A phase 1/2a, open-label trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of intrathecally administered VO659 in participants with spinocerebellar ataxia types 1, 3 and Huntington*s disease

Recruiting

Conditions: 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
10029299

Registration Number: NL-OMON53759

Lead Sponsor: VICO Therapeutics B.V.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 20

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 <=60 years of age inclusive, of any gender, at the time of signing the informed consent. Type of Indications and Disease Characteristics 3. Have SCA1, SCA3 or HD meeting one of the following criteria: a. SCA1 or SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of >=3 and <=18, b. HD: early manifested, 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. 4. Have genetically confirmed disease, defined by increased cytosine, adenine, and guanine (CAG)-repeat length in the disease-causing allele by direct DNA testing (detail see Section 8.6.1), for each indication the requirements are: a. SCA1: >=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: 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 <100,000/µl (i.e., <100 x 109/L) • Estimated GFR (eGFR) <45 mL/min/1.73m2 based on the modification of diet in renal disease (MDRD) formula (see Section 10.5) 13. 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. 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