Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecal VO659 in Spinocerebellar Ataxia Types 1, 3, and Huntington's Disease

Trial ID: 2024-514328-18-00
Protocol: VO659-CT01
Sponsor: Vico Therapeutics B.V.

Trial statistics

science

test molecule

location_city

research sites

public

countries

medical_information

diseases

person_search

investigators

handshake

vendor

Diseases & Conditions

Hereditary ataxia Huntington's disease

Objectives

The primary objective of this phase 1/2a, open-label trial is to evaluate the **safety** and **tolerability** of multiple doses of intrathecal (IT) lumbar bolus administrations of VO659 in participants with clinically manifest Spinocerebellar Ataxia types 1, 3, or Huntington's Disease. This is clinically relevant as it aims to determine the potential adverse effects and overall acceptability of VO659, which is crucial for assessing its viability as a therapeutic option for these neurodegenerative conditions.

Secondary objectives include: - Characterizing the cerebrospinal fluid (CSF) and blood pharmacokinetic (PK) profile of single and multiple doses of IT lumbar bolus administrations of VO659 in participants with clinically manifest Spinocerebellar Ataxia types 1, 3, or Huntington's Disease. This will provide insights into the drug's absorption, distribution, metabolism, and excretion, which are essential for understanding its therapeutic potential and optimizing dosing regimens.

Participants

The clinical trial involves a total of **3 participants** diagnosed with **Spinocerebellar ataxia types 1, 3**, or **Huntington's disease**. The study population includes individuals aged between **25 and 60 years**, encompassing both male and female participants. Participants were selected based on their clinically manifest conditions of SCA1, SCA3, or Huntington's disease, with specific genetic confirmations required for each condition. The trial population is characterized by good general health, aside from their primary diagnosis, and includes individuals with stable and well-controlled chronic illnesses, such as hypertension, that do not impact the trial's primary objectives. Participants are required to have a body weight of at least **50 kg** and a body mass index (BMI) within the range of **18-32 kg/m²**. Lifestyle considerations include adherence to contraceptive requirements as per local regulations for the duration of the trial and a specified period thereafter. The trial does not involve a vulnerable population, and the selection criteria ensure that participants are capable of providing informed consent.

Plans and Procedures

The clinical trial is a **phase 1/2a, open-label** study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the investigational product **VO659**. This product is administered intrathecally as a lumbar bolus injection to participants diagnosed with **spinocerebellar ataxia types 1, 3**, and **Huntington's disease**. The trial aims to assess the incidence and dose relationships of treatment-related adverse events, including serious adverse events and adverse events of special interest, as well as changes in clinical safety parameters such as physical and neurological examinations, vital signs, and laboratory safety parameters.

The trial is expected to run from February 2023 to June 2025, with participant involvement lasting until the end of the study. The study includes several key visits: an initial screening visit to confirm eligibility, multiple follow-up visits to monitor safety and efficacy, and a final end-of-study visit. During the screening visit, participants will undergo genetic testing to confirm the presence of disease-causing alleles, and their general health will be assessed to ensure they meet the inclusion criteria. Follow-up visits will involve regular assessments of clinical status, laboratory tests, and neuroimaging to monitor the effects of the treatment.

Participants are expected to remain in the study for its entire duration unless specific conditions necessitate early termination. These conditions include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is not categorized as low-intervention, and it involves a first-in-human approach, emphasizing the importance of close monitoring and adherence to protocol. The study is conducted under the sponsorship of VICO THERAPEUTICS B.V., with the investigational product being an antisense oligonucleotide solution provided with a diluent of artificial cerebrospinal fluid.

Treatment

The clinical trial involves the administration of **VO659**, an experimental medication designed to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics in participants with spinocerebellar ataxia types 1, 3, and Huntington's disease. **VO659** is an antisense oligonucleotide provided as a **solution for injection** or **concentrate for solution for infusion**. The active substance, **VO659**, is derived from nucleic acid and is administered intrathecally via a bolus injection into the intrathecal space. This method of administration is intended to deliver the medication directly to the central nervous system, targeting the underlying pathophysiology of the diseases under investigation. The trial is structured to assess multiple ascending doses of **VO659** to determine the optimal dosing regimen.

