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

Overview

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 in Dose-level Cohorts 1-3 is up to approximately 45 weeks, consisting of a screening period of up to 6 weeks, a 14-week dosing period, and a 25-week post-dosing period.

The total duration of trial participation for each participant in Dose-level Cohort 4 is up to approximately 58 weeks, consisting of a screening period of up to 7 weeks, a 26-week dosing period, and a 25-week post dosing period. The total duration of trial participation for each participant in Dose-level Cohort 5 is up to approximately 58 weeks, consisting of a screening period of up to 7 weeks, a single dosing followed by a 51-week period of non-dosing, observational visits (split into a 26-week 'dosing period' and a 25-week 'post-dosing period' for consistency in the SoA with Dose-level Cohort 4).

Interventions

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

Primary outcome measures

• 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]
• Vital signs [Time frame: Day 0-253]
• Body weight [Time frame: Day 0-253]
• Electrocardiogram (ECG) RR interval [Time frame: Day 0-253]
• Electrocardiogram (ECG) - PR interval [Time frame: Day 0-253]
• Electrocardiogram (ECG) - QTc interval [Time frame: Day 0-253]
• Laboratory safety parameters in blood - white blood cell count [Time frame: Day 0-253]
• Laboratory safety parameters in blood - hemoglobin [Time frame: Day 0-253]
• Laboratory safety parameters in blood - platelets [Time frame: Day 0-253]
• Laboratory safety parameters in blood - prothrombin time (PT) [Time frame: Day 0-253]

Secondary outcome measures (7)

• Concentrations of VO659 in cerebrospinal fluid (CSF) [Time frame: _Day 1, 29, 57, 85, 120, 204, 253]
• Concentrations of VO659 in plasma [Time frame: _Day 1, 29, 57, 85, 120, 204, 253]
• Maximum plasma concentration (Cmax) for VO659 [Time frame: Day 1, Day 85]
• Time to maximum plasma concentration (Tmax) for VO659 [Time frame: Day 1, Day 85]]
• 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]]
• Terminal half-life (t1/2) of VO659 in plasma [Time frame: Days 1, 2, 8]
• Terminal half-life (t1/2) of VO659 in cerebrospinal fluid (CSF) [Time frame: Day 1 through Day 253]

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:

• SCA1 and SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of ≥3 and ≤18
• 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:

• SCA1: ≥41 contiguous, uninterrupted CAG repeats in the ATXN1 gene
• SCA3: ≥61 repeats in the ATXN3 gene
• HD: ≥40 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 4 centers

• Katholisches Klinikum Bochum — Bochum
• Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE) — Bonn
• Universitatsklinikum Essen - Neurologie — Essen
• Universitatsklinikum Tübingen — Tübingen

France · 3 centers

• Centre Hospitalier Universitaire dÁngers — Angers
• CHU Gui de Chauliac Montpellier- Expert Center of Neurogenetic diseases, Department of Neu — Montpellier
• Universtiry Hospitals Pitie Salpetriere - Charles foix - Paris — Paris

Israel · 2 centers

• Meir Medical Center — Kfar Saba
• Sourmansky Medical Center — Tel Aviv

Netherlands · 2 centers

• Leiden University Medical Center LUMC — Leiden
• Radbout University Medical Centre — Nijmegen

United Kingdom · 2 centers

• University College London Hospitals NHS Foundation — London
• John Radcliffe Hospital — Oxford

Denmark · 1 center

• Rigshospitalet — Copenhagen

Publications

• Bonsor M, Ammar O, Schnoegl S, Wanker EE, Silva Ramos E. Polyglutamine disease proteins: Commonalities and differences in interaction profiles and pathological effects. Proteomics. 2024 Jun;24(12-13):e2300114. doi: 10.1002/pmic.202300114. Epub 2024 Apr 14. PMID 38615323
• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: March 2024. J Huntingtons Dis. 2024;13(1):1-14. doi: 10.3233/JHD-240017. PMID 38489195

Identifiers

NCT: NCT05822908 · VO659-CT01 · 2024-514328-18-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