Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Treatment-naïve Adult Male Patients With Fabry Disease

NCT02228460 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: ACT137392013-005324-41U1111-1152-1456
• Study Type: interventional
• Target: 11
• Locations: 5 countries
• Sites: 8

Brief Summary

Primary Objective: To assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and exploratory efficacy of GZ/SAR402671 in enzyme replacement therapy treatment-naïve adult male participants diagnosed with Fabry disease.

Conditions

Fabry Disease

Keywords

Venglustat

Outcome Measures

Primary Outcomes (2)

• Change From Baseline at Week 26 in Skin Globotriaosylceramide (GL-3) Score in Superficial Skin Capillary Endothelium: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26

  Skin biopsies taken at Baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe), where higher score indicated more severe condition. A single score per participant per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of participants with shift from Baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from Baseline to Week 26 indicates less severe condition at Week 26.

  Baseline, Week 26

• Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium

  Skin biopsies taken at Baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe), where higher score indicated more severe condition. A single score per participant per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Change from Baseline in GL-3 score was obtained by subtracting Baseline value from post-baseline value at Week 26. A negative change from Baseline indicates less severe condition at Week 26.

  Baseline, Week 26

Secondary Outcomes (18)

• Change From Baseline in Plasma GL-3 Concentration at Week 26

  Baseline, Week 26

• Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26

  Baseline, Week 26

• Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26

  Baseline, Week 26

• Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Endothelial Cells: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26

  Baseline, Week 26

• Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Smooth Muscle Cells: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26

  Baseline, Week 26

Study Arms (1)

GZ/SAR402671

EXPERIMENTAL

GZ/SAR402671 15 milligram (mg) once daily orally for 26 weeks.

Drug: GZ/SAR402671

Interventions

GZ/SAR402671 DRUG

Pharmaceutical form: Capsule; Route of administration: Oral

GZ/SAR402671

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• The participant was greater than equal to (\>=) 18 years of age and less than (\<) 50 years of age.
• The participant was male.
• The participant had provided a signed informed consent.
• The participant had a confirmed diagnosis of Fabry disease as documented by leukocyte α- Galactosidase A (αGAL) activity of \<4 nanomole/hour/milligram (nmol/hr/mg) leukocyte (preferred assay; results from a central laboratory) or plasma αGAL \<1.5 nanomole/hour/milliliter (nmol/hr/mL) (results from a central laboratory).
• The participant had a plasma globotriaosylsphingosine (lyso-GL3) \>=65 nanogram per milliliter (ng/mL).
• The participant had never been treated with a Fabry disease-specific treatment.
• If the participant was on renin-angiotensin-aldosterone system (RAAS) blockers and antidepressants, the dose should be stable (i.e., prescribed dose and frequency) for at least the immediate 3 months prior to screening.

You may not qualify if:

• The participant had an estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m\^2 using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
• The participant had a median urine protein/creatinine ratio (PCR) \>=0.5 gram per gram (g/g) (median of 3 overnight urine collections. Collection of each of the 3 samples must occur between 4 and 7 days of each other, and all samples must be collected within a 15 day period). All 3 samples must be collected regardless of the results and results available prior to Day 1.
• The participant had undergone a kidney transplant.
• The participant had either active or a history of clinically significant organic disease (with the exception of the symptoms related to Fabry disease), including clinically significant cardiovascular, hepatic, pulmonary, hematologic, neurological or renal disease, or other medical condition, serious inter-current illness, or extenuating circumstances that, in the opinion of the Investigator, would preclude participation in the trial.
• The participant had abnormal liver function (serum total bilirubin \> the upper limit of normal, or serum alanine aminotransferase (\[ALT\] and aspartate aminotransferase \[AST\] \>2.0 times the upper limit of normal).
• The participant had, according to World Health Organization (WHO) grading a cortical cataract (COR) \> one-quarter of the lens circumference (Grade COR-2) or a posterior subcapsular cataract (PSC) \>2 millimeter (mm) (Grade PSC-2). Participants with nuclear cataracts were not excluded.
• The participant was currently receiving potentially cataractogenic medications.
• The participant had received strong or moderate inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) per Food and Drug Administration (FDA) classification within 14 days prior to enrollment or within 5 times the elimination half-life or PD half-life of the medication, whichever is longer.
• The participant was scheduled for in-patient hospitalization, including elective surgery, during the study.
• The participant had a positive result on any of the following tests: hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab). Participants with a positive hepatitis B surface antibody (HBsAb) test with a history of prior hepatitis B immunization were eligible if other criteria met (i.e., negative tests for: HBsAg, hepatitis B core antibody \[HBcAb\], and hepatitis C virus antibody \[HCVAb\]).
• The participant had participated in a study involving an investigational drug within the past 30 days of the start of the trial.
• The participant was unwilling to comply with the requirements of the protocol.
• The participant was a sexually active man who was not willing to use 2 forms of birth control including a barrier method during the study until 6 weeks after the last treatment with investigational medicinal product (IMP).
• The participant had a history or ongoing clinically significant cardiac arrhythmia, defined as either atrial fibrillation, sustained or non-sustained ventricular tachycardia.
• The participant had any contraindication to magnetic resonance imaging (MRI).

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (8)

Investigational Site Number 840002

Atlanta, Georgia, 30322, United States

Location

Investigational Site Number 840003

Cincinnati, Ohio, 45229, United States

Location

Investigational Site Number 840001

Fairfax, Virginia, 22030, United States

Location

Investigational Site Number 250001

Garches, 92380, France

Location

Investigational Site Number 616001

Warsaw, 04-730, Poland

Location

Investigational Site Number 643002

Moscow, 125167, Russia

Location

Investigational Site Number 826003

Birmingham, B15 2TH, United Kingdom

Location

Investigational Site Number 826002

Cambridge, CB2 OQQ, United Kingdom

Location

Related Publications (1)

• Deegan PB, Goker-Alpan O, Geberhiwot T, Hopkin RJ, Lukina E, Tylki-Szymanska A, Zaher A, Sensinger C, Gaemers SJM, Modur V, Thurberg BL, Sharma J, Najafian B, Mauer M, DasMahapatra P, Wilcox WR, Germain DP. Venglustat, an orally administered glucosylceramide synthase inhibitor: Assessment over 3 years in adult males with classic Fabry disease in an open-label phase 2 study and its extension study. Mol Genet Metab. 2023 Feb;138(2):106963. doi: 10.1016/j.ymgme.2022.11.002. Epub 2022 Nov 9.

  PMID: 36481125 DERIVED

MeSH Terms

Conditions

Fabry Disease

Interventions

venglustat

Condition Hierarchy (Ancestors)

Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2014
• First Posted: August 29, 2014
• Study Start: November 1, 2014
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: December 17, 2019
• Results First Posted: December 17, 2019

Record last verified: 2016-09

Locations

RU (1); GB (2); PL (1); US (3); FR (1)