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（和先前批准的）ind使能

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.