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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05822908
Other study ID # VO659-CT01
Secondary ID 2022-001314-19
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date February 14, 2023
Est. completion date September 15, 2025

Study information

Verified date April 2024
Source Vico Therapeutics B. V.
Contact Chief Medical Officer
Phone +31 71 2036800
Email info@vicotx.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The goal of this first-in-human clinical trial is to assess the safety and tolerability of four doses of a new study drug called VO659 in people with genetic disorders called spinocerebellar ataxia type 1, type 3 or Huntington's disease. Another aim is to determine the concentrations of the study drug in the cerebral spinal fluid and blood after single and multiple doses. Study drug will be administered by lumbar intrathecal bolus injections.


Description:

Spinocerebellar ataxia types 1 and 3 (SCA1 and SCA3), as well as Huntington's disease (HD) are severely debilitating, monogenic, neurodegenerative diseases that presently have no treatments to slow or stop clinical progression. Preclinical data suggest that VO659 may be a disease-modifying therapy in these disorders through its binding to the expansion of CAG repeats in the RNA transcripts of the causative genes, thus interfering with RNA translation and reducing the intracellular level of the harmful mutant proteins. The present trial is the first-in-human (FiH) evaluation of VO659. This is an open-label, multiple ascending dose, multi-centre phase 1/2a trial investigate the safety, tolerability and pharmacokinetics and explore the pharmacodynamics of intrathecally administered study drug VO659. The trial population comprises generally ambulatory participants with mild to moderate SCA1 or SCA3, or early manifest HD. Participants are assigned to dose-ascending treatment cohorts based on the order of enrolment. Dose-escalation is planned in up to five dose levels. Dose-level cohorts one and two will comprise participants with SCA3 only, and from dose-level cohorts three onwards participants with SCA1, SCA3 and HD will be enrolled. The total duration of trial participation for each participant is up to approximately 42 weeks, consisting of a screening period of up to 6 weeks, a 13-week dosing period with the study drug VO659 being administered intrathecally four times and a 23-week post-dosing period. During the four dosing blocks, CSF and blood samples for safety and pharmacokinetics (PK) will be collected at specific time points.


Recruitment information / eligibility

Status Recruiting
Enrollment 65
Est. completion date September 15, 2025
Est. primary completion date September 1, 2025
Accepts healthy volunteers No
Gender All
Age group 25 Years to 60 Years
Eligibility Main Inclusion Criteria: - 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. - Is =25 and =60 years of age inclusive, of any gender, at the time of signing the informed consent. - Have SCA1, SCA3 or HD meeting one of the following criteria: 1. SCA1 and SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of =3 and =18 2. 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 each indication the requirements are: 1. SCA1: =41 contiguous, uninterrupted CAG repeats in the ATXN1 gene 2. SCA3: =61 repeats in the ATXN3 gene 3. HD: =36 CAG repeats in the HTT gene. - Please note there will be additional inclusion criteria Main Exclusion Criteria: - Have any condition that would prevent participation in trial assessments. - 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. - Have clinical diagnosis of moderate or severe chronic migraines or history of the post-lumbar-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 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. - Have uncompensated cardiovascular disorder, any past or present cardiac arrhythmia, QTcF values on screening ECG of >470 ms, familial history of long QT syndrome or sudden unexpected death. - Have a history of attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to screening. - 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 treatment with an antisense oligonucleotide (including siRNA). - Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial. - Unable to undergo and tolerate MRI scans. - Please note there will be additional exclusion criteria

Study Design


Intervention

Drug:
VO659
VO659 is an antisense oligonucleotide targeting CAG repeats in mRNA transcripts

Locations

Country Name City State
Denmark Rigshospitalet Kopenhagen
France Centre Hospitalier Universitaire dÁngers Angers
France CHU Gui de Chauliac Montpellier- Expert Center of Neurogenetic diseases, Department of Neurology Montpellier
France Universtiry Hospitals Pitie Salpetriere - Charles foix - Paris Paris
Germany Katholisches Klinikum Bochum Bochum
Germany Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE) Bonn
Germany Universitatsklinikum Essen - Neurologie Essen
Germany Universitatsklinikum Tübingen Tübingen
Israel Meir Medical Center Kfar Saba
Israel Sourmansky Medical Center Tel Aviv
Netherlands Leiden University Medical Center LUMC Leiden
Netherlands Radbout University Medical Centre Nijmegen
Poland Institute of Psychiatry and Neurology Warsaw
United Kingdom University College London Hospitals NHS Foundation London
United Kingdom John Radcliffe Hospital Oxford

Sponsors (1)

Lead Sponsor Collaborator
Vico Therapeutics B. V.

