Vico Therapeutics has shared an interim update from their Phase 1/2a clinical trial of VO659, a drug targeting CAG repeats in patients with Huntington's disease (HD) and spinocerebellar ataxias (SCA1 and SCA3). The data suggests that VO659 may reduce levels of the toxic HD protein and provides insights into safety.
VO659 is an antisense oligonucleotide (ASO) designed to bind to genetic message molecules containing long strings of repeating CAGs, like those found in the expanded HTT gene in people with HD. By targeting these repeats, VO659 aims to reduce the levels of toxic proteins produced by CAG expansion diseases.
Targeting CAG Repeats in Multiple Diseases
Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and spinocerebellar ataxia type 3 (SCA3) are caused by expansions of CAG repeats in the HTT, Ataxin-1, and Ataxin-3 genes, respectively. These expansions lead to the production of toxic proteins that drive neurological disease. VO659's mechanism of action makes it a potential therapeutic for all CAG repeat expansion diseases.
Vico's approach differs from other ASOs in development for HD. Some target total HTT (both unexpanded and CAG-expanded), while others target only the disease-form of HTT. VO659 targets the CAG repeats present on both the expanded and unexpanded copies of HTT, with a preference for longer CAG repeats found in the disease-causing genes.
Basket Trial Design
To efficiently test VO659, Vico designed a "basket trial" enrolling patients with SCA1, SCA3, and HD who have increased CAG repeats in their respective genes. This approach allows for quicker assessment of safety and efficacy across multiple rare diseases.
Participants in the trial are between 25-60 years old with a genetic diagnosis of SCA1 (41+ CAG repeats), SCA3 (61+ CAG repeats), or HD (36+ CAG repeats). They must also be in the early stages of their disease, as defined by specific clinical metrics such as the Scale for Assessment Rating of Ataxia (SARA) score for SCA1/3 and the Total Functional Capacity (TFC) score for HD.
The interim data presented is from 23 participants: 6 with HD, 3 with SCA1, and 14 with SCA3. The trial is testing three different doses of VO659 (10, 20, and 40 mg), with all HD patients receiving the highest dose. Participants receive four doses of the drug every 4 weeks, with a 23-week follow-up period after dosing.
Interim Results: Safety and Efficacy
The interim update, shared at recent conferences, revealed that VO659 was generally safe and tolerated, although further analysis provided a more nuanced picture. Four of the six HD patients receiving the 40 mg dose experienced radiculitis, a painful nerve condition. This side effect has been observed with other ASO therapies. Vico plans to mitigate this issue by lowering the drug amount in future trials. Other side effects were minor, including headaches, dizziness, and nausea.
Neurofilament light (NfL), a biomarker of brain health, showed a slight increase after dosing in some patients, which is expected after a lumbar puncture. However, long-term NfL levels did not significantly increase in most patients. More recent data suggests a 2.5% decrease in NfL levels in 5 HD patients receiving the 40 mg dose after 120 days.
In HD patients, a 28% reduction in expanded HTT levels was observed after the fourth dose of 40mg VO659. More recent data showed a 38% reduction in HTT levels in 3 patients at 120 days, suggesting a long-lasting effect even after dosing has stopped.
Data from SCA3 patients showed no change in expanded Ataxin-3 levels in spinal fluid, but some reduction was observed in blood samples. No dose-dependent effect was seen, and further data is needed to confirm these findings.
Future Directions
Vico is continuing the Phase 1/2a study to collect more data. They are also in discussions with regulators regarding a Phase 2 trial of VO659 in HD patients. Future studies will likely involve less frequent dosing (1-3 times per year) to address potential safety issues related to drug accumulation.
