy space,” she said in an interview. “Probably more downs over the recent years.” Several gene therapy makers, including bluebird bio — which saw its sickle cell gene therapy Lyfgenia get approved last year — are struggling after interest in the once-bustling field has waned amid the broader biotech downturn and questions about the profitability of making these therapies. That said, new biotechs are still emerging, with plans to focus on neurodegenerative and CNS diseases , cancers and other areas. Aiach-Pignet joined Genespire after bringing Lysogene from the lab to Phase 3 with a gene therapy that missed the bar on improving cognitive development in Sanfilippo syndrome type A, a serious inherited neurodegenerative lysosomal storage disorder. Aiach-Pignet said a patient group called Blue Daisy has acquired the program. Sofinnova Partners, which had backed Lysogene, co-led Genespire’s Series B. XGEN Venture, CDP Venture Capital and Indaco Venture Partners SGR are also investors in Genespire. Aiach-Pignet said it is too soon to commit to a time frame for the Phase 1/2 study, though it is likely more than a year away, she said. The company still needs to coordinate the study with regulators and patient advocacy groups, according to the CEO. “Something that I really pay great attention to is the viewpoints, the experience, the expertise of patient groups,” Aiach-Pignet said. “The reason why I wanted to include them in the process is because we need to have a very robust clinical protocol, but we also need to have a protocol that makes sense for the patients and will make sense for the payers down the line.” Moderna is aiming for approval of its own experimental medicine for MMA by 2028. The biotech is in Phase 1/2 with an mRNA infusion treatment candidate known as mRNA-3705. Meanwhile, a BridgeBio subsidiary called CoA Therapeutics terminated a Phase 1 of its oral drug BBP-671 last year. Editor’s note: This story was updated to include additional information on Blue Daisy acquiring Lysogene’s gene therapy.

PRESS RELEASE Genespire appoints Karen Aiach-Pignet as Chief Executive Officer Karen’s appointment bolsters Genespire’s position as a leader in in-vivo lentiviral gene therapy Milan, Italy, 12 September 2024 – Genespire, a biotechnology company developing off-the-shelf gene therapies for pediatric patients affected by genetic diseases, today announces the appointment of Karen Aiach-Pignet as Chief Executive Officer following Dr. Julia Berretta, the former CEO, stepping down. Karen has an outstanding track-record in gene therapy applied to genetic neurodegenerative diseases having founded and led Lysogene, a global leader in the field. During her tenure, she pioneered the development of an adeno-associated virus (AAV) vector for patients with the rare neurodegenerative condition Sanfilippo Type A, initiated and executed an international Phase 3 gene therapy clinical trial, and raised funds via partnering deals and by listing the company on the Euronext Stock Exchange. Karen joins Genespire as the company progresses lead candidate, GENE202, for the treatment of methylmalonic acidemia (MMA) into clinical development. MMA is a devastating genetic disorder impairing the metabolism of certain amino acids and fats. Onset occurs in early infancy, is associated with significant mortality and