Vico Therapeutics' investigational antisense oligonucleotide (ASO) therapy, VO659, has demonstrated promising results in reducing mutant huntingtin protein (mHTT) levels in patients with Huntington's disease (HD). Interim data from a Phase 1/2 clinical trial (NCT05822908), presented at the European Huntington's Disease Network's EHDN & Enroll-HD 2024 meeting, indicate that VO659 could potentially modify the course of this devastating neurodegenerative disorder.
Interim Phase 1/2 Results
The open-label, multiple ascending dose study evaluated the safety, tolerability, and efficacy of VO659 in patients with early manifest HD, as well as those with mild to moderate spinocerebellar ataxia types 1 (SCA1) and 3 (SCA3). The interim analysis focused on HD patients receiving a 40 mg dose of VO659. By day 85, these patients exhibited a 28% mean reduction in mHTT levels in cerebrospinal fluid (CSF) relative to baseline, measured from day 29 after the first dose.
Notably, the treatment did not cause sustained increases or decreases in neurofilament light protein (Nf-L), a marker of neuroaxonal damage, suggesting that VO659's mechanism of action is not associated with neurotoxicity at the tested dose. The drug was reported to be generally safe and well-tolerated.
Mechanism of Action and Potential for Infrequent Dosing
VO659 is designed to target the CAG repeat expansion in the mutant huntingtin mRNA transcript, inhibiting its translation and reducing the production of mHTT. This allele-preferential approach aims to selectively suppress the mutant protein while sparing the wild-type huntingtin protein, which is essential for normal cellular function. The drug's long half-life suggests that it may be administered infrequently, potentially once or twice per year, which could significantly improve patient compliance and quality of life.
Executive Perspectives
"We are very pleased to announce these first data from our Phase 1/2a clinical trial of VO659 in participants living with HD," said Micah Mackison, chief executive officer at Vico. "It is highly encouraging that we saw immediate reductions in CSF mHTT and no changes in Nf-L protein, two key biomarkers in HD, in treated patients over the available follow-up period. Given VO659's long anticipated half-life, there is clear potential for this therapy to have an infrequent dosing schedule, and we look forward to exploring this further in clinical trials."
Scott Schobel, MD, chief medical officer at Vico, added, "VO659's allele-preferential action and direct targeting of the CAG repeat expansion that causes HD is a unique approach to treating this disease with a promising future for the HD community. The Phase 1/2a interim clinical data reinforce the potent, targeted nature of VO659 and add to a growing body of evidence supporting VO659's advancement in the clinic for HD as well as its broad potential applications for all CAG repeat expansion diseases."
Study Design and Patient Population
The ongoing Phase 1/2a trial is a multicenter, open-label study involving patients aged 25 to 60 years with genetically confirmed SCA1, SCA3, or early manifest HD. HD patients were required to have a total functional capacity score between 11 and 13 and a Unified Huntington’s Disease Rating Scale diagnostic confidence level of 4. The primary endpoints include the evaluation of pharmacodynamic biomarkers (mHTT, total HTT, mATXN3, total ATXN3, and neurofilament light chain) in CSF, plasma pharmacokinetics, and clinical outcome measures.
Huntington's Disease Context
Huntington's disease is a progressive neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene, leading to the production of mutant HTT protein (mHTT). This results in motor, cognitive, and psychiatric symptoms. Current treatments primarily address symptomatic relief, highlighting the urgent need for disease-modifying therapies. VO659 has received Orphan Drug designation from both the FDA and EMA for the treatment of HD, underscoring its potential to address this unmet need.
