Spinocerebellar ataxia types 1 and 3 (SCA1 and SCA3), as well as Huntington's disease (HD) are severely debilitating, monogenic, neurodegenerative diseases that presently have no treatments to slow or stop clinical progression. Preclinical data suggest that VO659 may be a disease-modifying therapy in these disorders through its binding to the expansion of CAG repeats in the RNA transcripts of the causative genes, thus interfering with RNA translation and reducing the intracellular level of the harmful mutant proteins.~The present trial is the first-in-human (FiH) evaluation of VO659. This is an open-label, multiple ascending dose, multi-centre phase 1/2a trial investigate the safety, tolerability and pharmacokinetics and explore the pharmacodynamics of intrathecally administered study drug VO659.~The trial population comprises generally ambulatory participants with mild to moderate SCA1 or SCA3, or early manifest HD. Participants are assigned to dose-ascending treatment cohorts based on the order of enrolment. Dose-escalation is planned in up to five dose levels. Dose-level cohorts one and two will comprise participants with SCA3 only, and from dose-level cohorts three onwards participants with SCA1, SCA3 and HD will be enrolled.~The total duration of trial participation for each participant is up to approximately 42 weeks, consisting of a screening period of up to 6 weeks, a 13-week dosing period with the study drug VO659 being administered intrathecally four times and a 23-week post-dosing period.~During the four dosing blocks, CSF and blood samples for safety and pharmacokinetics (PK) will be collected at specific time points.
The goal of this first-in-human clinical trial is to assess the safety and tolerability of four doses of a new study drug called VO659 in people with genetic disorders called spinocerebellar ataxia type 1, type 3 or Huntington's disease. Another aim is to determine the concentrations of the study drug in the cerebral spinal fluid and blood after single and multiple doses. Study drug will be administered by lumbar intrathecal bolus injections.