Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein.Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development.

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Our understanding of potential roles of RNAs in maintaining normal health and contribution to various diseases is increasing; thus directly targeting RNAs (with second generation ASOs) present a compelling therapeutic strategy. Further, the similar clinical PK properties across the class of second generation ASOs helps facilitate their clinical development. The majority of published information available for assessment is restricted to acute/sub-acute early clinical development. A limited but growing database on chronic dosing of second generation ASOs, across various patient and special populations, and also with non-systemic local delivery approaches, will help further characterize the clinical PK properties of these compounds and better quantify the extent and sources of any observed PK variability and potential impact on clinical response.

Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.