A Study to Assess the Safety and Tolerability of Lucerastat in Subjects With Fabry Disease

Study Overview
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Brief Summary
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The primary purpose of this study was to assess the safety and tolerability of lucerastat in adults with Fabry Disease receiving Enzyme Replacement Therapy (ERT). The secondary objectives were to investigate the effects of lucerastat on plasma and urine levels of biomarkers, to assess its effects on renal and cardiac functions and to determine the pharmacokinetic profile of lucerastat at steady-state.

Official Title
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A Single-center, Open-label, Randomized, Versus a Control Group, Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Oral Lucerastat in Adult Subjects With Fabry Disease Receiving Enzyme Replacement Therapy

Conditions
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Fabry Disease

Intervention / Treatment
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* Drug: Lucerastat
* Drug: Enzyme replacement therapy (ERT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form Male and female adult subjects with a diagnosis of Fabry Disease (FD) based on historical assessments (residual α-GAL A activity level below lower limit of normal for males and presence of a galactosidase alpha mutation for females) and a history of clinical symptoms of FD On ERT for at least 24 months without any change in dose within the last 6 months prior to screening Exclusion Criteria: Severe renal function impairment Severe residual neurologic deficit Clinically significant unstable cardiac disease Any circumstances or conditions, which, in the opinion of the investigator, may have affected full participation in the study or compliance with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lucerastat group<br>Ten subjects with Fabry Disease received 1000 mg of oral lucerastat twice daily for 12 weeks in addition to their standard of care treatment (enzyme replace therapy). | Drug: Lucerastat<br>* Hard gelatin capsules for oral administration formulated at a strength of 250 mg, and administered as 4 capsules in the morning and 4 capsules in the evening.<br>* Other names: ACT-434964;Drug: Enzyme replacement therapy (ERT)<br>* All the subjects received an ERT as background therapy for at least 24 months prior to the screening visit and they had to continue receiving this treatment during the conduct of the study.<br>* Other names: Replagal;|
| Experimental: Control group<br>Four subjects with Fabry Disease under enzyme replace therapy (ERT) as standard of care treatment were included as a control group. | Drug: Enzyme replacement therapy (ERT)<br>* All the subjects received an ERT as background therapy for at least 24 months prior to the screening visit and they had to continue receiving this treatment during the conduct of the study.<br>* Other names: Replagal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in blood pressure |  | Up to Week 12 | 
| Change from baseline in heart rate |  | Up to Week 12 | 
| Change from baseline in electrocardiogram (ECG) variables | The duration (in ms) of the different ECG variables were measured using a standard 12-lead ECG | Up to Week 12 | 
| Change from baseline in body weight |  | Up to Week 12 | 
| Number of subjects with treatment-emergent adverse events and serious adverse events |  | Up to Week 12 | 
| Number of subjects with adverse events leading to premature discontinuation of lucerastat or ERT |  | Up to Week 12 | 
| Number of subjects with treatment-emergent abnormalities in laboratory variables |  | Up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in plasma biomarkers of Fabry Disease | Biomarkers reflecting glycolipid metabolism were measured (unit of measure: ng/mL) | Up to Week 12 | 
| Change from baseline in urine biomarker of Fabry Disease | Biomarker reflecting glycolipid metabolism was measured (unit of measure: ng/mg) | Up to Week 12 | 
| Change from baseline in left ventricular ejection fraction (LVEF) | LVEF was used to monitor cardiac function in subjects with Fabry Disease | Up to Week 12 | 
| Change from baseline in left ventricular mass index (LVMi) | LVMi was used to monitor cardiac function in subjects with Fabry Disease | Up to Week 12 | 
| Change from baseline in estimated glomerular filtration rate (eGFR) | eGFR was used to monitor renal function in subjects with Fabry Disease | Up to Week 12 | 
| Change from baseline in urine albumin-to-creatinine ratio (UACR) | UACR was used to monitor renal function in subjects with Fabry Disease | Up to Week 12 | 
| Maximum plasma concentration (Cmax) of lucerastat | Cmax was determined directly from the observed plasma concentration-time curves of lucerastat. Blood samples for PK analyses were drawn at scheduled time points at the Week 4 visit | At Week 4 visit, blood samples drawn at the following time points: pre-dose, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h post-dose | 
| Time to reach Cmax (tmax) of lucerastat | tmax was determined directly from the observed plasma concentration-time curves of lucerastat. Blood samples for PK analyses were drawn at scheduled time points at the Week 4 visit | At Week 4 visit, blood samples drawn at the following time points: pre-dose, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h post-dose | 
| Area under the plasma concentration-time curve [AUC(tau)] of lucerastat | AUC(tau) corresponds to the area under the plasma concentration time curve of lucerastat over a dosing interval (tau = 12 hours) | At Week 4 visit, blood samples drawn at the following time points: pre-dose, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h post-dose | 
| Terminal half-life [t(1/2)]of lucerastat |  | At Week 4 visit, blood samples drawn at the following time points: pre-dose, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fabry disease, lucerastat