morbidity, and there are currently no disease-modifying treatments available. Genespire’s technology has the potential to help treat many other genetic diseases with a one-time, off-the-shelf treatment, for both adult and pediatric patients. Karen Aiach-Pignet, CEO at Genespire, commented: “I strongly believe in a better world for patients with metabolic diseases. Leading Genespire, with the aim to develop and deliver safe and efficacious life changing therapies for patients with substantial needs, is therefore a huge honour. Our unique ISLV technology platform, our investors, the team and I, will all come together to make this company a success. Embarking on this new partnership with Sofinnova Partners and working with other high-profile investors, provides huge endorsement for what we are aiming to achieve.” Joern Aldag, Chairman at Genespire, commented: “I am incredibly proud of what the Genespire team has achieved and would like to thank Dr. Julia Berretta, our previous CEO, for her excellent work over the past four and a half years and for orchestrating a seamless transition of leadership. We wish her all the best for the future. “Karen’s extensive experience and knowledge in the development of gene therapies for rare diseases and paediatric indications is a true inspiration. She has incredible drive, ambition and the ability to deliver fast results which will be an invaluable asset to Genespire as we progress our lead lentiviral-based therapy into the clinic.” In addition to her many prestigious accomplishments, Karen is a founding executive member of the International Rare Diseases Research Consortium, was a Member of the Paediatric Committee at the European Medicines Agency and served on the French Ethical Review Board at Ambroise Paré Hospital. She has supported several not-for-profit organizations engaged in advocacy and research in the field of rare diseases. Acknowledgements of Karen’s work include the Ordre National du Merite, a French order of merit, awarded by the French President. Karen recently studied Digital Health at Harvard Business School. She is a graduate from the ESSEC Business School and majored in Economics at the Institut d’Études Européennes of University Paris 8. -ENDS- Enquiries: Genespire Tel: +39 02 80896651 info@genespire.com ICR Consilium Tel: +44 (0) 20 3709 5700Amber Fennell/Ashley Tapp/Jonathan EdwardsGenespire@consilium-comms.com About GenespireGenespire is a biotechnology company, developing off-the-shelf gene therapies based on immune shielded lentiviral vectors (ISLVs) for pediatric patients affected by genetic diseases. ISLVs are designed to be used intravenously and allow the life-long production of the therapy directly from the patient’s liver. Genespire is initially advancing therapeutic programs in inherited metabolic diseases with high unmet medical need. Based in Milan, Italy, Genespire was founded in March 2020 by gene therapy pioneers Prof. Luigi Naldini and Dr. Alessio Cantore, Fondazione Telethon and Ospedale San Raffaele. Genespire is a spin-out of SR-Tiget, a world leading cell and gene therapy research institute. Find out more about us at www.genespire.com. Attachment 240912 Genespire CEO Appointment FINAL

