Antisense Oligonucleotide VO659 Reduces Mutant Huntingtin Protein, Interim Phase 1/2 Data Show
VO659 was considered safe and well tolerated, with treated patients showing no sustained increase in neurofilament light protein through day 85 of treatment.
Micah Mackison
In a phase 1/2 trial (NCT05822908), treatment with Vico Therapeutics’ investigational allele-preferential antisense oligonucleotide (ASO) therapy VO659 resulted in reductions in mutant huntingtin protein (mHTT) among patients with Huntington disease (HD). These interim results, presented at the European Huntington's Disease Network's EHDN & Enroll-HD 2024 meeting, highlighted the potential of VO659 in this patient population.1
Through day 85 of the study, patients on 40 mg of VO659 demonstrated a 28% mean reduction in cerebrospinal fluid (CSF) mHTT relative to the first dose at day 29. During this time, there were no sustained increase or decrease in neurofilament light protein, a marker of neuroaxonal damage, in CSF across treated participants. Above all, the therapy, which is designed to target the CAG repeat expansion that causes all nine known polyglutamine diseases, was safe and well tolerated at doses of 40 mg. Furthermore, it showed a long half-life, indicating the potential for infrequent dosing estimated at 1-2 times per year.
"We are very pleased to announce these first data from our Phase 1/2a clinical trial of VO659 in participants living with HD," Micah Mackison, chief executive officer at Vico, said in a statement.1 "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."
The trial is a multicenter, open-label basket study that investigates the safety and tolerability of multiple ascending doses of VO659 given intrathecally to patients with early manifest HD or mild to moderate spinocerebellar ataxia types 1 (SCA1) and 3 (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.
Mackison added, "These data are a significant milestone for our team and for the HD community that so desperately needs treatment options, and we look forward to continuing assessments from the trial and advancing VO659 as quickly as possible for patients and their families."
VO659 preferentially targets expanded CAG repeats in the mutant mRNA transcript and inhibits mRNA translation leading to reduction of mutant protein with the goal of stopping or reversing disease progression. The newly announced data build on preclinical findings, where treatment with VO659 resulted in significant and dose-dependent reductions of mHTT and improvement in motor function in disease mouse models of HD. In vitro data have also showed allele-preferential reductions of mHTT in HD patient cell models as well.
Scott Schobel, MD
In terms of patient demographics, the phase 1 study includes those aged between 25 and 60 years who have either SCA1, SCA3, or HD. For SCA1 and SCA3, these patients must have a mild to moderate disease with a Scale for Assessment and Rating of Ataxia score of at least 3 and less than or equal to 18. For HD, these patients must have a total functional capacity score of between 11-13 and a Unified Huntington’s Disease Rating Scale diagnostic confidence level of 4. Furthermore, patients included in the study have genetically confirmed disease, defined by increased cytosine, adenine, and guanine repeat length in the disease-causing allele by direct DNA testing.2
"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," Scott Schobel, MD, chief medical officer at Vico, said in a statement.1 "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."
Earlier this year, Vico announced a $60 million series B financing to advance VO659’s clinical-stage program. The financing will support overall company operations including the ongoing phase 1/2 trial as well as help support discover and research efforts to further expand the company’s pipeline in other genetic neurological diseases. The financing was led by new investor Ackermans & van Haaren (AvH) with existing co-leads Droia Ventures, EQT Life Sciences and Kurma Partners along with prior investors Polaris Partners, Pureos Bioventures and Eurazeo.3
