Data from a second participant receiving the gene therapy will be shared Feb. 3. Eli Lilly says an investigational gene therapy has restored hearing in one child who has experienced hearing loss since birth. The early phase 1/2 data examines a single administration of a dual adeno-associated viral vector-based gene therapy known as AK-OTOF and was shared Jan. 23 by Lilly’s wholly owned subsidiary Akouos. More data, including initial data from a second participant, will be shared during the 2024 Association for Research in Otolaryngology MidWinter Meeting on Saturday, Feb. 3. For now, Lilly has said hearing restoration was observed within 30 days of AK-OTOF administration in the first study participant, an 11-year-old that is also the first person to receive gene therapy for a genetic form of hearing loss in the U.S. The child’s hearing was restored across all tested frequencies and fell within the normal hearing range at some frequencies on day 30. No serious adverse events were reported, according to the Big Pharma, and both the surgical administration procedure and investigational therapy were well tolerated. AK-OTOF, which has snagged both orphan drug and rare pediatric disease status from the FDA, is designed to treat sensorineural hearing loss due to mutations in the otoferlin gene (OTOF) via gene transfer and durable expression of normal, functional otoferlin protein to the inner hair cells of the cochlea. The Akouos delivery device, which is being developed in parallel for intracochlear administration, is made to deliver AK-OTOF throughout the cochlea. The phase 1/2 trial is a dose-escalating study, with participants in cohort 1 receiving AK-OTOF at a dose of 410 billion total vector genomes and a second group expected to receive 810 billion total vector genomes. The study, which launched last year, is slated to wrap up in 2028 and enroll a total of 14 participants, according to ClinicalTrials.gov. "Gene therapy for hearing loss is something physicians and scientists around the world have been working toward for over 20 years," John Germiller, M.D., Ph.D., attending surgeon and director of clinical research for otolaryngology at Children's Hospital of Philadelphia and a principal investigator of the AK-OTOF-101 trial, said in the Jan. 23 release. "These initial results show that it may restore hearing better than many thought possible." Currently, no approved pharmacologic treatments designed to restore hearing exist.

临床研究孤儿药基因疗法

2024-01-23

·BioSpace

Positive Phase 1/2 Clinical Trial Data for an Investigational Gene Therapy for Genetic Hearing Loss to be Presented at the Association for Research in Otolaryngology 2024 MidWinter Meeting

