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

摘要：该项目的目标是执行所需的(和之前批准的)IND启用 治疗脊髓性肌萎缩症(SMA)的新药E1v1.11的实验工作。SMA是常染色体 隐性遗传病是全球婴儿死亡的主要遗传原因，发生在大约1：10,000个活体中 出生。负责SMA的基因被称为存活运动神经元-1(SMN1)。SMn2几乎与 然而，如果SMN1被保留，SMN1的突变不会产生临床后果。SMN2不能阻止 在没有SMN1的情况下疾病的发展，这是由于大多数SMN2衍生的转录本是 选择性剪接，导致无功能和不稳定的蛋白质。然而，由于SMN2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， 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的致病选择性剪接。 此前，我们优化了各种基于吗啉齐聚物(PMO)的磷二酰胺ASO，并已 确定了领先的候选药物(E1v1.11)，该候选药物在细胞内检查的一系列剂量中显示出更高的有效性 和SMA的动物模型。我们已经将这些结果与Spinraza(目前的 治疗SMA患者的市场领先药物)在相同的动物模型(和相似的剂量方案)和 显示动物存活率提高12倍，最大耐受量增加150倍。我们有 还证明了目前用于合成E1v1.11的制造方法符合FDA 可批准的GMP生产要求。 Shift已经收到了FDA关于我们在Pre-Pre-IND中建议的IND实验的反馈 开会。我们计划进行所有IND支持实验(CMC和临床前)，以实现 最初的第一阶段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FDA在IND前会议上的书面反馈)对幼年Spraogue-Dawley大鼠和非 GLP协议下的人类灵长类使用我们的药物物质和GMP制造的药物产品 为我们的IND申报和临床研究做准备。最后，Shift在SMA中招募了意见领袖 加入我们的临床咨询委员会的空间。他们帮助该公司确定了患者在 SMA空间，即与目前可用的相比，成人SMA患者的治疗反应有所改善 毒品。在这笔赠款期间，他们将协助制定临床试验方案。 SMA是一种复杂的遗传性疾病，具有广泛的临床图谱。随着2016年FDA批准的第一个 SMA特异性药物(Spiranza)的不断发展对SMA疗法的发展具有重要意义。我们相信 E1ASO Morpholino将是SMA产品组合中令人兴奋和有价值的补充，以进一步打击这一问题 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.