A Phase 2, open-label trial to investigate the long-term safety of VO659 administered intrathecally in participants with Huntington’s disease and spinocerebellar ataxia type 1 and 3

Prior treatment

• Participants who have experienced an SAE (assessed as related or possibly related at the time of enrolment) in a previous trial with VO659.
• Have a history of attempted suicide or suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to screening. For patients with (i) a suicidal ideation score ≥4 on the Columbia Suicide Severity Rating Scale (C-SSRS) within the last 12 months, or (ii) suicidal behaviours within the last 12 months (as measured by the answer “Yes” on any of the C-SSRS Suicidal Behaviour Items), a risk assessment should be done by an appropriately-qualified mental health professional (e.g., a psychiatrist or licensed clinical psychologist) to assess whether it is safe for the patient to participate in the trial.
• Treatment with another IMP, biological agent, or device within 3 months prior to screening, or 5 half-lives of the investigational agent whichever is longer.
• Riluzole use, unless stable dose for at least 4 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial.
• Treatment for spasticity unless stable dose for at least 4 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial.
• Antidepressant or benzodiazepine use unless stable dose for at least 4 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial. NOTE: Single occasional administration of a short-acting benzodiazepine for procedural anxiety related to MRI scanning is allowed, provided that no trial-related assessments are carried out on that day after the MRI scan is completed, and that investigators monitor such participants after the benzodiazepine is administered per their institutional guidelines.
• Current or recent (within the last 3 months) use of antipsychotics (prescribed for psychosis), acetylcholinesterase inhibitors, memantine, or amantadine. Use of antipsychotics (prescribed for treatment of motor symptoms) and/or tetrabenazine/deutetrabenazine and valproic acid unless stable for at least 12 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial.
• Supplement use (e.g., coenzyme Q10, vitamins, creatine) unless stable dose for 6 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial.
• Prior treatment with an antisense oligonucleotide (including siRNA) other than VO659.
• Concurrent or planned concurrent participation in any other clinical trial evaluating IMPs other than VO659, unless the Sponsor’s Medical Expert or Medical Monitor concurs that the participation in the other trial is unlikely to interfere with any of the VO659-CT03 trial requirements; for observational and non-interventional trials, the same applies.
• Have a positive urine drug screen for amphetamines, barbiturates, cocaine, opiates, cannabinoids, or benzodiazepines at the screening visit. NOTE: benzodiazepines are acceptable if consistent with the declared concomitant medication which may include benzodiazepine use with a stable dose for at least 4 weeks prior to screening. NOTE: cannabinoids/tetrahydrocannabinol (THC) are acceptable if use is stable for at least 4 weeks prior to screening and for a medical and not for recreation purpose.

Other illness

• Have a history of hospitalisation for any major medical or surgical procedure involving general anaesthesia within 6 weeks of screening or planned during the trial.
• Have a history of psychosis, bipolar disorder, or schizophrenia, or deemed to be at significant risk of an acute depressive episode, confusional state, or showing violent behaviour.
• History of gene therapy or cell transplantation or any experimental brain surgery.
• Have any condition that would prevent participation in trial assessments.
• Is unable to undergo and tolerate MRI scans, e.g., due to metal implants including MRI incompatible intrauterine devices (IUDs), claustrophobia, any movement disorder of a severity that precludes MRI scans or jeopardises the quality of the MRI scan, or any other condition that renders MRI scans intolerable for the patient.
• Participant with hypersensitivity to iodinated contrast media, including gadolinium
• Have a history of any malignancy or obligatory precancerous condition of any organ system, except cervical carcinoma of Stage 1B or less, or non-invasive basal cell or squamous cell skin carcinoma that has been successfully treated.
• Have acquired immunodeficiency, including human immunodeficiency virus infection.
• Have positive serology for hepatitis B surface antigen or active hepatitis C infection.
• Have any significant (moderate or severe) newly diagnosed acute or chronic liver or kidney disease.

Lab values

• Have uncompensated cardiovascular disorder, any past or present cardiac arrhythmia, QT interval corrected for heart rate by Fridericia’s cube root formula (QTcF) values on screening ECG of >450 ms for males and >470 ms for females, familial history of long QT syndrome or sudden unexpected death.
• Drugs known to prolong the QT interval, unless the treatment stopped at least 5 times the half-lives of the respective drug at the time of the first dosing with VO659.
• Antiplatelet or anticoagulant therapy (except warfarin) that cannot be safely stopped in time prior to a lumbar puncture. Warfarin use at the time of screening, and any previous warfarin use unless the INR is normal at screening.
• Have a history of bleeding diathesis or coagulopathy or a platelet count less than the lower limit of normal, unless stable and assessed by the investigator to be not clinically significant.
• Have deviations of any of the laboratory parameters that are deemed clinically significant by the investigator.

Other

• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
• Participants unable to walk. Participants who have the ability to walk assisted with a cane or walker are eligible. For long-distance (e.g., 50 meters) use of wheelchairs for convenience or transfer is permitted.
• Adenoviral vector-based vaccination within 45 days of the first dosing with VO659.
• Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.
• Have a regular daily alcohol consumption, in any form, of more than 24 g (for men) or 12 g (for women). NOTE: 24 g of alcohol corresponds to approximately 500 mL of usual beer or 250 mL of usual wine; 12 g of alcohol corresponds to approximately 250 mL of usual beer or 125 mL of usual wine.
• Have a close affiliation with the Sponsor or the trial site, e.g., a close relative of the investigator, dependent person (e.g., employee or student of the trial site).

• Participants who have been enrolled into other interventional VO659 program studies and have finished their dosing period.
• Provide written informed consent (signed and dated). Participants should be assessed for their ability to give informed consent using the Evaluation to Sign Consent tool.
• Have good general health, in the opinion of the investigator, apart from having HD or SCA1 or SCA3.
• Have the ability to comply with protocol requirements. The advancement of HD, SCA1 or SCA3 must be taken into account so that compliance with trial assessments is deemed feasible by the investigator.
• Body weight of ≥50 kg and body mass index within the range of ≥17.5 and <32.5 kg/m2.
• Is willing to follow contraceptive requirements per local regulations regarding the methods of contraception for those participating in clinical trials. In case local regulations deviate from the contraception methods listed in the protocol, local regulations apply and will be described in the Informed Consent Form (ICF). a. Male participants: Non-sterilised males who can produce sperm and are sexually active with a female partner of childbearing potential need to agree to use a condom as a method of contraception during the entire period from first IMP (VO659) administration up to 225 days after the last IMP administration and not to donate sperm during this period. Additionally, contraception for the female partner of childbearing potential should be considered. b. Female participants: For women of childbearing potential (WOCBP), a negative result in a pregnancy test at screening and prior to each IMP administration AND agreement to practice a highly effective method of contraception that is maintained during the entire treatment period and until 225 days after the last IMP administration is required. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for at least 12 months without an alternative medical cause. Women under the age of 55 years must have both no menses for at least 12 months and a follicle-stimulating hormone (FSH) level >40 mIU/mL (while not on any therapy that may interfere with FSH levels) in order to confirm menopause. In the absence of 12 months of amenorrhea, an FSH measurement in itself is insufficient to establish menopause.