IND Enabling Non-Clinical Development of E1v1.11, a Morpholino Anti-Sense Oligonucleotide for the treatment of Spinal Muscular Atrophy.

IND 促进 E1v1.11 的非临床开发，E1v1.11 是一种用于治疗脊髓性肌萎缩症的吗啉代反义寡核苷酸。

• 批准号: 10569744
• 负责人: Steve OConnor
• 金额: $ 36.09万
• 依托单位: SHIFT PHARMACEUTICALS HOLDINGS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569744
• 关键词: Acceleration; Adolescent; Adult; Adult Spinal Muscular Atrophy; Alternative Splicing; Animal Model; Animals; Antisense Oligonucleotides; Binding; Biodistribution; Cell model; Clinical; Clinical Research; Clinical Trials; Code; Complex; Development; Disease; Documentation; Dose; Drug Packaging; Exhibits; Exons; Feedback; Genes; Genetic; Genetic Diseases; Goals; Grant; Human; In Vitro; Institutional Review Boards; Live Birth; Macaca fascicularis; Marketing; Maximum Tolerated Dose; Mediation; Methods; Micronucleus Tests; Mus; Mutation; Neurodegenerative Disorders; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Preparation; Proteins; Protocols documentation; Publishing; Rattus; Recovery; Regimen; Report (document); Research Design; SMN1 gene; SMN2 gene; Safety; Site; Spinal Muscular Atrophy; Sprague-Dawley Rats; Testing; Therapeutic; Time; Toxic effect; Toxicokinetics; Transcript; Work; Writing; autosome; clinical development; clinical trial protocol; combat; drug candidate; experimental study; genotoxicity; improved; in vivo; infant death; lead candidate; manufacture; nonhuman primate; novel therapeutics; participant enrollment; phase 2 study; phosphorodiamidate morpholino oligomer; pre-Investigational New Drug meeting; pre-clinical; prevent; recruit; subcutaneous; treatment response; trial planning

Abstract: The objective of this project is to perform the required (and previously approved) IND-enabling experimental work for E1v1.11, a novel drug candidate for Spinal Muscular Atrophy (SMA). SMA is an autosomal recessive disorder that is the leading genetic cause of infantile death worldwide, occurring in ~1:10,000 live births. The gene responsible for SMA is called survival motor neuron-1 (SMN1). SMN2 is nearly identical to SMN1, however, mutations in SMN2 have no clinical consequence if SMN1 is retained. SMN2 cannot prevent disease development in the absence of SMN1 due to the fact that the majority of SMN2-derived transcripts are alternatively spliced, resulting in a non-functional and unstable protein. However, since SMN2 is present in all SMA patients and the overlapping protein coding sequence is still capable of producing “normal” SMN, the presence of SMN2 opens the door to a number of exciting therapeutic strategies including modulating the pathogenic alternative splicing of SMN2 exon 7. Previously, we optimized a variety of phosphorodiamidate Morpholino oligomer (PMO)-based ASOs and have identified a lead candidate (E1v1.11) that exhibits greater efficacy across a range of doses examined in cellular and animal models of SMA. We have compared these results to published results of Spinraza (the current market leading drug for treating SMA patients) in the same animal models (and similar dosing regimen) and show a 12x-fold improvement in animal survival and a 150x-fold increase in maximum tolerated dose. We have also demonstrated that the manufacturing methods currently being used to synthesize E1v1.11 meet FDA requirement for approvable GMP manufacturing. Shift has received feedback from the FDA regarding our proposed IND experiments in a pre-pre-IND meeting. We plan to conduct all of the IND enabling experiments (both CMC and pre-clinical) that will allow initial Phase 1 clinical trials to begin at the conclusion of this project. We will conduct safety experiments (following written FDA feedback from our pre-IND meeting) on both juvenile Sprague-Dawley rats and non- human primates under GLP protocols using our drug substance and drug products manufactured under GMP in preparation for our IND filing and clinical studies. Finally, Shift has recruited opinion leaders in the SMA space to join our Clinical Advisory Board. They have helped the company to identify a “key” patient need in the SMA space, namely improved therapeutic responses in adult SMA patients compared to currently available drugs. They will assist with the development of clinical trial protocols during this grant. SMA is a complex genetic disorder with a broad clinical spectrum. With the 2016 FDA approval of the first SMA-specific drug (Spiranza), it is important to continue to the development of SMA therapeutics. We believe an E1 ASO Morpholino will be an exciting and valuable addition to the SMA portfolio to further combat this devastating disease.

摘要：该项目的目标是执行所需的（和先前批准的） IND 支持 E1v1.11 的实验工作是一种治疗脊髓性肌萎缩症 (SMA) 的新药物。 隐性遗传病是全球婴儿死亡的主要原因，发生率约为 1:10,000 负责 SMA 的基因称为生存运动神经元-1 (SMN1)，与 SMN2 几乎相同。 然而，如果 SMN1 不能被保留，SMN2 的突变不会产生临床后果。 由于大多数 SMN2 衍生的转录本都是在缺乏 SMN1 的情况下发生疾病的 然而，由于 SMN2 存在于所有蛋白质中，因此产生了非功能性且不稳定的蛋白质。 SMA 患者和重叠的蛋白质编码序列仍然能够产生“正常”SMN，即 SMN2 的存在为许多令人兴奋的治疗策略打开了大门，包括调节 SMN2 外显子 7 的致病性选择性剪接。 此前，我们优化了多种基于磷酸二酰胺吗啉代低聚物 (PMO) 的 ASO，并获得了 确定了一种主要候选药物 (E1v1.11)，该候选药物在细胞中检查的一系列剂量中表现出更大的功效 我们将这些结果与 Spinraza 的已发表结果（当前的结果）进行了比较。 在相同的动物模型（和相似的给药方案）中治疗 SMA 患者的市场领先药物 动物存活率提高了 12 倍，最大耐受剂量提高了 150 倍。 还证明目前用于合成E1v1.11的制造方法符合FDA要求 批准 GMP 生产的要求。 Shift 已收到 FDA 关于我们在预预 IND 中拟议的 IND 实验的反馈 我们计划进行所有 IND 实验（CMC 和临床前实验），以实现这一目标。 最初的一期临床试验将在该项目结束时开始，我们将进行安全性实验。 （根据我们的 IND 前会议的 FDA 书面反馈）对幼年 Sprague-Dawley 大鼠和非 根据 GLP 协议使用我们的原料药和根据 GMP 生产的药品对人类灵长类动物进行研究 最后，Shift 在 SMA 中招募了意见领袖。 他们帮助公司确定了患者的“关键”需求。 SMA 空间，即与现有技术相比，成年 SMA 患者的治疗反应有所改善 他们将在这笔拨款期间协助药物制定临床试验方案。 SMA 是一种复杂的遗传性疾病，具有广泛的临床谱，并于 2016 年获得 FDA 批准。 SMA特异性药物（Spiranza），我们认为继续开发SMA疗法很重要。 E1 ASO Morpholino 将成为 SMA 产品组合中令人兴奋且有价值的补充，以进一步解决这一问题 可怕的疾病。