[23-January-2024] Hearing restoration was observed within 30 days of a single administration of AK-OTOF in the initial AK-OTOF-101 study participant, the first to receive gene therapy in the United States for a genetic form of hearing loss AK-OTOF is a gene therapy being developed for the treatment of sensorineural hearing loss due to mutations in the otoferlin gene (OTOF) INDIANAPOLIS, Jan. 23, 2024 /PRNewswire/ -- Akouos, Inc., a wholly owned subsidiary of Eli Lilly and Company (NYSE: LLY), today announced positive initial clinical results from the Phase 1/2 AK-OTOF-101 study, which demonstrated pharmacologic hearing restoration within 30 days of AK-OTOF administration in the first participant, an individual with a decade-plus history of profound hearing loss. Results, including initial data from a second participant to receive AK-OTOF, will be presented during the Late Breaking Presidential Symposium at the 2024 Association for Research in Otolaryngology (ARO) MidWinter Meeting. Details of the presentation are listed below: Title: Clinical development of AK-OTOF gene therapy for OTOF-mediated hearing loss Session: Late Breaking Presidential Symposium Date/Time: Saturday, February 3, 10:00 a.m. PT Location: Anaheim Marriott, Anaheim, California The first participant to receive AK-OTOF in the study, an 11-year-old at the time of AK-OTOF administration with profound hearing loss from birth, experienced restored hearing within 30 days of AK-OTOF administration. In this individual, hearing was restored across all tested frequencies, achieving thresholds of 65 to 20 dB HL, and within the normal hearing range at some frequencies at the Day 30 visit. Both the surgical administration procedure and the investigational therapy were well tolerated, and no serious adverse events were reported. "Gene therapy for hearing loss is something physicians and scientists around the world have been working toward for over 20 years," said Professor John Germiller, M.D., Ph.D., attending surgeon and Director of Clinical Research in the Division of Otolaryngology at Children's Hospital of Philadelphia, and a principal investigator of the AK-OTOF-101 Clinical Trial who administered AK-OTOF to this participant. "These initial results show that it may restore hearing better than many thought possible." In the AK-OTOF-101 trial, eligible participants receive a single, unilateral intracochlear administration of AK-OTOF, with hearing restoration assessed by behavioral audiometry and auditory brainstem response (ABR), a clinically accepted and objective measure of hearing sensitivity. Participants in cohort 1 receive AK-OTOF at a dose of 4.1E11 total vector genomes. "Children with OTOF-mediated hearing loss are often born with profound hearing loss, yet only a small fraction have undergone genetic testing to receive a definitive diagnosis," said Dr. Oliver Haag, pediatric otolaryngologist, Head of Otolaryngology at Sant Joan de Deu Hospital in Barcelona, and an investigator in Akouos's AK-OTOF-NHS-002 Natural History Study in which the first individual to receive AK-OTOF was participating. "The AK-OTOF-101 Clinical Trial and AK-OTOF-NHS-002 Natural History Study demonstrate the power of international collaboration in the development of new medicines for rare genetic conditions. It is gratifying to see this collaborative effort provide benefit to the first participant to receive AK-OTOF." Hearing loss is the most common sensory condition, and with no approved pharmacologic treatments to restore hearing, represents a significant area of unmet need in medicine. Millions of individuals worldwide have disabling hearing loss because one of their genes generates an incorrect or incomplete version of a protein the ear requires for hearing. In many of these cases – including for some of the estimated 200,000 individuals worldwide who live with OTOF-mediated hearing loss – delivering a healthy version of the gene to a target cell within the inner ear has the potential to restore auditory function and enable high-acuity physiologic hearing. OTOF-mediated hearing loss is the first monogenic form of hearing loss to be investigated as part of a gene therapy clinical trial. "We are grateful to the participants, their families, the investigators and other collaborators who are working together with us on this pioneering trial," said Emmanuel Simons, Ph.D., M.B.A., CEO of Akouos and SVP, Gene Therapy at Lilly. "These initial results highlight the potential impact genetic medicines could have on individuals with OTOF-mediated hearing loss and reinforce our mission to make healthy hearing available to all." AK-OTOF has been granted Orphan Drug Designation and Rare Pediatric Disease Designation by the FDA and has received a positive opinion on orphan drug designation by the EMA Committee for Orphan Medicinal Products. About AK-OTOF and the AK-OTOF-101 Clinical Trial AK-OTOF (AAVAnc80-hOTOF) is a dual adeno-associated viral (AAV) vector-based gene therapy designed to restore auditory function by gene transfer and durable expression of normal, functional otoferlin protein to the inner hair cells of the cochlea. AK-OTOF utilizes AAVAnc80, a capsid with high transduction efficiency for inner hair cells, together with a strong ubiquitous promoter to achieve expression of otoferlin, observed only in the target inner hair cells, at levels that have the potential to restore high acuity physiologic hearing. The Akouos delivery device, being developed in parallel specifically for intracochlear administration, enables a minimally invasive surgical approach to deliver AK-OTOF throughout the cochlea. The AK-OTOF-101 Clinical Trial (NCT05821959) is a Phase 1/2 trial that is assessing the safety, tolerability, and bioactivity of escalating doses of AK-OTOF delivered via the Akouos delivery device. More information about the trial can be found at . About the OTOF-mediated Hearing Loss Natural History Study The AK-OTOF-NHS-002 Natural History Study (NCT05572073) is designed to characterize the natural history of OTOF-mediated hearing loss, including progression of physiologic responses and audiologic outcomes over time, potential genotype-phenotype relationships, and longitudinal assessment of clinical outcomes. More information about the study can be found at . About Lilly Lilly unites caring with discovery to create medicines that make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 51 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer's disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news or follow us on Facebook, Instagram and LinkedIn. C-LLY Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about AK-OTOF as a potential treatment for sensorineural hearing loss due to mutations in the otoferlin gene (OTOF) and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, or that AK-OTOF will receive regulatory approvals, or be commercially successful. For further discussion of risks and uncertainties relevant to Lilly's business that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. Company Codes: NYSE:LLY

