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

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

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.

Study Overview

• Status: Completed
• Conditions: Fabry Disease
• Intervention / Treatment: Drug: Lucerastat; Drug: Enzyme replacement therapy (ERT)

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Würzburg, Germany, 97080
    • Investigator Site

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lucerastat group; 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; 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.; Other Names: ACT-434964; Drug: Enzyme replacement therapy (ERT); 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.; Other Names: Fabrazyme; Replagal
Experimental: Control group; 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); 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.; Other Names: Fabrazyme; Replagal

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.
• Investigators: Study Director: Nicolas Guérard, Actelion

Publications and helpful links

General Publications

• Guerard N, Morand O, Dingemanse J. Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects. Orphanet J Rare Dis. 2017 Jan 14;12(1):9. doi: 10.1186/s13023-017-0565-9.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: October 10, 2016
• First Submitted That Met QC Criteria: October 10, 2016
• First Posted (Estimate): October 12, 2016

Study Record Updates

• Last Update Posted (Actual): July 10, 2018
• Last Update Submitted That Met QC Criteria: July 6, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Fabry disease; lucerastat
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease
• Other Study ID Numbers: AC-069-104