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

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02228460
• Collaborator: (none)
• Enrollment: 11
• Locations: 8
• Arm: 1
• Actual Duration (Months): 22
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Fabry Disease	Drug: GZ/SAR402671	Phase 2

Detailed Description

The total duration of study per participant was 7 to 8 months for participants who entered a planned extension study and approximately 13 to 14 months for participants who did not enter a planned extension study. A 2-year extension study was planned for eligible participants.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Enzyme Replacement Therapy (ERT) Treatment-naïve Adult Male Patients Diagnosed With Fabry Disease
• Actual Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GZ/SAR402671 GZ/SAR402671 15 milligram (mg) once daily orally for 26 weeks.	Drug: GZ/SAR402671; Pharmaceutical form: Capsule; Route of administration: Oral

Outcome Measures

Primary Outcome Measures

1. 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 [Baseline, 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.

2. Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium [Baseline, 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. 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.

Secondary Outcome Measures

1. Change From Baseline in Plasma GL-3 Concentration at Week 26 [Baseline, Week 26]

   Change from Baseline in plasma GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-3 in plasma was determined using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method.

2. Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26 [Baseline, Week 26]

   Change from Baseline in plasma Lyso-GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of lyso-GL-3 in plasma was determined using a validated LC-MS/MS method.

3. Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26 [Baseline, Week 26]

   Change from Baseline in plasma GL-1 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-1 in plasma was determined using a validated LC-MS/MS method.

4. 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]

   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.

5. 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]

   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.

6. Change From Baseline at Week 26 in Skin GL-3 Score in Perineurium Cells: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26 [Baseline, 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.

7. Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at Week 26 [Baseline, Week 26]

   Change from Baseline in urine GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-3 in urine was determined using a validated LC-MS/MS method.

8. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [From Baseline up to 212 days]

   Any untoward medical occurrence in a participant who received study drug was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened during on-treatment period (period from the first administration of study drug through the last administration of the study drug plus 30 days or end of study participation for participant, whichever occurs first).

9. Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671 [Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)]

   Maximum plasma concentration observed for study drug was reported.

10. PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671 [Predose on Days 14, 28, 56, 84, 126, and 182]

    Ctrough was defined as the plasma concentration of study drug observed just before treatment administration during repeated dosing.

11. PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671 [Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)]

    Tmax was defined as time to reach maximum plasma concentration of study drug.

12. PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671 [Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)]

    Area under the plasma concentration versus time curve of study drug from time 0 to 24 hours (AUC0-24) was calculated using the trapezoidal method over the dosing interval.

13. PK: Terminal Half-life (t1/2z) of GZ/SAR402671 [Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)]

    Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half. The t1/2z was estimated based on 24-hour post-dose PK.

14. PK: Apparent Total Body Clearance of GZ/SAR402671 at Steady State (CLss/F) [Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182]

    Apparent total body clearance at steady state was a quantitative measure of rate of clearance of drug from the blood following oral administration, and is described in terms of volume of fluid clear of drug per time unit (eg, mL/min).

15. PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State [Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182]

    Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of drug.

16. PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24) [0-24 hours on Day 182]

    Ae0-24 was the cumulated amount of study drug excreted in urine during the time interval of 0 to 24 hours.

17. PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24) [0-24 hours on Day 182]

    fe0-24 was the fraction of dose excreted in urine during the time interval of 0 to 24 hours.

18. PK: Renal Clearance (CLR) of GZ/SAR402671 From 0 to 24 Hours [0-24 hours on Day 182]

    CLR was calculated by dividing the cumulative amount of drug excreted in urine during the dosing interval of 0-24 hours by area under the plasma drug concentration time-curve during the dosing interval of 0-24 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 49 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion criteria:

• 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.

Exclusion criteria:

• 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).

• The participant had one of the following central nervous system exclusion criteria:

• Acute stroke, within 3 months of the screening visit.