In addition to the experimental treatment, the study utilizes a diluent, artificial cerebrospinal fluid (aCSF), to facilitate the administration of the antisense oligonucleotide. The use of aCSF is standard in such trials to ensure the proper delivery and dispersion of the medication within the cerebrospinal fluid. The trial does not include a placebo or comparator treatment, focusing solely on the effects of **VO659**. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to accurately assess the treatment's safety and efficacy.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the incidence and dose relationships of treatment-related adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESI), and severe events classified as NCI-CTCAE Grade 3 or higher. Additionally, changes in clinical safety parameters will be evaluated, including physical and neurological examinations, vital signs, body weight, ECG, cardiac monitoring, and suicidal ideation and behavior risk monitoring using the Columbia Suicide Severity Rating Scale (C-SSRS). Structural MRI scans will also be reviewed. Laboratory safety parameters will be monitored through blood tests (haematology, haemostasis, clinical chemistry), cerebrospinal fluid (CSF) analysis (cell counts, protein, glucose), and urine analysis (urinalysis). Adverse changes in clinical status will be assessed based on exploratory clinical, biochemical, and neuroimaging assessments.

Secondary endpoints will include the pharmacokinetic (PK) profiles of VO659. The CSF concentration-time profile will be analyzed, including the derived PK parameter of elimination half-life (t1/2), if possible. The plasma concentration-time profile will also be evaluated, with derived PK parameters such as the area under the curve (AUC), peak plasma concentration (Cmax), and t1/2 being measured. These assessments will provide comprehensive data on the pharmacokinetics and pharmacodynamics of VO659 in participants with **spinocerebellar ataxia** types 1, 3, and **Huntington's disease**.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Informed Consent 1. 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.
Age 2. Is ≥25 and ≤60 years of age, of any gender, at the time of signing the informed consent.
Type of Indications and Disease Characteristics 3. Have SCA1, SCA3 or HD meeting 1 of the following criteria: a. SCA1 and SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of ≥3 and ≤18 b. HD: early manifest, Stage I disease with a Total Functional Capacity (TFC) Score of ≥11 and ≤13 and a Unified Huntington’s Disease Rating Scale (UHDRS) Diagnostic Confidence Level (DCL) of 4.
Have genetically confirmed disease, defined by increased cytosine, adenine, and guanine (CAG) repeat length in the disease-causing allele by direct DNA testing (for details, see Section 8.6.1). For each indication the requirements are: a. SCA1: ≥41 contiguous, uninterrupted CAG repeats in Ataxin 1 gene / mRNA transcript (ATXN1) b. SCA3: ≥61 repeats in Ataxin 3 gene / mRNA transcript (ATXN3) c. HD: ≥40 CAG repeats in Huntingtin gene/mRNA transcript (HTT). NOTE: Genetic testing will be performed during screening, which will serve as a reference for criterion.
Have good general health, in the opinion of the investigator, apart from having SCA1, SCA3, or HD. NOTE: Patients with a chronic illness (e.g., hypertension) will be eligible if in the opinion of the investigator, the illness is stable and well-controlled and will not impact the primary objectives of the trial.
Weight 6. Body weight of ≥50 kg and body mass index within the range of ≥17.5 and <32.5 kg/m2 (inclusive).
Reproductive status and Contraceptive/Barrier Requirements 7. 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 Section 10.4, local regulations apply and will be described in the Informed Consent Form. a. Male participants: Applicable for Europe (NOTE: details according to the Clinical Trial Facilitation Group [CTFG] Contraception Guidance Version 1.1, issued 2020; see Section 10.4): Non-sterilised males who are sexually active with a female partner of childbearing potential: Agreement to use a condom as a method of contraception during the entire period from first IMP (VO659) administration up to 90 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: Applicable for Europe (NOTE: Details according to CTFG Contraception Guidance version 1.1, issued 2020; see Section 10.4): Women of childbearing potential: 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 during the entire period from informed consent up to 6 months after the last IMP administration. 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 >40m IU/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.

