A Global Study to Assess the Drug Dynamics, Efficacy, and Safety of Venglustat (GZ/SAR402671) in Parkinson's Disease Patients Carrying a Glucocerebrosidase (GBA) Gene Mutation

Multicenter, Randomized, Double-blind, Placebo Controlled Study to Assess the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of GZ/SAR402671 in Patients With Early-stage Parkinson's Disease Carrying a GBA Mutation or Other Pre-specified Variant

Primary Objectives:

• Part 1: To determine the safety and tolerability of 4, 8, and 15 milligrams of GZ/SAR402671 (venglustat) administered orally for 4 weeks, as compared to placebo in participants with early-stage Parkinson's disease (PD) carrying a glucocerebrosidase gene (GBA) mutation or other pre-specified variants.
• Part 2: To determine the efficacy of GZ/SAR402671 administered orally daily, as compared to placebo in participants with early-stage PD carrying a GBA mutation or other pre-specified variants.

Secondary Objectives:

Part 1:

• To assess the pharmacokinetic (PK) profile of oral dosing of GZ/SAR402671 in plasma when administered in early-stage PD participants carrying a GBA mutation.
• To assess the exposure of GZ/SAR402671 in cerebrospinal fluid (CSF) when administered in early-stage PD participants carrying a GBA mutation.

Part 2:

• To demonstrate overall safety and tolerability of GZ/SAR402671 administered orally for 52 weeks in early-stage PD participants carrying a GBA mutation as compared to placebo.
• To assess the pharmacodynamic response to daily oral dosing of GZ/SAR402671 in plasma and CSF as measured by glucosylceramide (GL-1) when administered in early-stage PD participants carrying a GBA mutation over a 52-week period.

Part 1: the total duration was as following:

i) Rest of the world (ROW): up to approximately 50 weeks (8.5 weeks of screening, maximum of 36 weeks of treatment and 6 weeks follow-up).

ii) Japan only: up to approximately 66 weeks (8.5 weeks of screening, maximum of 52 weeks of treatment and 6 weeks follow-up).

Part 2: the total duration was up to approximately 224 weeks that consisted of 8.5 weeks of screening period, 52 weeks of treatment period, 156 weeks of long-term follow-up (LTFU) period and 8 weeks of post-treatment period.

At the end of a 52-week main placebo-controlled treatment period, all participants were evaluated for possibility to transition to receive active treatment for 156 weeks plus 8-week post-treatment observation.

Inclusion criteria:

• Male and female adults with a diagnosis of PD and who were heterozygous carriers of a GBA mutation associated with PD.
• Participants carrying known sequence variants associated with GBA-PD must had rapid eye movement (REM) sleep behavior disorder (RBD) confirmed by historically documented polysomnography or by questionnaire.
• Age greater than or equal to (>=) 18 years to 80 years inclusive at the time of informed consent signing (FOR JAPANESE PARTICIPANTS ONLY: Age >=20 years to 80 years, inclusive, at the time of signing the informed consent. Note: Japanese participants refers only to Japanese participants enrolled and living in Japan).
• Had symptoms of PD >=2 years.
• Hoehn and Yahr (H and Y) stage of 2 or lower at baseline.
• Stable medication regimen of PD drugs for at least 30 days (at least 60 days for rasagiline) prior to randomization.
• The participant was willing to abstain from grapefruit containing products for 72 hours prior to administration of the first dose of GZ/SAR402671 and for the duration of the entire treatment period (Part 1 and Part 2, Periods 2 and 3).
• Signed written consent.

Exclusion criteria:

• Parkinsonism due to drug(s) or toxin(s).
• Participants carrying the LRRK2 G2019S mutation.
• Participants with Gaucher disease (GD) as defined by clinical signs and symptoms (i.e., hepatosplenomegaly, cytopenia, skeletal disease) and/or marked deficiency of GCase activity compatible with GD.
• Montreal Cognitive Assessment score less than 20.
• Participants with prior surgical history of deep brain stimulation (DBS).
• Participants with baseline brain MRI without contrast showing a structural abnormality that is a possible cause of their PD signs or symptoms.
• Hepatic insufficiency with liver function tests (LFT) greater than (>) 2 times upper limit of normal at Screening Visit.
• The participant had a documented diagnosis, as per local regulations, of any of the following infections: hepatitis B, hepatitis C, human immunodeficiency virus 1 or 2.
• Renal insufficiency as defined by creatine >1.5 times normal at Screening Visit.
• The participant had received strong or moderate inducers or inhibitors of CYP3A4 within 30 days or 5 half-lives prior to randomization, whichever is longer.
• The participant had, according to World Health Organization (WHO) Grading, a cortical cataract > one-quarter the lens circumference (grade cortical catact-2 [COR-2]) or a posterior subcapsular cataract >2 millimeters (grade posterior subscapsular cataract [PSC-2]). Participant with nuclear cataracts would not be excluded.
• The participant was currently receiving potentially cataractogenic medications, including chronic regimen (more frequently than every 2 weeks) of any dose or route of corticosteroids or any medication that could cause cataract or worsen the vision of participants with cataract (eg, glaucoma medications) according to the Prescribing Information.
• If female, pregnant (defined as positive beta-human chorionic gonadotrophin [Beta-HCG] blood test) or lactating or breast-feeding.
• Any medical disorders and/or clinically relevant findings that, in the opinion of the Investigator, could interfere with study-related procedures. This included condition(s) that precluded the safe performance of routine lumbar punctures, such as prohibitive spinal diseases, bleeding diasthesis, or clinically significant coagulopathy or thrombocytopenia.
• Current participation in another investigational interventional study.
• Any medications specifically used for treating memory dysfunction, such as, but not limited to cholinesterase inhibitors or memantine, within 30 days or 5 half-lives of these medications prior to randomization, whichever was longer.

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