• History of seizures.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 840002	Atlanta	Georgia	United States	30322
2	Investigational Site Number 840003	Cincinnati	Ohio	United States	45229
3	Investigational Site Number 840001	Fairfax	Virginia	United States	22030
4	Investigational Site Number 250001	Garches		France	92380
5	Investigational Site Number 616001	Warszawa		Poland	04-730
6	Investigational Site Number 643002	Moscow		Russian Federation	125167
7	Investigational Site Number 826003	Birmingham		United Kingdom	B15 2TH
8	Investigational Site Number 826002	Cambridge		United Kingdom	CB2 OQQ

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT02228460
• Other Study ID Numbers: ACT13739; 2013-005324-41; U1111-1152-1456
• First Posted: Aug 29, 2014
• Last Update Posted: Dec 17, 2019
• Last Verified: Sep 1, 2016

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Genzyme, a Sanofi Company: Venglustat
• Additional relevant MeSH terms: Fabry Disease

Study Results

Participant Flow

Recruitment Details	Participants were enrolled in the study at 8 centers in 5 countries between 11 November 2014 and 06 September 2016. A total of 14 participants were screened in the study.
Pre-assignment Detail	Out of 14 screened participants, 11 participants were enrolled and treated in the study.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 milligram (mg) once daily, orally for 26 weeks.
Period Title: Overall Study
STARTED	11
COMPLETED	9
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Overall Participants	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.5 (7.6)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	11 100%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on full analysis set (FAS) that included all participants who received at least 1 dose of study treatment. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Baseline Score: 1 / Week 26 Score: 1	4 36.4%
Baseline Score: 1 / Week 26 Score: 2	1 9.1%
Baseline Score: 2 / Week 26 Score: 1	3 27.3%
Baseline Score: 2 / Week 26 Score: 2	1 9.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GZ/SAR402671
	Comments	A McNemar test was used to test the treatment effect based on paired pre-treatment and post-treatment (Week 26) frequencies of skin GL-3 score grouped into the categories (0 to <2; 2 to 3).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3173
	Comments	Threshold for significance at 0.05 level.
	Method	McNemar Test
	Comments

2. Primary Outcome

Title	Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Mean (95% Confidence Interval) [score on a scale]	-0.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GZ/SAR402671
	Comments	Wilcoxon signed rank test was used to assess the mean change from Baseline to Week 26 in skin GL-3 score.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.625
	Comments	Threshold for significance at 0.05 level.
	Method	Wilcoxon signed rank test
	Comments

3. Secondary Outcome

Title	Change From Baseline in Plasma GL-3 Concentration at Week 26
Description	Change from Baseline in plasma GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-3 in plasma was determined using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Mean (Standard Deviation) [mcg/mL]	-3.62 (1.07)

4. Secondary Outcome

Title	Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26
Description	Change from Baseline in plasma Lyso-GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of lyso-GL-3 in plasma was determined using a validated LC-MS/MS method.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Mean (Standard Deviation) [ng/mL]	-30.99 (22.83)

5. Secondary Outcome

Title	Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26
Description	Change from Baseline in plasma GL-1 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-1 in plasma was determined using a validated LC-MS/MS method.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Mean (Standard Deviation) [mcg/mL]	-3.26 (1.43)

6. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Baseline Score: 1 / Week 26 Score: 1	1 9.1%
Baseline Score: 2 / Week 26 Score: 1	2 18.2%
Baseline Score: 2 / Week 26 Score: 2	6 54.5%

7. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Baseline Score: 1.5 / Week 26 Score: 1.5	2 18.2%
Baseline Score: 2 / Week 26 Score: 2	7 63.6%

8. Secondary Outcome

Title	Change From Baseline at Week 26 in Skin GL-3 Score in Perineurium Cells: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Baseline Score: 1 / Week 26 Score: 2	1 9.1%
Baseline Score: 2 / Week 26 Score: 2	8 72.7%

9. Secondary Outcome

Title	Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at Week 26
Description	Change from Baseline in urine GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-3 in urine was determined using a validated LC-MS/MS method.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on FAS. Here, 'overall number of participants analyzed' = participants with available data at both Baseline and Week 26.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	8
Mean (Standard Deviation) [mg/mmol Cr]	-0.25 (0.19)

10. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	Any untoward medical occurrence in a participant who received study drug was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened during on-treatment period (period from the first administration of study drug through the last administration of the study drug plus 30 days or end of study participation for participant, whichever occurs first).
Time Frame	From Baseline up to 212 days

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population which included all enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	11
Count of Participants [Participants]	9 81.8%

11. Secondary Outcome

Title	Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671
Description	Maximum plasma concentration observed for study drug was reported.
Time Frame	Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population which included all participants for whom the primary PK data were considered sufficient and interpretable. Here, 'number analyzed' = participants with available data at specified time-point.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	11
Day 1	24.7 (5.89)
Day 182	192.0 (96.4)

12. Secondary Outcome

Title	PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671
Description	Ctrough was defined as the plasma concentration of study drug observed just before treatment administration during repeated dosing.
Time Frame	Predose on Days 14, 28, 56, 84, 126, and 182

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'number analyzed' = participants with available data at specified time-point.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	11
Day 14	152.0 (68.9)
Day 28	165.0 (66.1)
Day 56	182.0 (90.3)
Day 84	164.0 (124.0)
Day 126	175.0 (94.7)
Day 182	164.0 (89.4)

13. Secondary Outcome

Title	PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671
Description	Tmax was defined as time to reach maximum plasma concentration of study drug.
Time Frame	Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'number analyzed' = participants with available data at specified time-point.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	11
Day 1	8.00
Day 182	4.00

14. Secondary Outcome

Title	PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671
Description	Area under the plasma concentration versus time curve of study drug from time 0 to 24 hours (AUC0-24) was calculated using the trapezoidal method over the dosing interval.
Time Frame	Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'number analyzed' = participants with available data at specified time-point.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	11
Day 1	476 (125)
Day 182	4110 (2090)

15. Secondary Outcome

Title	PK: Terminal Half-life (t1/2z) of GZ/SAR402671
Description	Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half. The t1/2z was estimated based on 24-hour post-dose PK.
Time Frame	Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'number analyzed' = participants with available data at specified time-point.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	11
Day 1	86.8 (39.6)
Day 182	128.0 (59.0)

16. Secondary Outcome

Title	PK: Apparent Total Body Clearance of GZ/SAR402671 at Steady State (CLss/F)
Description	Apparent total body clearance at steady state was a quantitative measure of rate of clearance of drug from the blood following oral administration, and is described in terms of volume of fluid clear of drug per time unit (eg, mL/min).
Time Frame	Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Mean (Standard Deviation) [mL/hour]	7490 (10900)

17. Secondary Outcome

Title	PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State
Description	Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of drug.
Time Frame	Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182

Outcome Measure Data

Analysis Population Description

Since the percent extrapolation of AUC for all participants was >30%, AUC could not be determined and hence, Vss/F could not be calculated.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	0

18. Secondary Outcome

Title	PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24)
Description	Ae0-24 was the cumulated amount of study drug excreted in urine during the time interval of 0 to 24 hours.
Time Frame	0-24 hours on Day 182

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Mean (Standard Deviation) [mcg]	3210.0 (1640.0)

19. Secondary Outcome

Title	PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24)
Description	fe0-24 was the fraction of dose excreted in urine during the time interval of 0 to 24 hours.
Time Frame	0-24 hours on Day 182

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily orally for 26 weeks.
Measure Participants	9
Mean (Standard Deviation) [percentage of dose]	21.4 (10.9)

20. Secondary Outcome

Title	PK: Renal Clearance (CLR) of GZ/SAR402671 From 0 to 24 Hours
Description	CLR was calculated by dividing the cumulative amount of drug excreted in urine during the dosing interval of 0-24 hours by area under the plasma drug concentration time-curve during the dosing interval of 0-24 hours.
Time Frame	0-24 hours on Day 182