在ADC药物偶联技术的基础之上，延伸出的更多药物偶联形式开始受到关注。病毒样药物偶联物（virus-like drug conjugates, VDC）便是其中之一，并且研发进度并不缓慢。这项创新性的偶联方式，主要根据美国国立癌症研究所癌症研究中心John Schiller博士的研究成果进行了落地转化，Aura Biosciences就是VDC领域的先行者。Aura Biosciences成立于2009年，希望将正在开发的新型VDC疗法用于治疗多种肿瘤适应症。根据Aura的设计，VDC的靶向端选择将人乳头瘤病毒（HPV）衣壳设计为非感染性蛋白质纳米颗粒（VLP）作为高效递送载体，载荷则采用红外光可激活的细胞毒药物。这种设计之下，药物的靶向端可选择性地附着在修饰的硫酸乙酰肝素蛋白聚糖（HSPG）表面，实现对实体肿瘤细胞的靶向与结合，偶联的红外光激活细胞毒药物被激活后，就能破坏肿瘤细胞，导致肿瘤细胞急性坏死的同时，激活免疫系统产生抗肿瘤应答。 AU-001正是Aura Biosciences开发的第一款核心VDC产品。落地创新VDC疗法，聚焦眼科、泌尿科肿瘤到目前为止，VDC在行业内仍然是一种新兴疗法，但Aura Biosciences的发展历程已经持续了15年。自2009年成立以来，Aura Biosciences共完成了多轮融资，并在2021年3月完成了8000万美元的超额认购融资。在Aura的每一轮融资背后，都能看到一家投资机构的身影——Advent Life Sciences。这家机构专注于英国、欧洲和美国的生命科学公司投融资，拥有长期的创投成功记录。Aura 在Advent Life Sciences以及其他投资者一如既往的投资支持下，实现了产品的转化落地。2021年10月，Aura Biosciences在纳斯达克上市，首次公开募股达到7560万美元。Aura在成立后，基本以每两年一次融资的速度，保证了现金流的稳定，和核心产品的稳步推进。Aura Biosciences能循序渐进不断取得里程碑成果的背后，是经验丰富的管理团队的支撑。Eli de los Pinos 是 Aura 的创始首席执行官，公司的战略和运营工作由她负责。在在创立 Aura 之前，她曾在礼来担任要职，负责肺癌药物Alimta在欧洲市场的上市。Jill Hopkins是 Aura 的首席医疗官兼研发总裁。在加入 Aura 之前，Jill 曾担任诺华高级副总裁、眼科和探索性开发部门全球主管，以及诺华子公司Gyrograph Therapeutics 的首席执行官，负责公司全球眼科产品线的开发和上市推广。Jill也曾在基因泰克积累了十余年的工作经验。这些工作经历让Jill 在眼科领域拥有 30 多年的跨部门经验。Mark Plavsic是Aura 的首席技术官。在加入 Aura 之前，Mark曾担任Fate Therapeutics和基因治疗公司Lysogene 的首席技术官。他还曾在赛诺菲、阿斯利康等MNC工作，拥有30年的全球生物制药经验，包含了技术运营、制剂研究、商业化等领域。完整的团队和清晰的分工，让Aura Biosciences拥有稳固的核心，也在专注的疾病领域上非常明晰且有主心骨。Aura专注眼科肿瘤和泌尿科肿瘤。其第一个VDC候选药物，正在开发用于早期脉络膜黑色素瘤的一线治疗。脉络膜黑色素瘤是一种罕见癌症，在美国和欧洲每年约有11000名新发患者。尽管目前采用放射治疗，但该病长期预后较差，超过50%的病例会最终死亡。目前，还没有FDA批准的相关疗法上市。在泌尿科肿瘤，Aura聚焦膀胱癌。膀胱癌是涉及泌尿系统的最常见恶性肿瘤。在美国，非肌层浸润性膀胱癌 (NMIBC) 和肌层浸润性膀胱癌 (MIBC) 年发病率为81000例。NMIBC和MIBC目前采用手术、免疫疗法和化疗相结合的治疗方法，但很大一部分受试者可能会有疾病进展，需要进行膀胱切除术。在Aura看来，其核心VDC产品可以在很大程度上缓解和满足这两类疾病的临床需求。核心产品bel-sar已进入Ⅲ期临床，有望成为全球首款VDC疗法目前，Aura Biosciences已建立成熟的技术平台。其基于病毒样颗粒的新型靶向肿瘤学平台，通过利用HPV的病毒样颗粒 (VLP) 实现对广泛实体瘤的靶向。同时，Aura的VDC疗法通过靶向修饰的肿瘤相关糖胺聚糖（GAG）来实现对肿瘤的杀伤。修饰的肿瘤相关糖胺聚糖 (GAG) 是在细胞外基质和癌细胞膜上发现的一大分子家族。肿瘤会用关键的硫酸化基序对GAG进行特异性修饰，为许多配体提供高结合特异性。因此，GAG 是肿瘤发展的关键角色，会调节肿瘤进展的许多方面，包括增殖、侵袭、血管生成和癌转移。Aura的VLP能够选择性地结合修饰的肿瘤相关 GAG，从而消灭肿瘤。这让VDC疗法具有更多优势：首先，递送更加高效，单个VDC可以递送数百个衣壳蛋白缀合的细胞毒性分子；而且，VDC靶向GAG，基于VLP与许多肿瘤类型中存在的修饰肿瘤相关GAG结合的能力，VDC有潜力广泛用于多种癌症，而不与正常细胞结合，从而限制了脱靶毒性；同时，VDC 拥有大量修饰的肿瘤相关 GAG 的结合位点，这种多价性保证了药物与肿瘤细胞的强力结合；最重要的一点是，VDC 具有双重作用机制，首先可导致肿瘤细胞的急性坏死，然后通过创建高免疫原性环境来诱导抗肿瘤特异性免疫反应，从而实现更强大和持久的治疗。目前，其核心产品AU-001即Belzupacap sarotalan (bel-sar)，在临床中对VDC疗法的疗效进行了充分验证。图片来源：Aura Biosciences官网这款产品的原理为，Bel-sar被注射到眼球中，选择性地与脉络膜黑色素瘤细胞的细胞膜结合。一旦Bel-sar与肿瘤细胞膜结合，就会释放出一种有效的光敏药物，然后被红外光激活。由于 Bel-sar 与肿瘤细胞有针对性地结合，在光激活后，bel-sar 会触发单线态氧的产生，从而导致细胞膜的物理破坏，进而触发肿瘤细胞急性坏死。这一过程还将激活患者的先天性和适应性免疫系统，以进一步识别和破坏具有转移潜力的癌细胞。目前，用于治疗脉络膜黑色素瘤的bel-sar已被美国FDA授予孤儿药和快速通道资格，随后也被欧盟EMA授予孤儿药资格认定。Aura介绍，bel-sar在临床上的使用也非常方便。它能同时保留关键的眼睛结构，有望保留患者的视力，并减少放射治疗的其他长期并发症。医生可使用眼科、办公室常见的设备进行给药递送，不需要外科手术，这为患者和医生都提供了一种潜在的侵入性更小、更方便的治疗方法。2021年底，Aura Biosciences公布了AU-011在不确定病变（ILs）和脉络膜黑色素瘤（CM）中的临床数据，包括玻璃体（IVT）注射给药的Ⅰb/Ⅱ期的最终安全性和有效性数据，以及使用脉络膜上（SC）给药的2期更新安全性结果。2023年，Aura Biosciences在黄斑学会第46届年会上，公布了Bel-sar用于一线治疗早期脉络膜黑色素瘤患者的积极中期Ⅱ期安全性和有效性数据。数据显示，在对接受三个治疗周期的患者进行平均9个月的随访后，患者显示出对Bel-sar治疗的良好反应，肿瘤控制率为89%-100%。此外，Bel-sar的安全性良好，只有一名患者丧失视力，该药并且没有出现与治疗相关的 SAE 或显著AE。这一最新的临床数据，有力的支持了Bel-sar的Ⅲ期临床的开展。2023年12月，Aura Biosciences 宣布完成对全球Ⅲ期CoMpass试验中第一位患者的给药，未来将有更多的临床数据出炉。Bel-sar在膀胱癌的治疗上也显示出了潜力。据悉，这款药物已获得 FDA 的快速通道认定，并启动了一项Ⅰ期临床试验，用于评估Bel-sar用于局部治疗 NMIBC 和MIBC的安全性和耐受性。目前，除了Aura Biosciences外，还没有更多的药企进行VDC疗法的布局。期待Aura在未来更新更多临床数据，为VDC领域探索出一条可行的道路。*封面图片来源：123rf文|王瑾瑶微信|wxid_9365193653812添加时请注明：姓名-公司-职位网站、公众号等转载请联系授权：Rekkiiie近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台