Countries where clinical trial is conducted

Denmark,  France,  Germany,  Israel,  Netherlands,  Poland,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Incidence & dose relationships of treatment-related AEs, SAEs, AEs of special interest (AESI), severe events (NCI- CTCAE Grade 3 or higher). As measured in each dose group and overall. Unit of measurement: proportion Day 0-253
Primary Vital signs temperature in centigrade, heart rate in beats per minute (BPM), systolic and diastolic blood pressure blood pressure, respiratory rate in breaths per minute Day 0-253
Primary Body weight In kilograms Day 0-253
Primary Electrocardiogram (ECG) RR interval In milliseconds (ms) Day 0-253
Primary Electrocardiogram (ECG) - PR interval In milliseconds (ms) Day 0-253
Primary Electrocardiogram (ECG) - QTc interval In milliseconds (ms) Day 0-253
Primary Laboratory safety parameters in blood - white blood cell count In cells/mL Day 0-253
Primary Laboratory safety parameters in blood - hemoglobin In g/dL Day 0-253
Primary Laboratory safety parameters in blood - platelets In cells/cL Day 0-253
Primary Laboratory safety parameters in blood - prothrombin time (PT) In seconds Day 0-253
Primary Laboratory safety parameters in blood - activated partial thromboplastin clotting time (aPTT) In seconds Day 0-253
Primary Laboratory safety parameters in blood - international normalised ratio (INR) as a ration Day 0-253
Primary Laboratory safety parameters in blood - blood urea nitrogen In mg/dL Day 0-253
Primary Laboratory safety parameters in blood - carbon dioxide In mEq/L Day 0-253
Primary Laboratory safety parameters in blood - creatinine In mg/dL Day 0-253
Primary Laboratory safety parameters in blood - glucose In mg/dL Day 0-253
Primary Laboratory safety parameters in blood - chloride In mEq/L Day 0-253
Primary Laboratory safety parameters in blood - potassium In mEq/L Day 0-253
Primary Laboratory safety parameters in blood - sodium In mEq/L Day 0-253
Primary white blood cell (WBC) count in cerebrospinal fluid (CSF) 1/µL Day 0-253
Primary Protein levels in cerebrospinal fluid (CSF) in g/L Day 0-253
Primary Structural imaging assessment of any new abnormalities Structural MRI sequences to assess safety as qualitatively assessed by a trained neuroradiologist (3D T1 weighted, 3D T2weighted-FLAIR and susceptibility-weighted imaging (SWI) sequences) Day 0-253
Primary Percentage of participants with suicidal ideation or behaviour, as assessed by the Columbia suicide severity rating scale (C-SSRS). The C-SSRS is a structured tool to assess suicidal ideation and behavior. Four constructs are measured: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories, and composite endpoints based on the categories are followed over time to monitor patient safety. Day 0-253
Secondary Concentrations of VO659 in cerebrospinal fluid (CSF) in µg/mL _Day 1, 29, 57, 85, 120, 204, 253
Secondary Concentrations of VO659 in plasma in µg/mL _Day 1, 29, 57, 85, 120, 204, 253
Secondary Maximum plasma concentration (Cmax) for VO659 in µg/mL Day 1, Day 85
Secondary Time to maximum plasma concentration (Tmax) for VO659 in days Day 1, Day 85]
Secondary Area under the plasma concentration time curve for VO659 from time 0 to last quantifiable concentration of (AUC0-t) µg*h/L Days 1, 2, 8, Days 85, 86, 92]
Secondary Terminal half-life (t1/2) of VO659 in plasma In days Days 1, 2, 8
Secondary Terminal half-life (t1/2) of VO659 in cerebrospinal fluid (CSF) in days Day 1 through Day 253
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