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

Huntington Disease Clinical Trial

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

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
• 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
• 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

Related Conditions & MeSH terms

• Ataxia
• Cerebellar Ataxia
• Huntington Disease
• Machado-Joseph Disease
• Spinocerebellar Ataxia Type 1
• Spinocerebellar Ataxia Type 3
• Spinocerebellar Ataxias
• Spinocerebellar Degenerations

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