Targeting TGF-ß in the Central Nervous System: Assessment of Cynomolgus Monkey—Toxicity and Pharmacokinetics for an LNA-Antisense Oligonucleotide

Increasingly antisense oligonucleotides (ASOs) are developed for potential treatment of CNS disorders, and due to the inability cross blood brain barrier, they require direct administration into cerebrospinal fluid (CSF). In this regard, intrathecal (i.th.) in cynomolgus monkeys (Macaca fascicularis) is a well-established approach preclinical safety studies. Here, we present an innovative that intended support rapid entry clinical development with ASOs targeting CNS. The comprises one non-GLP study 26 non-human primates, followed by pivotal GLP repeated dose toxicity same species. No rodent studies were conducted, regulatory guidance initiate was met vitro work. consists three separate phases: Phase A determines after i.th. administrations five escalating levels single male female animal, respectively. Dosing conducted on days 1, 8, 15, 22, 29 experiment terminated 36 start study. second phase (Phase B) investigates pharmacokinetics over 2- or 4-week period at two following eight (8) animals (4 females, 4 males). Finally, third C) (9×) dosing 13-week sixteen (8 8 males) animals. each phase, observations physical/neurological parameters investigated directly pre-dose, h 24 post-dose, all phases, CSF samples taken pre-dose dosing, determination test article concentration, biomarkers tolerability pharmacology. tissue from liver, kidney, spinal cord, collected NVP-13 concentrations. above concept has successfully supported first-in-human trials. entire program completed within less than six months requires fewer comparison conduct independent