A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD

• ClinicalTrials.gov Identifier: NCT05822908
• Recruitment Status: Recruiting
• First Posted: April 21, 2023
• Last Update Posted: April 8, 2024
• Sponsor: Vico Therapeutics B. V.
• Information provided by (Responsible Party): Vico Therapeutics B. V.

Tracking Information

• First Submitted Date: March 1, 2023
• First Posted Date: April 21, 2023
• Last Update Posted Date: April 8, 2024
• Actual Study Start Date: February 14, 2023
• Estimated Primary Completion Date: September 1, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 7, 2023)

• Incidence & dose relationships of treatment-related AEs, SAEs, AEs of special interest (AESI), severe events (NCI- CTCAE Grade 3 or higher). [ Time Frame: Day 0-253 ]
  As measured in each dose group and overall. Unit of measurement: proportion
• Vital signs [ Time Frame: Day 0-253 ]
  temperature in centigrade, heart rate in beats per minute (BPM), systolic and diastolic blood pressure blood pressure, respiratory rate in breaths per minute
• Body weight [ Time Frame: Day 0-253 ]
  In kilograms
• Electrocardiogram (ECG) RR interval [ Time Frame: Day 0-253 ]
  In milliseconds (ms)
• Electrocardiogram (ECG) - PR interval [ Time Frame: Day 0-253 ]
  In milliseconds (ms)
• Electrocardiogram (ECG) - QTc interval [ Time Frame: Day 0-253 ]
  In milliseconds (ms)
• Laboratory safety parameters in blood - white blood cell count [ Time Frame: Day 0-253 ]
  In cells/mL
• Laboratory safety parameters in blood - hemoglobin [ Time Frame: Day 0-253 ]
  In g/dL
• Laboratory safety parameters in blood - platelets [ Time Frame: Day 0-253 ]
  In cells/cL
• Laboratory safety parameters in blood - prothrombin time (PT) [ Time Frame: Day 0-253 ]
  In seconds
• Laboratory safety parameters in blood - activated partial thromboplastin clotting time (aPTT) [ Time Frame: Day 0-253 ]
  In seconds
• Laboratory safety parameters in blood - international normalised ratio (INR) [ Time Frame: Day 0-253 ]
  as a ration
• Laboratory safety parameters in blood - blood urea nitrogen [ Time Frame: Day 0-253 ]
  In mg/dL
• Laboratory safety parameters in blood - carbon dioxide [ Time Frame: Day 0-253 ]
  In mEq/L
• Laboratory safety parameters in blood - creatinine [ Time Frame: Day 0-253 ]
  In mg/dL
• Laboratory safety parameters in blood - glucose [ Time Frame: Day 0-253 ]
  In mg/dL
• Laboratory safety parameters in blood - chloride [ Time Frame: Day 0-253 ]
  In mEq/L
• Laboratory safety parameters in blood - potassium [ Time Frame: Day 0-253 ]
  In mEq/L
• Laboratory safety parameters in blood - sodium [ Time Frame: Day 0-253 ]
  In mEq/L
• white blood cell (WBC) count in cerebrospinal fluid (CSF) [ Time Frame: Day 0-253 ]
  1/µL
• Protein levels in cerebrospinal fluid (CSF) [ Time Frame: Day 0-253 ]
  in g/L
• Structural imaging assessment of any new abnormalities [ Time Frame: Day 0-253 ]
  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)
• Percentage of participants with suicidal ideation or behaviour, as assessed by the Columbia suicide severity rating scale (C-SSRS). [ Time Frame: Day 0-253 ]
  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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 7, 2023)

• Concentrations of VO659 in cerebrospinal fluid (CSF) [ Time Frame: _Day 1, 29, 57, 85, 120, 204, 253 ]
  in µg/mL
• Concentrations of VO659 in plasma [ Time Frame: _Day 1, 29, 57, 85, 120, 204, 253 ]
  in µg/mL
• Maximum plasma concentration (Cmax) for VO659 [ Time Frame: Day 1, Day 85 ]
  in µg/mL
• Time to maximum plasma concentration (Tmax) for VO659 [ Time Frame: Day 1, Day 85] ]
  in days
• Area under the plasma concentration time curve for VO659 from time 0 to last quantifiable concentration of (AUC0-t) [ Time Frame: Days 1, 2, 8, Days 85, 86, 92] ]
  µg*h/L
• Terminal half-life (t1/2) of VO659 in plasma [ Time Frame: Days 1, 2, 8 ]
  In days
• Terminal half-life (t1/2) of VO659 in cerebrospinal fluid (CSF) [ Time Frame: Day 1 through Day 253 ]
  in days

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD
• Official Title: 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
• Brief 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.

Detailed 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Multiple ascending dose design

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Spinocerebellar Ataxia Type 1
• Spinocerebellar Ataxia Type 3
• Huntington Disease

Intervention

Drug: VO659

VO659 is an antisense oligonucleotide targeting CAG repeats in mRNA transcripts

Study Arms

• Experimental: Cohort 1
  A dose of 10 mg of the trial IMP VO659 will be administered intrathecally four times on Day 1, Day 29, Day 57 and Day 85 within the planned dosing blocks. 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 and a 23-week post-dosing period.
  Intervention: Drug: VO659
• Experimental: Cohort 2
  A dose of 20 mg of the trial IMP VO659 will be administered intrathecally four times on Day 1, Day 29, Day 57 and Day 85 within the planned dosing blocks. 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 and a 23-week post-dosing period.
  Intervention: Drug: VO659
• Experimental: Cohort 3
  A dose of 40 mg of the trial IMP VO659 will be administered intrathecally four times on Day 1, Day 29, Day 57 and Day 85 within the planned dosing blocks. 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 and a 23-week post-dosing period.
  Intervention: Drug: VO659
• Experimental: Cohort 4
  A dose of 70 mg of the trial IMP VO659 will be administered intrathecally four times on Day 1, Day 29, Day 57 and Day 85 within the planned dosing blocks. 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 and a 23-week post-dosing period.
  Intervention: Drug: VO659
• Experimental: Cohort 5
  A dose of 100 mg of the trial IMP VO659 will be administered intrathecally four times on Day 1, Day 29, Day 57 and Day 85 within the planned dosing blocks. 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 and a 23-week post-dosing period.
  Intervention: Drug: VO659

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 7, 2023): 65
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 15, 2025
• Estimated Primary Completion Date: September 1, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 25 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Chief Medical Officer; +31 71 2036800; info@vicotx.com

• Listed Location Countries: Denmark, France, Germany, Israel, Netherlands, Poland, United Kingdom

Administrative Information

• NCT Number: NCT05822908
• Other Study ID Numbers: VO659-CT01; 2022-001314-19 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Vico Therapeutics B. V.
• Original Responsible Party: Same as current
• Current Study Sponsor: Vico Therapeutics B. V.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Chief Medical Officer; VICO Therapeutics

• PRS Account: Vico Therapeutics B. V.
• Verification Date: April 2024