临床结果孤儿药基因疗法临床研究

2023-08-21

·生物谷

20余年无新药上市，礼来、再生元纷纷布局，内耳疗法和听力损失之战拉开帷幕

听力损失是医学上未满足需求的最大领域之一，影响着全球约 4.66 亿人。听力损失可以追溯到多种原因，包括噪音损害、遗传、顺铂等化疗药物的耳毒性以及正常的衰老过程。听力损失是医学上未满足需求的最大领域之一，影响着全球约 4.66 亿人。听力损失可以追溯到多种原因，包括噪音损害、遗传、顺铂等化疗药物的耳毒性以及正常的衰老过程。过去一年里，大型药企达成的收购合作中，包括多个听力损失药物开发商，或被整体收购，或被收购部分资产。如礼来以高达 6.1 亿美元价格收购 Akouos；Korro Bio 与 Frequency Therapeutics 反向合并上市，后者拥有针对获得性感音神经性听力损失的候选药物。有机构预测，听力损失药物市场规模将从去年的 127.1 亿美元跃升至 2030 年的 186.6 亿美元，增幅达 47%。在与听力损失药物开发商 Decibel Therapeutics 合作 6 年后，再生元于近日豪掷 2.13 亿美元将其纳入麾下。根据交易条款，再生元将预付每股 4 美元，如果 Decibel 的主要研究候选药物达到特定里程碑则额外支付每股至多 3.50 美元，即约 1.09 亿美元预付款，以及 1.04 亿美元里程碑付款。再生元表示，其对 Decibel 的收购既将扩大买方的耳部疾病治疗产品线，又将与 Decibel 的产品线一起深化其基因治疗产品，其大部分产品是再生元通过六年的合作共同开发的。对于此次收购，Decibel 的投资者尤为看好，其股价从 2.79 美元/股上涨至 5.06 美元/股。另外，此次收购交易似乎还在解决 Decibel 因临床试验、研究和人员成本上升而面临的持续现金持有挑战。截至 3 月 31 日，Decibel 第一季度末现金、现金等价物和可供出售证券为 8794.1 万美元，较该公司截至 2022 年 12 月 31 日报告的 1.04561 亿美元下降了 16%。知名团队创立，最快管线至临床 I 期 Decibel 成立于 2013 年，并于 2021 年在纳斯达克上市。其创始人包括哈佛医学院耳科和喉科 Schuknecht 教授兼马萨诸塞州眼耳科伊顿-皮博迪实验室主任 Charles Liberman；密歇根大学克雷斯吉听力研究所所长 Gabriel Corfas；约翰·霍普金斯大学彭博杰出教授 Ulrich Mueller，以及哈佛医学院耳科和喉科教授兼马萨诸塞州眼耳科蒂洛森细胞生物学中心主任 Albert Edge。另外该公司还拥有多位来自哈佛医学院、密歇根大学、斯坦福大学等知名机构的专家作为科学顾问。在成立之初，Decibel 就获得了 Third Rock Ventures 、葛兰素史克 SR One 风险投资部门加注的 5200 万美元 A 轮融资。柯蒂氏器又称螺旋器，是听觉的感受器，位于哺乳动物的耳蜗内，可以将声音振动从中耳传输到听觉神经的神经末梢。噪音对耳蜗中近 15,000 个微小毛细胞和神经元或听觉神经造成的损害是迄今为止所谓的感音神经性听力损失的主要原因，其占到病例的90％。为了开发出精确靶向听觉神经或毛细胞的药物，Decibel 的研究人员研究了内耳的结构，深入到细胞水平。其方式是采用手术方式将基因引入内耳。 2017 年，Decibel 首次和再生元联手，通过价值未公开的合作“发现和开发新的潜在疗法来保护、修复和恢复听力”。当时，除了能够利用再生元的研究工具外，Decibel 也受益于其财务支持，并保留了管线开发和商业化权利。 2021 年，双方延长了合作关系。为此，再生元在 2022 年第四季度支付了 1000 万美元的合作延期费用。 Decibel 的主要听力损失候选药物是 DB-OTO，再生元正与其合作开发。