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Long‑term safety of intrathecal VO659 in participants with Huntington’s disease, spinocerebellar ataxia type 1 or type 3

Verified siteInvestigationalNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study looks at people with Huntington’s disease and the rare movement disorders spinocerebellar ataxia type 1 and spinocerebellar ataxia type 3. The investigational medicine is called VO659. It is given as a small amount of liquid injected directly into the fluid‑filled space around the spinal cord, a route known as intrathecal administration. This approach aims to deliver the drug close to the brain and spinal cord where the disease causes damage.

The main aim of the trial is to see whether repeated doses of the medicine are safe over a long period. Participants will receive a series of injections spaced out over several months and will attend regular visits for physical and neurological examinations, heart rhythm checks called ECG, imaging scans of the brain using MRI, and laboratory tests of blood, urine and CSF. Any side effects or changes in health will be recorded, and participants will be asked about their daily functioning and quality of life throughout the study.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline Assessments

    Before receiving the study medication, you will undergo a series of examinations to record your health status.

    These examinations include a physical and neurological exam, measurement of vital signs such as blood pressure and heart rate, an ECG (electrocardiogram) to check heart rhythm, and an MRI (magnetic resonance imaging) scan of the brain.

    Laboratory tests will be performed on blood, cerebrospinal fluid (CSF), and urine to evaluate safety parameters.

    You will also complete several questionnaires, including the Columbia‑Suicide Severity Rating Scale (C‑SSRS) and disease‑specific outcome measures.

  2. Step 2

    First Intrathecal Injection of VO659

    On the day of the first dose, a healthcare professional will administer VO659 as a single 60 mg bolus injection into the lumbar intrathecal space (the fluid‑filled area surrounding the spinal cord).

    The medication is provided as a sterile solution for injection.

  3. Step 3

    Immediate Post‑Injection Observation

    After the injection, you will be observed for a short period to monitor for any immediate reactions or side effects.

    Vital signs and symptoms will be checked regularly during this observation period.

  4. Step 4

    Scheduled Safety Monitoring Visits

    You will attend regular clinic visits after the injection to assess long‑term safety.

    Each visit includes a repeat physical and neurological exam, vital‑sign measurement, and an ECG.

    Brain imaging with MRI will be performed at specified intervals to look for structural changes.

    Blood, CSF, and urine samples will be collected to monitor laboratory safety parameters.

    You will complete follow‑up questionnaires such as the Unified Huntington’s Disease Rating Scale (UHDRS) for Huntington’s disease, the Scale for the Assessment and Rating of Ataxia (SARA) and Friedreich Ataxia Rating Scale (FARS) for ataxia, the Symbol Digit Modalities Test (SDMT), the Montreal Cognitive Assessment (MoCA), and the Clinical Global Impression (CGI) scales.

    Additional patient‑reported outcome tools, including the Patient Global Impression (PGI) scales, the Neuro‑QoL cognition short form, and the EuroQol five‑dimension questionnaire (EQ‑5D‑5L), will be administered.

    Levels of neurofilament light chain (NfL) in the CSF may also be measured.

  5. Step 5

    Long‑Term Follow‑Up Until Study Completion

    The study continues with periodic safety assessments for several years, ending on the estimated study completion date in September 2030.

    During this period, all previously described examinations and questionnaires will be repeated according to the study schedule to evaluate any long‑term effects of the medication.

Who can join the trial?

