a group of rare, inherited, genetic disorders that affect specific parts of the brain, including the cerebellum (the center of motor coordination), brain stem and spinal cord. These disorders can cause problems such as problems with balance, coordination, walking, swallowing and speaking. Huntingtons Disease Spinocerebellar ataxia
Conditions
Interventions
VO659 is a 2*-O-methyl-modified 21-mer antisense oligonucleotide with a
phosphorothioate backbone targeting CAG repeats in mRNA transcripts, provided
as a stock solution for dilution and IT administ
Sponsors
VICO Therapeutics B.V.
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Inclusive Criteria: Participants are eligible to be included in the trial only if all of the following criteria are met: Informed Consent 1. Provide written informed consent (signed and dated). Patients should be assessed for their ability to give informed consent using the Evaluation to Sign Consent tool. Age 2. Is >=25 and =3 and =11 and =41 contiguous, uninterrupted CAG repeats in ATXN1 b. SCA3: >=61 repeats in ATXN3 c. HD: >=36 CAG repeats in HTT. NOTE: Genetic testing will be performed during screening, which will serve as a reference for criterion. 5. Have good general health apart from having SCA1, SCA3, or HD at the discretion of the investigator. NOTE: In the presence a chronic illness (e.g., hypertension), a stable, well-controlled disease in the opinion of the investigator that will not impact the primary objectives of the trial is allowed. Weight 6. Have body weight of >= 50 kg and body mass index (BMI) within the range of 18-32 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 (CF). 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-sterilized 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 sterilization 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
Exclusion criteria
Exclusion criteria: Exclusion Criteria: Participants are excluded from the trial if any of the following criteria apply: Medical Conditions 1. Have any condition that would prevent participation in trial assessments. 2. Have 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 three days prior to dosing. 3. Have one or more pathogenic mutation(s) in another polyQ disease gene, i.e., ATXN2, CACNA1A, ATXN7, TBP, AR, and 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. 4. Have clinical diagnosis of moderate or severe chronic migraines or history of the post-lumbar-puncture headache of moderate or severe intensity requiring hospitalization or blood patch. 5. Have a brain, spinal or systemic disorder that would interfere with the LP process, CSF circulation, or safety assessments. 6. Have history of bleeding diathesis or coagulopathy, 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. 7. 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. 8. Have inherited or acquired immunodeficiency, including human immunodeficiency virus (HIV) infection. 9. Have positive serology for hepatitis B surface antigen (HbsAg) or active hepatitis C infection. 10. Have any known history of hypersensitivity or allergies to the antisense oligonucleotide (AON) (VO659) or any excipient contained in the IMP. 11. Have any significant (moderate or severe) acute or chronic liver or kidney disease. 12. Have deviations of any of the following laboratory parameters at screening: • Aspartate aminotransferase (AST) >2.0 x Upper Limit of normal range (ULN) • Alanine aminotransferase (ALT) >2.0 x ULN • Total bilirubin >1.5 x ULN • Platelets 450 ms for males and >470 ms for females, familial history of long QT syndrome or sudden unexpected death. 14. Have a history of uncontrolled hypokalemia or hypomagnesaemia. 15. Have a history of hospitalization for any major medical or surgical procedure involving general anesthesia within 6 weeks of screening or planned during the trial. 16. Have clinical evidence of acute COVID-19 or confirmed presence of COVID-19 / SARS-CoV-2 infection at any time during the screening period, or have long-term neurological consequences of Covid-19 / SARS-CoV-2 infection that have not resolved or stabilized at the time of screening. 17. Have a history of attempted suicide, suicidal ideation with
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Objective: To evaluate the safety and tolerability of multiple doses of intrathecal lumbar bolus administrations of VO659 in participants with clinically manifest SCA1, SCA3, or HD Endpoints: • Incidence and dose relationships of treatment-related: o Adverse events (AEs), o Serious adverse events (SAEs), o Adverse events of special interest (AESI), o Severe events (NCI-CTCAE Grade 3 or higher). • Changes in clinical safety parameters including physical and neurological examinations, vital signs, body weight, ECG ,cardiac monitoring, suicidal ideation and behavior risk monitoring by the Columbia Suicide Severity Rating Scale (C-SSRS), and review of structural MRI scans • Changes in laboratory safety parameters in blood (haematology, haemostasis, clinical chemistry), CSF (cell counts, protein, glucose), and urin (urinalysis). • Adverse changes in clinical status based on exploratory clinical, biochemical and neuroimaging assessments | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Objective : To characterize the CSF and blood PK profile of single and multiple doses of intrathecal lumbar bolus administrations of VO659 in participants with clinically manifest SCA1, SCA3 or HD Endpoints: • The CSF concentration-time profile of VO659, including the derived PK parameter of elimination half-life (t1/2), if possible. • The plasma concentration-time profile of VO659, including the derived PK parameters such as the area under the curve (AUC), peak plasma concentration (Cmax), elimination half-life (t1/2) Exploratory Objectives: • To assess the pharmacodynamic (PD) profile of single and multiple doses of intrathecal lumbar bolus administrations of VO659, including target engagement and off-target effects based on biochemical biomarkers and MRI neruoimaging assessments in participants with clinically manifest SCA1, SCA3 or HD. • To assess effects on clinical outcome assessments of intrathecal lumbar bolus administrations of VO659 in participants with clinically manifest SCA1, SCA3 or HD. Endpoints: • Changes in mutant ATXN1 (in participants with SCA1) mutant ATXN3 (in participants with SCA3) or mutant HTT (in participants with HD) in CSF and blood.* • Changes in total ATXN1, total ATXN3, total HTT in CSF and blood.* • Changes in biomarkers indicative of neurodegeneration, such as NfL, total tau, GFAP, and UCH-L1 in CSF and the blood • Changes in biomarkers indicative of inflammation, such as C3a, IL-1β, IL-6, TNFa and YKL-40 (CH3-L1) in CSF and the blood • Changes in neuroimaging outcomes, such as the volume of whole brain and brain regions of interest (including but not limited to the cerebellum, pons, brainstem, and striatum), diffusion MRI, quantitative MRI for iron content (R2* mapping), MRS (optional, only at select trial sites), and OCT (only at select trial sites) • Changes in clinical outcome measures, such as SARA, 9-HPT, FARS (part I & II), INAS (participants with SCA1 or SCA3); UHDRS TFC, FAS, IS, TMS/DCL (participants with HD) | — |
Countries
Netherlands
Outcome results
None listed