这是一种细胞选择性、腺相关病毒 (AAV) 双载体基因疗法，旨在为因 otoferlin 突变而患有严重听力损失的人提供持久的听力恢复（OTOF）基因。Decibel 去年获得 FDA 批准其 I/II 期 CHORD™ 试验（NCT05788536），该研究截至 7 月 17 日正在招募患者，预计招募 22 名患者。 ▲图 | Decibel 部分管线（来源：公司官网）此外，再生元和 Decibel 正在合作开发两种临床前候选药物，包括针对 GJB2 相关听力损失的临床前项目 AAV.103，旨在恢复 GJB2 缺陷患者的听力，GJB2 缺陷是先天性听力损失的最常见原因；针对 STRC 相关听力损失患者的 AAV.104，旨在恢复缺乏 STRC 的个体的听力。除了基因治疗产品组合外，Decibel 的产品线中还有 DB-020，这是一种硫代硫酸钠制剂，正在 1b 期测试中，用于治疗因顺铂化疗引起的听力损失患者。2022 年 6 月，Decibel 提供的数据显示，该疗法可以保护患者的接受治疗的耳朵免受听力损失。该公司还正在开发两种毛细胞再生项目，用于治疗平衡障碍双侧前庭病和感音神经性听力损失。内耳疗法和听力损失之战感音神经性听力损失是最常见的听力损失类型，占到了病例的 90％。感音神经是指内耳成千上万细小毛细胞的感觉能力。内耳（又称耳蜗）入口处的毛细胞将高频率的声音传递给大脑，所有的声波振动进入内耳都会经过这些毛细胞。感音神经性听力损失的主要原因是向大脑传递声音信号的毛细胞受损。尽管学术研究中心、初创公司和老牌制药公司经过 20 多年的努力，但目前还没有 FDA 批准的用于治疗感音神经性听力损失的内耳疗法。主要原因是难以进入内耳的脆弱结构进行研究和药物应用。听力损伤药物开发取得重大突破至少取决于三个关键研究方向的融合：了解基本病理生理机制，识别疾病靶点、开发候选药物或其他治疗剂，以及开发递送系统。 ▲图 | 内耳治疗药物开发的系统性障碍（来源：Frontiers）药物开发与耳科和听力学领域之间的新颖性接口也是一种限制。“由于听力领域的药物开发很少，听力专家对药物开发了解相对较新，而具有药物开发经验的科学家往往是第一次了解听力领域，”Akouos 创始人、总裁兼首席执行官 Manny Simons 表示，在这两个领域之间建立跨学科的努力正在成为迫切需要。作为 Decibel 的竞争对手，Akouos 公司的主导项目 AK-OTOF 使用基于腺相关病毒 (AAV) 载体的基因疗法来治疗由 otoferlin 基因突变引起的感音神经性听力损失。Otoferlin 是一种跨膜蛋白，参与钙介导的内毛细胞突触小泡响应声音的胞吐作用，这一过程对于将电信号传输到大脑至关重要。 2022 年，该公司获得 FDA 批准 AK-OTOF 的 IND 申请，并计划启动儿科 1/2 期临床试验，以评估该疗法治疗 OTOF 介导的听力损失。同年，该公司被礼来收购，扩大了礼来在基因药物领域的业务，将 Akouos 用于治疗内耳疾病的潜在一流 AAV 基因疗法产品组合纳入其中。但也有不少公司在开发候选药物的道路上折戟。由于 FX-322 未能达到人体研究目标，总部位于圣地亚哥的 Frequency Therapeutics 终止了感音神经性听力损失项目 FX-322 的开发，并正在裁员。FX-322 在获得性 SNHL 患者中进行的安慰剂对照 IIb 期研究，招募了 142 名患有突发性或噪音诱发的感音神经性听力损失的患者，但未能达到改善言语感知的主要疗效终点。数据显示，第 90 天时，接受 FX-322 治疗的患者与接受安慰剂的患者之间，言语感知有所改善的个体比例没有统计学意义的差异。该公司科学创始人包括 Robert Langer。目前，Frequency 已经同意与 Korro Bio 通过反向合并上市，将于第四季度完成。 Otonomy 也在经历一系列临床失败后，宣布关闭并解雇了所有员工。其候选药物 OTO-413 在高剂量条件下，并未出现有临床意义的改善。