Evaluation of Venglustat and Imiglucerase Combination Therapy in Adult Patients with Gaucher Disease Type 3: Safety, Tolerability, and Biomarker Analysis
- Trial ID
- 2023-508646-18-00
- Protocol
- PDY13949
- Sponsor
- Genzyme Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of **venglustat** in combination with Cerezyme in adult patients with Gaucher disease type 3 (GD3). This evaluation is conducted in both short-term (Part 2) and long-term (Part 3) treatment phases. Additionally, the study aims to assess the change in cerebrospinal fluid (CSF) central nervous system (CNS) biomarkers, specifically glucosylceramide (GL-1) and lyso-glucosylceramide (lyso-GL-1), in GD3 participants receiving the combination therapy during Part 2. In Part 4, the study further evaluates the safety and tolerability of venglustat as a monotherapy in participants who have remained systemically stable on the combination treatment. These objectives are clinically relevant as they aim to establish the safety profile of venglustat, both in combination with Cerezyme and as a standalone treatment, which is crucial for the management of GD3, a condition characterized by systemic and neurological manifestations.
Secondary objectives include: - Evaluating the pharmacokinetics of venglustat in adult GD3 participants during the combination treatment phases (Parts 2 and 3). - Assessing the efficacy of venglustat in combination with Cerezyme on systemic disease by measuring spleen volume, liver volume, hemoglobin level, and platelet count in adult GD3 participants during Parts 2 and 3. - Evaluating the efficacy of the combination therapy on neurological function by assessing ataxia using the Scale for the Assessment and Rating of Ataxia (SARA) in adult GD3 participants during Parts 2 and 3. - Evaluating plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 participants during Parts 2 and 3. - In Part 4, assessing the efficacy of venglustat monotherapy on systemic disease and neurological function, as well as evaluating plasma biomarkers in adult GD3 participants.
Participants
The clinical trial involves a total of **15 participants** diagnosed with **Gaucher disease type 1** or **Gaucher disease type 3**. The study population includes both male and female adults, with an age range of 18 to 40 years for Gaucher disease type 1 participants and 18 years and older for Gaucher disease type 3 participants. Participants were selected based on their clinical diagnosis and documented deficiency of acid beta-glucosidase activity, confirming their condition. All participants have been receiving enzyme replacement therapy (ERT) for at least three years prior to enrollment and are deemed clinically stable. Lifestyle considerations include the requirement for participants to abstain from grapefruit products for 72 hours before and during the treatment period. Additionally, female participants of childbearing potential and male participants must adhere to effective contraceptive methods throughout the study duration. The trial includes a vulnerable population, and participants must have maintained specific therapeutic goals related to hemoglobin levels, platelet count, spleen and liver volume, and absence of symptomatic bone disease to be eligible for the study.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of **venglustat** in combination with Cerezyme in adult patients with **Gaucher disease type 3**. This study is structured as a four-part, open-label, multicenter, multinational trial. The trial is not randomized or double-blind, as it aims to assess the effects of the investigational drug in a real-world setting. The estimated duration of the trial is from March 22, 2017, to October 30, 2026.
The trial consists of several key phases: Part 1 involves biomarker evaluation and screening to distinguish between Gaucher disease type 3 (GD3) and Gaucher disease type 1 (GD1) participants, and to identify GD3 participants eligible for subsequent treatment phases. Parts 2 and 3 focus on the combination treatment phases, assessing the short-term and long-term safety and tolerability of venglustat with Cerezyme, as well as changes in cerebrospinal fluid (CSF) biomarkers. Part 4 is an extended treatment phase with venglustat monotherapy, evaluating its safety and tolerability in participants who have remained stable on the combination therapy.
Study visits are sequenced as follows: an initial inclusion (screening) visit to confirm eligibility based on specific criteria, including age, clinical diagnosis, and stability on enzyme replacement therapy (ERT). Follow-up visits are scheduled throughout the treatment phases to monitor safety, collect pharmacokinetic and pharmacodynamic data, and assess clinical outcomes. The end-of-study visit marks the conclusion of the participant's involvement, where final assessments are conducted.
Participants are expected to be involved in the study for the duration of their respective treatment phase, with the maximum treatment period being 103 weeks for venglustat in capsule form. Conditions that may lead to early termination from the study include the occurrence of treatment-emergent adverse events (TEAEs) or failure to adhere to study protocols, such as dietary restrictions or contraceptive requirements. The primary endpoints include the number of participants with TEAEs and the assessment of pharmacodynamic parameters in CSF. Secondary endpoints involve pharmacokinetic assessments and evaluations of clinical parameters such as spleen and liver volume, hemoglobin, and platelet levels.
Treatment
The clinical trial involves the administration of **venglustat**, a chemical compound with the active substance name **venglustat** (also known as GZ/SAR402671 or (3S)-1-AZABICYCLO(2.2.2)OCTAN-3-YL N-(2-(2-(4-FLUOROPHENYL)-1,3-THIAZOL-4-YL)PROPAN-2-YL)CARBAMATE). This investigational medication is provided in two pharmaceutical forms: a **hard capsule** and a **tablet**, both intended for **oral use**. The maximum daily dose for venglustat is 15 mg, with a total treatment period of up to 103 days for the capsule form and 14 days for the tablet form. The medication is manufactured by Genzyme Corporation and is designated as an orphan drug under the number EU/3/14/1374.
In addition to venglustat, the study includes the use of **imiglucerase**, a non-experimental treatment. Imiglucerase is provided as a **powder for concentrate for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose of imiglucerase is 400 units, with a treatment period extending up to 81 days. Imiglucerase serves as a comparator treatment in the study, and its role is to evaluate the combination therapy's safety and efficacy in adult patients with Gaucher disease Type 3.
Efficacy
Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoints include the number of participants with Treatment Emergent Adverse Events (TEAEs) and the assessment of pharmacodynamic (PD) parameters, specifically **lyso-glucosylceramide (lyso-GL1)** and **glucosylceramide (GL-1)** levels in cerebrospinal fluid (CSF). These biomarkers are critical in evaluating the impact of the treatment on the central nervous system in patients with Gaucher disease Type 3.
Secondary endpoints will further explore the pharmacodynamic and pharmacokinetic parameters, including the levels of lyso-GL1 and GL-1 in plasma, and various pharmacokinetic measures such as Cmax, Tmax, AUC 0-24h, and Ctrough in both plasma and CSF. Additionally, assessments will be made on spleen and liver volumes, hemoglobin and platelet levels, and ataxia, with specific evaluations planned for Part 4 of the study. These parameters will be measured at designated timepoints throughout the trial to ensure comprehensive data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- -GD1 participant is ≥18 and ≤40 years of age.
- -GD3 participant is ≥18 years of age.
- -Participant must provide written informed consent prior to any study-related procedures being 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 to be eligible for this study: -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 has maintained GD therapeutic goals defined as all of the following to be eligible for entering Part 4 of this study: -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 -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 entering Part 4
- -Participant, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-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 participants 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.
Exclusion Criteria
- -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). Participants 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 participant with cataract (eg, alphaadrenergic 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).
- -Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
- -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).
- -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 participant 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 22 Mar 2017 | 3 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
venglustat GZ402671 - SAR402671 | Test | CAPSULE, HARD | ORAL USE | 15 | 103 | PRD10858858 |
IMIGLUCERASE | Other | — | INTRAVENOUS INFUSION | 400 | 81 | SUB08148MIG |
venglustat GZ402671 - SAR402671 | Test | TABLET | ORAL USE | 15 | 14 | PRD10858868 |