Clinical trial NCT05822908: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Spinocerebellar Ataxia Type 1
Spinocerebellar Ataxia Type 3
Huntington Disease
Keywords: hereditary ataxia
Machado-Joseph Disease (MJD)
Lead sponsor: Vico Therapeutics B. V.
Sponsor class: INDUSTRY
First posted: 2023-04-21
Enrollment: 65
Sex: ALL
Minimum age (years): 25
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Multiple ascending dose design
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Incidence & dose relationships of treatment-related AEs, SAEs, AEs of special interest (AESI), severe events (NCI- CTCAE Grade 3 or higher).
timeFrame: Day 0-253
measure: Vital signs
timeFrame: Day 0-253
measure: Body weight
timeFrame: Day 0-253
measure: Electrocardiogram (ECG) RR interval
timeFrame: Day 0-253
measure: Electrocardiogram (ECG) - PR interval
timeFrame: Day 0-253
measure: Electrocardiogram (ECG) - QTc interval
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - white blood cell count
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - hemoglobin
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - platelets
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - prothrombin time (PT)
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - activated partial thromboplastin clotting time (aPTT)
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - international normalised ratio (INR)
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - blood urea nitrogen
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - carbon dioxide
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - creatinine
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - glucose
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - chloride
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - potassium
timeFrame: Day 0-253
measure: Laboratory safety parameters in blood - sodium
timeFrame: Day 0-253
measure: white blood cell (WBC) count in cerebrospinal fluid (CSF)
timeFrame: Day 0-253
measure: Protein levels in cerebrospinal fluid (CSF)
timeFrame: Day 0-253
measure: Structural imaging assessment of any new abnormalities
timeFrame: Day 0-253
measure: Percentage of participants with suicidal ideation or behaviour, as assessed by the Columbia suicide severity rating scale (C-SSRS).
timeFrame: Day 0-253
Secondary outcomes:
measure: Concentrations of VO659 in cerebrospinal fluid (CSF)
timeFrame: _Day 1, 29, 57, 85, 120, 204, 253
measure: Concentrations of VO659 in plasma
timeFrame: _Day 1, 29, 57, 85, 120, 204, 253
measure: Maximum plasma concentration (Cmax) for VO659
timeFrame: Day 1, Day 85
measure: Time to maximum plasma concentration (Tmax) for VO659
timeFrame: Day 1, Day 85]
measure: Area under the plasma concentration time curve for VO659 from time 0 to last quantifiable concentration of (AUC0-t)
timeFrame: Days 1, 2, 8, Days 85, 86, 92]
measure: Terminal half-life (t1/2) of VO659 in plasma
timeFrame: Days 1, 2, 8
measure: Terminal half-life (t1/2) of VO659 in cerebrospinal fluid (CSF)
timeFrame: Day 1 through Day 253
Other outcomes:
Locations:
city: Kopenhagen
country: Denmark
facility: Rigshospitalet
city: Angers
country: France
facility: Centre Hospitalier Universitaire dÁngers
city: Montpellier
country: France
facility: CHU Gui de Chauliac Montpellier- Expert Center of Neurogenetic diseases, Department of Neurology
city: Paris
country: France
facility: Universtiry Hospitals Pitie Salpetriere - Charles foix - Paris
city: Bochum
country: Germany
facility: Katholisches Klinikum Bochum
city: Bonn
country: Germany
facility: Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE)
city: Essen
country: Germany
facility: Universitatsklinikum Essen - Neurologie
city: Tübingen
country: Germany
facility: Universitatsklinikum Tübingen
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Tel Aviv
country: Israel
facility: Sourmansky Medical Center
city: Leiden
country: Netherlands
facility: Leiden University Medical Center LUMC
city: Nijmegen
country: Netherlands
facility: Radbout University Medical Centre
city: Warsaw
country: Poland
facility: Institute of Psychiatry and Neurology
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
affiliation: VICO Therapeutics
name: Chief Medical Officer
role: STUDY_DIRECTOR
References: