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

翻译后摘要：本项目的目标是执行所需的（和以前批准的）IND使能 E1v1.11是一种治疗脊髓性肌萎缩症（SMA）的新型候选药物。SMA是一种常染色体 一种隐性疾病，是全球婴儿死亡的主要遗传原因，发生率约为1：10，000 出生负责SMA的基因被称为运动神经元生存-1（SMN 1）。SMN 2几乎与 然而，如果保留SMN 1，SMN 2中的突变没有临床后果。SMN 2无法阻止 由于大多数SMN 2衍生的转录物是由SMN 1引起的， 选择性剪接，导致无功能且不稳定的蛋白质。然而，由于SMN 2存在于所有 SMA患者和重叠的蛋白质编码序列仍然能够产生“正常”的SMN， SMN 2的存在为许多令人兴奋的治疗策略打开了大门，包括调节SMN 2的表达。 SMN 2外显子7的致病性选择性剪接。 之前，我们优化了多种基于磷酰二胺吗啉代寡聚物（PMO）的ASO，并已 确定了一种主要候选药物（E1v1.11），在细胞内检查的剂量范围内表现出更大的疗效。 和SMA的动物模型。我们将这些结果与Spinraza（目前的 用于治疗SMA患者的市场领先药物）在相同的动物模型中（和相似的给药方案）， 显示动物存活率提高12倍，最大耐受剂量增加150倍。我们有 还证明了目前用于合成E1v1.11的生产方法符合FDA GMP生产批准的要求。 Shift已收到FDA关于我们在pre-pre-IND中拟议IND实验的反馈 会议我们计划进行所有IND使能实验（CMC和临床前）， 初步的1期临床试验将在该项目结束时开始。我们将进行安全实验 （根据我们IND前会议的FDA书面反馈） 根据GLP方案使用我们的原料药和根据GMP生产的制剂进行人灵长类动物试验 为我们的IND申请和临床研究做准备。最后，Shift在SMA中招募了意见领袖 加入我们的临床顾问委员会。他们帮助该公司确定了一个“关键”的病人需求， SMA空间，即与目前可用的治疗相比，成人SMA患者的治疗反应有所改善 毒品他们将在此期间协助制定临床试验方案。 SMA是一种复杂的遗传性疾病，具有广泛的临床谱。随着2016年FDA批准的第一个 SMA特异性药物（Spiranza），继续开发SMA治疗药物非常重要。我们认为 E1阿索Morpholino将是SMA产品组合中令人兴奋和有价值的补充，以进一步解决这一问题 毁灭性的疾病

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.