cancel

Exclusion Criteria

Medical Conditions 1. Have any condition that would prevent participation in trial assessments.
Have an acute infection or febrile illness at the time of each dosing, or ongoing systemic antiviral or antimicrobial therapy that will not be completed at least 3 days prior to dosing.
Have 1 or more pathogenic mutation(s) in another polyglutamine (polyQ) disease gene, i.e., ATXN2, calcium voltage-gated channel subunit Alpha1 A gene / mRNA transcript (CACNA1A), Ataxin 7 gene / mRNA transcript (ATXN7), TATA-box binding protein gene / mRNA transcript (TBP), androgen receptor gene/mRNA transcript (AR), Ataxin 1 gene/mRNA transcript (ATN1), plus either ATXN3 and HTT (for patients with SCA1), ATXN1 and HTT (for participants with SCA3), or ATXN1 and ATXN3 (for participants with HD), in addition to the disease-causing mutation in the ATXN1 (patients with SCA1), ATXN3 (patients with SCA3) or HTT (patients with HD) gene. Pathogenic mutations are defined as: ≥41 contiguous, uninterrupted CAG repeats in ATXN1; ≥61 repeats in ATXN3; ≥36 CAG repeats in HTT; ≥38 CAG repeats in AR; ≥48 CAG repeats in ATN1; ≥33 CAG repeats in ATXN2; ≥34 CAG repeats in ATXN 7; ≥20 CAG repeats in CACNA1A; ≥41 CAG repeats in TBP.
Have clinical diagnosis of moderate or severe chronic migraines or history of the postlumbar-puncture headache of moderate or severe intensity requiring hospitalisation or blood patch.
Have a brain, spinal or systemic disorder that would interfere with the LP process, CSF circulation, or safety assessments.
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 and the Medical Monitor to be not clinically significant.
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 inherited or acquired immunodeficiency, including human immunodeficiency virus infection
Have positive serology for hepatitis B surface antigen or active hepatitis C infection.
Have any known history of hypersensitivity or allergies to the antisense oligonucleotide (VO659) or any excipient contained in the IMP.
Have any significant (moderate or severe) acute or chronic liver or kidney disease.
Have deviations of any of the following laboratory parameters at screening:  Aspartate aminotransferase >2.0 x Upper Limit of normal range (ULN)  Alanine aminotransferase >2.0 x ULN  Total bilirubin > 1.5 x ULN  Platelets <100,000/µl (i.e., <100 x 109 /L)  Estimated glomerular filtration rate <45 mL/min/1.73m2 based on the modification of diet in renal disease formula (see Section 10.5)
Have uncompensated cardiovascular disorder, any past or present cardiac arrhythmia, 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.
Have a history of uncontrolled hypokalaemia or hypomagnesaemia.
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 long-term neurological consequences of COVID-19 / SARS-CoV-2 infection that have not resolved or stabilised at the time of screening.
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 suicide 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.
Have a history of psychosis, bipolar disorder or schizophrenia and patients deemed to be at significant risk of an acute depressive episode, confusional state or violent behaviour.
Have medical, psychiatric, or other conditions that, in the judgement of the investigator, may compromise the patient’s ability to understand the patient information sheet, to give informed consent, to comply with all trial requirements, or to complete the trial.
Prior/Concomitant Therapy 20. Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter
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 12 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial
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 are not permitted unless stable for at least 12 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial.
Drugs known to prolong the QT interval (see Section 10.7), unless the treatment stopped at least five times the respective drug’s 1/2 in advance of the first dosing with VO659.
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.
Antiplatelet or anticoagulant therapy within 14 days prior to screening or anticipated use during the trial, including but not limited to dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban; aspirin ≤100 mg/day or clopidogrel are permitted
Prior treatment with an antisense oligonucleotide (including small interfering RNA (siRNA)).
History of gene therapy or cell transplantation or any experimental brain surgery.
Adenoviral vector-based vaccination within 45 days of the first dosing.
History of chemical meningitis
Prior/Concurrent Clinical Trial Experience 33. Concurrent or planned concurrent participation in any other clinical trial evaluating IMPs; for observational and non-interventional trials, the same applies, unless approved by the Sponsor’s Medical Expert or Medical Monitor.
Other Exclusions. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.
Have a history of any drug or alcohol abuse in the past 5 years or 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 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 12 weeks prior to screening – see exclusion criterion No.24. NOTE: cannabinoids/tetrahydrocannabinol (THC) are acceptable if use is stable for at least 12 weeks prior to screening and for a medical but not recreational purposes.
Is unable to undergo and tolerate MRI scans, e.g., due to metal implants including MRIincompatible intrauterine devices, 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.
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).