Executive Director Ionis Pharmaceuticals Carlsbad, California, United States
The interest for applying MOE ASOs to treat CNS diseases comes from their efficient uptake into neuronal cells and long half-lives that support therapeutic use despite the need for intrathecal (IT) administration. The toxicology properties of systemically administered MOE ASOs have been relatively well characterized over the years, but there have been a number of technical challenges associated with conducting the expected nonclinical safety assessment based on the ICHM3(R2) guidance using the IT route of administration. The NHP is considered the most relevant species, but valuable tolerability information can also be obtained in rodents. One of the primary challenges is in completing repeated administration by the intended route of clinical administration in 2 species. Administration to mice via intracerebroventricular (ICV) administration or rats using IT administration are limited by anatomic differences, especially in terms of covering chronic exposure. The toxicology assessment focuses more on the local tolerability, which is supported by enhanced neuropathology and also more detailed assessment of neurobehavioral changes, in addition to the typical systemic toxicology endpoints. Regardless of the species, being aware of the procedural related lesions is very important. Further challenges include the inability to do precise toxicokinetic sampling of the central compartment. While plasma exposure can be used to assess total systemic exposure, the inability to get CSF Cmax or AUC values limits the ability to establish detailed exposure-response relationships. One also needs to take a modified approach to completing the assessment of reproductive toxicity, carcinogenicity and impurity qualification. While there are challenges, these are surmountable with several programs having progressed through to Phase 3 studies and two approved IT-administered ASOs for CNS indications.