7 criteria

  • Must have already taken part in earlier VO659 studies and finished all dosing periods.
  • Must sign a written agreement called informed consent after showing they understand the study, using a special tool that checks their ability to give consent.
  • Must be in generally good health, apart from having one of the following conditions: Huntington's disease (HD), Spinocerebellar ataxia type 1 (SCA1), or Spinocerebellar ataxia type 3 (SCA3).
  • Must be able to follow all study visits and procedures; the doctor must decide that the disease is not so advanced that the participant cannot complete the required assessments.
  • Must have a body weight of at least 50 kg and a body mass index (BMI) of 17.5 or higher but less than 32.5; BMI is a number that relates weight to height.
  • Must agree to use birth control methods as required by local rules:
    • Male participants who can produce sperm and have a sexually active partner who could become pregnant must use a condom from the first dose until 225 days after the last dose and must not donate sperm during that time; the female partner should also use birth control.
    • Female participants who could become pregnant must have a negative pregnancy test before screening and before each dose, and must use a highly effective method of contraception during the study and until 225 days after the last dose. Women are considered able to become pregnant from the start of menstrual periods (menarche) until they become permanently unable to have children (through surgery such as hysterectomy or naturally after menopause). Menopause is defined as no periods for at least 12 months without another medical cause, and for women under 55 years, a hormone test (FSH level > 40 mIU/mL) may be needed to confirm menopause.

Who cannot join the trial?

32 criteria

  • Serious adverse event (SAE) related to VO659 in a previous study prevents participation.
  • Uncontrolled heart problems, any past or present irregular heartbeat, or a prolonged QT interval on an ECG (over 450 ms for men or 470 ms for women), as well as a family history of long QT syndrome or sudden unexpected death, exclude you.
  • Hospital stay for a major surgery that used general anaesthesia within 6 weeks before screening, or any similar surgery planned during the trial, makes you ineligible.
  • A history of suicide attempt or serious suicidal thoughts with a plan that required hospital admission within the past 12 months, or certain scores on a suicide‑risk questionnaire, will exclude you.
  • Having had psychosis, bipolar disorder, schizophrenia, or being at high risk for severe depression, confusion, or violent behaviour disqualifies you.
  • Having an implanted shunt to drain cerebrospinal fluid or any implanted brain‑related catheter excludes you.
  • Use of another investigational drug, biological product, or medical device within 3 months before screening (or until five half‑lives of that product have passed) prevents participation.
  • Taking the medication Riluzole is not allowed unless you have been on a steady dose for at least 4 weeks and the dose will not change during the study.
  • Medications for muscle stiffness (spasticity) are not allowed unless you have been on a stable dose for at least 4 weeks with no expected changes.
  • Use of antidepressants or benzodiazepines is only permitted if the dose has been stable for at least 4 weeks and will not change; a single short‑acting benzodiazepine for MRI‑related anxiety is allowed under strict monitoring.
  • Current or recent (within 3 months) use of antipsychotic drugs, acetylcholinesterase inhibitors, memantine, or amantadine disqualifies you, unless antipsychotics for motor symptoms, tetrabenazine/deutetrabenazine, or valproic acid have been stable for at least 12 weeks.
  • If you are unable to walk at all (even with a cane or walker), you cannot join the trial.
  • Medications that are known to lengthen the QT interval are not allowed unless they have been stopped for at least five half‑lives before the first VO659 dose.
  • Taking dietary supplements such as coenzyme Q10, vitamins, or creatine is only allowed if the dose has been steady for at least 6 weeks and will not change.
  • Use of blood‑thinning medicines (antiplatelet or anticoagulant drugs) that cannot be safely stopped before a lumbar puncture excludes you, except for warfarin if your blood‑clotting test (INR) is normal at screening.
  • Previous treatment with any antisense oligonucleotide (a type of genetic medicine) other than VO659 disqualifies you.
  • A history of experimental brain procedures such as gene therapy, cell transplantation, or other brain surgery makes you ineligible.
  • Receiving an adenoviral‑vector vaccine (a type of viral vaccine) within 45 days before the first VO659 dose excludes you.
  • Being enrolled in, or planning to join, another clinical trial that uses an investigational product (unless approved by the study doctors) prevents participation.
  • Pregnant women, women who are breastfeeding, or women who plan to become pregnant or breast‑feed during the study cannot take part.
  • Regular daily alcohol intake above 24 g for men (about one regular beer) or 12 g for women (about half a beer) excludes you.
  • A positive urine test for amphetamines, barbiturates, cocaine, opiates, cannabinoids, or benzodiazepines (unless the drug use is stable, medically indicated, and meets the study’s specific conditions) disqualifies you.
  • Any medical condition that would prevent you from completing the study’s required tests and visits makes you ineligible.
  • Having a close relationship with the study sponsor or site staff (such as being a close relative, employee, or student) excludes you.
  • Inability to undergo or tolerate an MRI scan—due to metal implants, MRI‑incompatible intrauterine devices, severe claustrophobia, serious movement disorders, or any other reason—prevents participation.
  • Allergy (hypersensitivity) to iodinated contrast agents, including gadolinium, used during imaging excludes you.
  • A history of bleeding problems (bleeding diathesis) or a platelet count below the normal range disqualifies you, unless your doctor judges it stable and not clinically important.
  • Any past cancer or precancerous condition, except early‑stage cervical cancer (stage 1B or less) or non‑invasive skin cancers that have been successfully treated, excludes you.
  • Acquired immune deficiency, including infection with the human immunodeficiency virus (HIV), makes you ineligible.
  • Positive test for hepatitis B surface antigen or active hepatitis C infection disqualifies you.
  • Significant newly diagnosed acute or chronic liver disease or kidney disease prevents participation.
  • Laboratory test results that the investigator judges to be clinically significant (abnormal) exclude you.
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Investigated drugs

