Overview

Primary Objectives:

Part 1:

Cohorts 1, 2 and 3

• Evaluate cerebrospinal fluid (CSF) biomarkers in adult Gaucher disease (GD) Type 3 patients that distinguish GD3 from adult Gaucher disease Type 1 (GD1) patients.
• Screen adult and pediatric GD3 patients who qualify for treatment with venglustat in Parts 2 and 3.

Parts 2 and 3:

Cohort 2

• Evaluate short-term (Part 2) and long-term (Part 3) safety and tolerability of venglustat in combination with Cerezyme in adult GD3 patients.
• Evaluate the change in CSF central nervous system (CNS) biomarkers (glucosylceramide [GL-1] and lyso-glucosylceramide [lyso-GL1]) from adult GD3 patients receiving venglustat in combination with Cerezyme (Part 2 only).

Cohort 3

• Evaluate the efficacy of venglustat in combination with Cerezyme in adult and pediatric GD3 patients by assessing:
• Ataxia using the Scale for the Assessment and Rating of Ataxia (SARA)
• Cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

Secondary Objectives:

Parts 2 and 3:

Cohort 2

• Evaluate the pharmacokinetics (PK) of venglustat in adult GD3 patients.

Cohort 3

• Evaluate the efficacy of venglustat in combination with Cerezyme in adult and pediatric GD3 patients by assessing:
• CSF Lyso-GL1 levels
• Modified Friedreichs Ataxia Rating Scale - Activities of Daily Living (FARS-ADL)
• Brain resting-state functional Magnetic Resonance Imaging (rs-fMRI) reflecting connectivity between parieto-occipital areas
• Bone disease manifestations
• Evaluate safety and tolerability of venglustat in combination with Cerezyme in adult and pediatric GD3 patients
• Evaluate PK of venglustat in adult and pediatric GD3 patients.

Eligibility

Inclusion criteria:

• For participants 18 years of age: Participant must provide written informed consent prior to any study-related procedures being performed.
• For participants 12 and <18 years of age: Parent(s)/legal guardian(s) must provide written informed consent prior to any study related procedures being performed. If the patient is considered able by local regulation, assent will also be obtained before any study related procedures are performed.
• Participant has a clinical diagnosis of Gaucher Disease Type 1 (GD1) or Gaucher Disease Type 3 (GD3) and documented deficiency of acid beta-glucosidase activity confirming this diagnosis.
• Participant has received ERT (Cerezyme or other ERT; as deemed appropriate by local regulations) for at least 3 years prior to enrollment, on a stable dose for at least 6 months and is within the therapeutic goals defined below, and is deemed clinically stable for at least 1 year by the Investigator.
• Participant has reached Gaucher disease therapeutic goals defined as all of the following
• Hemoglobin level of 11.0 g/dL for females and 12.0 g/dL for males.
• Platelet count 100,000/mm3.
• Spleen volume <10 multiples of normal (MN), or total splenectomy (provided the splenectomy occurred >3 years prior to randomization).
• Liver volume <1.5 MN.
• No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to screening.
• Participant, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (-hCG)] at baseline.
• If participant has a history of seizures, except for myoclonic seizures, they are well controlled under appropriate medication not identified as a strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A.
• Participant is willing to abstain from consumption of grapefruit, grapefruit juice, or grapefruit containing products for 72 hours prior to administration of the first dose of venglustat and for the duration of the treatment period.
• Oculomotor apraxia characterized by a horizontal saccade abnormality.
• Female participants of childbearing potential and male patients must be willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception for the duration of the study and for at least 6 weeks for females and 90 days for males following their last dose of venglustat.

Cohort 1 only:

• GD1 participant is 18 and 40 years of age.

Cohort 2 only:

• GD3 participant is 18 years of age.

Cohort 3 only:

• GD3 adult participant 18 years of age.
• GD3 pediatric participant is 12 years of age <18 years and 30 kg of weight. For male patients 12 to <18 years of age: There is a potential risk for venglustat to impact male fertility particularly when used in patients who have not reached a certain stage of sexual maturation. If a patient has not reached Tanner Stage 3 by the screening visit, the Investigator should assess and discuss with the patient the potential benefits and risks when considering eligibility for study participation. In this benefit/risk assessment-discussion, the parent(s)/legal guardian(s), the patient (if considered able by local regulation), and the Sponsor's medical representative (if considered appropriate) shall be consulted.

Exclusion criteria:

• Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
• Participant has had a partial or total splenectomy within 3 years prior to randomization.
• Participant is blood transfusion-dependent.
• Prior esophageal varices or liver infarction or current liver enzymes (alanine aminotransferase [ALT]/ aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal, unless the patient has a diagnosis of Gilbert Syndrome.
• Participant has any clinically significant disease, other than GD, including cardiovascular (congenital cardiac defect, coronary artery disease, valve disease or left sided heart failure; clinically significant arrhythmias or conduction defect), hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, hypokalemia, hypomagnesemia) or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation.
• Participant has renal insufficiency, as defined by an estimated glomerular filtration rate <30 mL/min/1.73m2 at the screening visit.
• Participant has received an investigational product within 30 days prior to enrollment.
• Participant has a history of cancer, with the exception of basal cell carcinoma.
• Participant has myoclonic seizures.
• Participant is pregnant or lactating.
• Participant has, according to World Health Organization (WHO) Grading, a cortical cataract >one-quarter of the lens circumference (Grade cortical cataract-2) or a posterior subcapsular cataract >2 mm (Grade posterior subcapsular cataract-2). Patients with nuclear cataracts will not be excluded.
• Participant requires use of invasive ventilatory support.
• Participant requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
• Participant is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme treatment to ensure maintenance of Gaucher treatment goals.
• Participant is currently receiving potentially cataractogenic medications (corticosteroids, psoralens used in dermatology with ultraviolet light therapy [PUVA], typical antipsychotics, and glaucoma medications) or any medication that may worsen the vision of a patient with cataract (eg, alpha-adrenergic glaucoma medications).
• Participant has received strong or moderate inducers or inhibitors of CYP3A within 15 days or 5 half-lives from screening, whichever is longer, prior to enrolment in Part 2. This also includes the consumption of grapefruit, grapefruit juice, or grapefruit containing products within 72 hours of starting venglustat administration in Parts 2 and 3.
• Participant is scheduled for in-patient hospitalization including elective surgery, during the study.
• Participant has had a major organ transplant (e.g., bone marrow or liver).
• Participant, in the opinion of the investigator, is unable to adhere to the requirements of the study or unable to undergo study assessments (e.g., contraindications for magnetic resonance imaging).

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.