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
Measure Participants	9
Mean (Standard Deviation) [mL/hour]	925 (407)

Adverse Events

Time Frame	Baseline up to 212 days
Adverse Event Reporting Description	Reported AEs are TEAEs that is AEs developed/worsened during "on treatment period" (from first administration through last administration of study drug + 30 days or end of study participation for participant, whichever occurs first). Analysis was performed on safety population that included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title	GZ/SAR402671
Arm/Group Description	GZ/SAR402671 15 mg once daily, orally for 26 weeks.
All Cause Mortality
	GZ/SAR402671
	Affected / at Risk (%)	# Events
Total	0/11 (0%)
Serious Adverse Events
	GZ/SAR402671
	Affected / at Risk (%)	# Events
Total	3/11 (27.3%)
Blood and lymphatic system disorders
Haemolysis	1/11 (9.1%)
Musculoskeletal and connective tissue disorders
Floppy infant	1/11 (9.1%)
Psychiatric disorders
Depressed mood	1/11 (9.1%)
Other (Not Including Serious) Adverse Events
	GZ/SAR402671
	Affected / at Risk (%)	# Events
Total	9/11 (81.8%)
Cardiac disorders
Atrial fibrillation	1/11 (9.1%)
Ear and labyrinth disorders
Tinnitus	2/11 (18.2%)
Eye disorders
Blepharitis	1/11 (9.1%)
Chalazion	1/11 (9.1%)
Eye pain	1/11 (9.1%)
Lacrimation increased	1/11 (9.1%)
Lenticular opacities	1/11 (9.1%)
Retinal vascular disorder	1/11 (9.1%)
Vision blurred	1/11 (9.1%)
Gastrointestinal disorders
Constipation	1/11 (9.1%)
Dry mouth	1/11 (9.1%)
Nausea	2/11 (18.2%)
Oesophageal discomfort	1/11 (9.1%)
Toothache	1/11 (9.1%)
Vomiting	2/11 (18.2%)
General disorders
Fatigue	2/11 (18.2%)
Feeling hot	2/11 (18.2%)
Influenza like illness	1/11 (9.1%)
Non-cardiac chest pain	1/11 (9.1%)
Pyrexia	2/11 (18.2%)
Infections and infestations
Ear infection	1/11 (9.1%)
Nasopharyngitis	1/11 (9.1%)
Rhinitis	2/11 (18.2%)
Upper respiratory tract infection	2/11 (18.2%)
Injury, poisoning and procedural complications
Muscle strain	1/11 (9.1%)
Wound	1/11 (9.1%)
Investigations
Electrocardiogram T wave abnormal	1/11 (9.1%)
Electrocardiogram abnormal	1/11 (9.1%)
Nuclear magnetic resonance imaging brain abnormal	1/11 (9.1%)
Vibration test abnormal	1/11 (9.1%)
Musculoskeletal and connective tissue disorders
Muscle twitching	1/11 (9.1%)
Musculoskeletal chest pain	1/11 (9.1%)
Myalgia	1/11 (9.1%)
Neck pain	1/11 (9.1%)
Pain in extremity	1/11 (9.1%)
Nervous system disorders
Amnesia	1/11 (9.1%)
Dizziness	2/11 (18.2%)
Headache	4/11 (36.4%)
Hypoaesthesia	1/11 (9.1%)
Migraine	1/11 (9.1%)
Paraesthesia	1/11 (9.1%)
Sinus headache	1/11 (9.1%)
White matter lesion	1/11 (9.1%)
Psychiatric disorders
Anxiety	1/11 (9.1%)
Depressed mood	1/11 (9.1%)
Respiratory, thoracic and mediastinal disorders
Cough	2/11 (18.2%)
Dyspnoea	2/11 (18.2%)
Oropharyngeal pain	1/11 (9.1%)
Skin and subcutaneous tissue disorders
Acne	1/11 (9.1%)
Angiokeratoma	2/11 (18.2%)
Hyperhidrosis	1/11 (9.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.