VO659 is an experimental medicine being tested for safety when it is injected directly into the fluid around the spinal cord (intrathecal injection). In this study, participants with Huntington’s disease or spinocerebellar ataxia type 1 or type 3 receive a single dose of the drug into the lower back. The purpose is to see how well the body tolerates the medicine over a long period and to monitor any side effects. This drug is classified as an orphan drug, meaning it is intended for a rare condition and has special development status.

What is already known about the treatment

VO659 - VO659 is given as a sterile solution for injection, delivered by a one‑time bolus injection into the intrathecal space (the fluid around the spinal cord). It is an experimental, orphan‑drug compound currently in early clinical testing and not yet approved for routine medical use. The drug is being studied for Huntington’s disease and spinocerebellar ataxia types 1 and 3, conditions that cause progressive loss of coordination. VO659 works by inhibiting a specific enzyme that adds a small protein tag (ubiquitin) to other proteins, helping to reduce the buildup of abnormal proteins that damage nerve cells; it belongs to the class of proteasome‑modulating agents.

Investigated diseases

  • Spinocerebellar ataxia type 1

    A hereditary disorder that slowly damages the cerebellum and spinal cord, causing loss of coordination, unsteady gait, and slurred speech. Early signs often include difficulty with balance and fine motor tasks. Over time the walking problems become more pronounced and daily activities require increasing assistance. Some people also develop mild eye movement abnormalities. The disease typically progresses over many years, gradually reducing mobility and independence.

  • Spinocerebellar ataxia type 3

    Also known as Machado‑Joseph disease, this inherited condition leads to degeneration of the cerebellum, brainstem, and spinal pathways. It begins with clumsiness, unsteady walking, and involuntary eye movements. Muscle stiffness and occasional weakness may appear as the disease advances. Coordination continues to decline, making tasks such as writing or buttoning clothes increasingly difficult. The worsening course usually spans decades, with gradual loss of independence.

  • Huntington disease

    An autosomal‑dominant neurodegenerative disorder that causes involuntary jerking movements, problems with thinking, and changes in mood. Symptoms typically start in adulthood and slowly become more severe. Motor control worsens, leading to difficulty walking and maintaining posture. Cognitive abilities decline, affecting memory and decision‑making. Psychiatric symptoms such as irritability or depression may also emerge and intensify over time.

Trial detailsLast updated 28 Oct 2026
Age18+ yearsPhasePhase IITrial ID2026-526408-60-00Protocol codeVO659-CT03Estimated enrolment75 patientsSponsorVico Therapeutics B.V.

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