Dosing Commenced in Phase 1/2a Trial of VO659 in Huntington Disease and Spinocerebellar Ataxia Types 1 and 3


VO659, the only clinical candidate targeting the CAG repeat expansion that causes all polyglutamine diseases, is designed to reduce mutant HTT and spare wildtype HTT.

Scott Schobel, MD, chief medical officer at Vico Therapeutics

Scott Schobel, MD

In recent news, Vico Therapeutics announced that the first patient has been dosed in a phase 1/2a clinical study evaluating its investigational agent VO659 for the treatment of Huntington’s disease (HD) and spinocerebellar ataxia types 1 (SCA1) and 3 (SCA3). The treatment, an antisense oligonucleotide (ASO) investigational therapy, targets the CAG repeat expansion known to cause all 9 known polyglutamine diseases and enables potent target engagement across multiple disease models.1

Findings from preclinical data showed that VO659 induced a significant reduction of mutant ATXN1 (mATXN1) and mutant ATXN3 (mATXN3) protein levels in vivo and in vitro in disease mouse models and patient cell models of SCA1 and SCA3, respectively. Additionally, results showed significant and dose-dependent reductions of mutant huntingtin protein (mHTT) and improvement in motor function observed in vivo in disease mouse models of HD. Notably, allele-preferential reductions of mHTT were reported in vitro in HD patient cell models as well.

“We are encouraged by the continued progress of our development program and very pleased to announce the first patient dosed in this phase 1/2a study of VO659 in HD, SCA1 and SCA3,” said Scott Schobel, MD, chief medical officer at Vico said in a statement.1 “VO659 is the first allele-preferential ASO in clinical development with broad application to all CAG repeat expansion diseases. The robust preclinical data package for VO659 demonstrates favorable brain uptake, potency and durability of effect, and we look forward to assessing the translation of these characteristics in this clinical trial.”

The trial is a multi-center, open-label basket study that is investigating the safety and tolerability of multiple ascending doses of VO659 given intrathecally to patients with early manifest HD or mild to moderate SCA1 or SCA3. Endpoints of the study include the evaluation of the pharmacodynamic biomarkers (mHTT, total HTT, mATXN3, total ATXN3 and neurofilament light chain) in cerebrospinal fluid (CSF), plasma pharmacokinetics, and clinical outcome measures. Approximately 71 participants are expected to enroll into the study.

Additionally, the company reported that investigators will highlight the preclinical data of VO659 and trial design of the phase 1/2 study during an oral presentation as well as in several poster presentations at the CHDI Foundation’s 18th Annual Huntington’s Disease Therapeutics Conference being held in Dubrovnik, Croatia, from April 24-27, 2023.1

“It is our mission to bring safe, effective therapies to patients and families affected by devastating neurological diseases, and today marks an important milestone in our journey to realize this mission. We are grateful to the trial investigators and patients participating in our phase 1/2a study as we assess the potential of VO659 in HD, SCA1 and SCA3. We also look forward to sharing more details about the study at CHDI’s Annual Huntington’s Disease Therapeutics Conference later this month,” said Micah Mackison, chief executive officer at Vico said in statement.1

Although there has only been a handful of agents to show efficacy in HD, recently announced findings from the SELECT-HD trial (NCT05032196) of WVE-003 (Wave Life Sciences), a stereopure antisense oligonucleotide, showed a reduced HD-specific mHTT protein in CSF, as well as preserved wild-type huntingtin (wtHTT) protein.2 All told, WVE-003 was well-tolerated and safe for doses up to 90 mg. For those who received 30- and 60-mg single doses of the agent, pooled analysis showed a 22% median reduction in CSF mHTT from baseline to day 85, and an even greater difference in mean reduction (35%) when compared with placebo.

Additional findings from the SELECT-HD trial showed that treatment with the agent in 30- or 60-mg doses preserved wtHTT protein, which appeared consistent with allele-selectivity. Notably, some participants showed increases in neurofilament light. Overall, patients showed no clinically meaningful changes in CSF white blood cell counts or protein that would indicate inflammation in the central nervous system, nor did they show meaningful changes in clinical outcome measures, although the dataset and duration were not sufficient to assess clinical effects.2

1. Vico Therapeutics Announces First Patient Dosed in Phase 1/2a Clinical Trial of VO659 in Huntington's Disease and Spinocerebellar Ataxia Types 1 and 3. News Release. Vico Therapuetics. Published April 3, 2023. Accessed April 6, 2023.
2. Wave Life Sciences announces positive update from phase 1b/2a SELECT-HD trial with initial results indicating allele-selective target engagement with WVE-003 in Huntington’s disease. News release. Wave Life Sciences. September 20, 2022. Accessed April 6, 2023.
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