Venglustat in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3 With Venglustat Monotherapy Extension (LEAP)

A 4-part, Open-label, Multicenter, Multinational Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamic, and Exploratory Efficacy of Venglustat in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3 With Venglustat Monotherapy Extension

Part 1: Biomarker evaluation/screening phase

Primary Objectives:

• Evaluate cerebrospinal fluid (CSF) biomarkers in adult Gaucher disease Type 3 (GD3) participants that distinguish GD3 from adult Gaucher disease Type 1 (GD1) participants
• Screen adult GD3 participants who qualify for treatment with venglustat in Parts 2, Part 3, and Part 4 Parts 2 and 3: Combination treatment phases

Primary objectives:

• Evaluate short-term (Part 2) and long-term (Part 3) safety and tolerability of venglustat in combination with Cerezyme in adult GD3 participants
• Evaluate the change in CSF central nervous system (CNS) biomarkers (glucosylceramide [GL-1] and lyso-glucosylceramide [lyso-GL-1]) from adult GD3 participants receiving venglustat in combination with Cerezyme (Part 2 only) Part 4: Extended treatment phase with monotherapy

Primary objectives:

• Evaluate safety and tolerability of venglustat monotherapy in adult GD3 participants who have remained systemically stable on venglustat in combination with Cerezyme Parts 2 and 3: Combination treatment phases

Secondary Objectives:

• Evaluate the pharmacokinetics (PK) of venglustat in adult GD3 participants
• Evaluate the efficacy of venglustat in combination with Cerezyme in systemic disease in adult GD3 participants by assessing spleen volume, liver volume, hemoglobin level and platelet count
• Evaluate the efficacy of venglustat in combination with Cerezyme on neurological function in adult GD3 participants by assessing Ataxia using the Scale for the Assessment and Rating of Ataxia (SARA)
• Evaluate plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 participants Part 4: Extended treatment phase with monotherapy

Secondary objectives:

• Evaluate the efficacy of venglustat in systemic disease in adult GD3 participants by assessing spleen volume, liver volume, hemoglobin level and platelet count
• Evaluate the efficacy of venglustat on neurological function in adult GD3 participants by assessing Ataxia using the Scale for the Assessment and Rating of Ataxia (SARA)
• Evaluate plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 participants

Study Overview

• Status: Active, not recruiting
• Conditions: Gaucher Disease Type 1; Gaucher Disease Type 3
• Intervention / Treatment: Drug: imiglucerase; Drug: venglustat (GZ402671)

Detailed Description

The total duration for GD1 participants is 45 days (Part 1), while for GD3 participants the total duration is up to approximately 10 years

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Mainz, Germany, 55131
    • Investigational Site Number : 276001
• Japan
  • Tokyo
    • Minato-ku, Tokyo, Japan, 105-8471
      • Investigational Site Number : 392001
• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 OQQ
      • Investigational Site Number : 826003
  • Manchester
    • Salford, Manchester, United Kingdom, M6 8HD
      • Investigational Site Number : 826002
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine Site Number : 840002
  • Texas
    • Dallas, Texas, United States, 75226
      • Baylor Institute of Metabolic Diseases Site Number : 840001
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Lysosomal and Rare Disorders Research and Treatment Center, Inc Site Number : 840003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

GD3 and GD1 participants must meet the following criteria to be eligible for this study:

• 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:

Participants are excluded from the study if any of the following criteria apply:

• 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 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.
• 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).
• 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open label (OL) venglustat; Administered once a day orally for up to approximately 10 years. Participants will continue their usual dose of Cerezyme during Part 1, Part 2 and Part 3. There is no administration of Cerezyme in Part 4 unless administrated as rescue treatment.	Drug: imiglucerase; Pharmaceutical form: sterile lyophilized product Route of administration: intravenous; Other Names: Cerezyme; Drug: venglustat (GZ402671); Pharmaceutical form: capsule or tablet Route of administration: oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in cerebrospinal fluid (CSF)	From screening through Week 52
Number of participants with Treatment Emergent Adverse Events (TEAEs)	From screening up to end of study, up to approximately 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of plasma pharmacokinetic parameter: Ctrough	Plasma trough concentration (Ctrough)	Weeks 12 and 39 (Part 2), and on Weeks 78, 104, and 156 (for Part 3)
Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in plasma	Change from baseline in plasma lyso-GL1 and GL1	From screening up to end of study, up to approximately 10 years
Assessment of plasma pharmacokinetic parameter: Cmax (Part 2)	Plasma maximum concentration (Cmax)	Day 1
Assessment of plasma pharmacokinetic parameter: Tmax (Part 2)	Plasma time at Cmax (Tmax)	Day 1
Assessment of plasma pharmacokinetic parameter: AUC0-24h (Part 2)	Plasma area under the curve (AUC0-24h)	Day 1
Assessment of CSF pharmacokinetic parameter: Cmax	CSF maximum concentration (Cmax)	Week 4, Week 26, and Week 52
Assessment of spleen volume	Percent change from baseline in spleen volume assessed by Magnetic Resonance Imaging (MRI)	From screening up to end of study, up to approximately 10 years
Assessment of spleen volume (Part 4)	Percent change from Part 4 baseline in spleen volume assessed by MRI	From Week 260 up to end of study, up to approximately 10 years
Assessment of liver volume	Percent change from baseline in liver volume assessed by MRI	From screening up to end of study, up to approximately 10 years
Assessment of liver volume (Part 4)	Percent change from Part 4 baseline in liver volume assessed by MRI	From Week 260 up to end of study, up to approximately 10 years
Assessment of hemoglobin level	Change from baseline in hemoglobin level	From screening up to end of study, up to approximately 10 years
Assessment of hemoglobin level (Part 4)	Change from Part 4 baseline in hemoglobin level	From Week 260 up to end of study, up to approximately 10 years
Assessment of platelet level	Percent change from baseline in platelet count	From screening up to end of study, up to approximately 10 years
Assessment of platelet level (Part 4)	Percent change from Part 4 baseline in platelet count	From Week 260 up to end of study, up to approximately 10 years
Assessment of Ataxia	Ataxia is assessed by using the Scale for the Assessment and Rating of Ataxia (SARA), which consists of 8 items that are related to gait, stance, sitting, speech disturbance, finger-chase test, nose-finger test, fast alternating hand movements and heel-shin slide test. A modified scoring algorithm is used to determine the SARA modified total score from 0 (no ataxia) to 32 (very severe ataxia). Change from baseline in SARA modified total score.	From screening up to end of study, up to approximately 10 years
Assessment of Ataxia (Part 4)	Ataxia is assessed by using the Scale for the Assessment and Rating of Ataxia (SARA), which consists of 8 items that are related to gait, stance, sitting, speech disturbance, finger-chase test, nose-finger test, fast alternating hand movements and heel-shin slide test. A modified scoring algorithm is used to determine the SARA modified total score from 0 (no ataxia) to 32 (very severe ataxia). Change from Part 4 baseline in SARA modified total score.	From Week 260 up to end of study, up to approximately 10 years

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2017
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2026

Study Registration Dates

• First Submitted: July 20, 2016
• First Submitted That Met QC Criteria: July 20, 2016
• First Posted (Estimated): July 25, 2016

Study Record Updates

• Last Update Posted (Estimated): March 26, 2025
• Last Update Submitted That Met QC Criteria: March 21, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Disease; Gaucher Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Venglustat
• Other Study ID Numbers: PDY13949; 2014-002550-39 (EudraCT Number); U1111-1156-4278 (Registry Identifier: ICTRP); 2023-508646-18 (Registry Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No