A Study of Oral AT2101 (Afegostat Tartrate) in Treatment-naive Patients With Gaucher Disease

Phase 2

Completed

• Conditions: Gaucher Disease; Type 1 Gaucher Disease; Gaucher Disease, Type 1
• Interventions: Drug: afegostat tartrate

• Registration Number: NCT00446550
• Lead Sponsor: Amicus Therapeutics

Brief Summary

This study evaluated the safety and tolerability of afegostat tartrate in participants with type 1 Gaucher disease who were not receiving enzyme replacement therapy (ERT) or substrate reduction therapy (SRT).

Detailed Description

This was a Phase 2, open-label study in participants with Gaucher disease, a lysosomal storage disorder. Afegostat tartrate (also known as AT2101 or isofagomine tartrate) is designed to act as a pharmacological chaperone by selectively binding to misfolded β-glucocerebrosidase (GCase) and helping it fold correctly, intended to restore GCase activity. The study consisted of a 21-day screening period, a 24-week treatment period, and follow-up visit (Day 183, end-of-study). Participants were randomized in a 1:1 ratio to 1 of 2 treatment regimens for afegostat tartrate (3 days on treatment/4 days off or 7 days on treatment/7 days off).

Study Timeline

• Study First Submitted: 2007-03-09
• Study First Submitted QC: 2007-03-09
• Study First Posted: 2007-03-13
• Study Start: 2008-06-11
• Primary Completion: 2009-08-20
• Study Completion: 2009-08-20
• Disposition First Submitted: 2011-05-12
• Disposition First Submitted QC: 2011-05-12
• Disposition First Posted: 2011-05-18
• Status Verified: 2018-07
• Results First Submitted: 2018-07-23
• Results First Submitted QC: 2018-07-23
• Last Update Submitted: 2018-07-23
• Results First Posted: 2018-08-15
• Last Update Posted: 2018-08-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

• Confirmed diagnosis of type 1 Gaucher disease with a known genotype and a documented missense gene mutation in at least 1 of the 2 gene-encoding β-glucosidase (GBA) alleles
• Clinically stable
• Treatment naïve to ERT and SRT or had not received ERT or SRT in the 12 months before screening
• Willing to not initiate ERT or SRT treatment during study participation
• Male or female participants, 18 to 74 years old, inclusive
• At the screening period (Day -21 to Day -1), participants must have met at least 2 of the following criteria: platelet count of ≤150,000 per microliter, hemoglobin ≤12 grams/deciliter (g/dL) for females and ≤13 g/dL for males, liver volume ≥1.25 multiples of normal (MN), and spleen volume ≥2 MN
• All participants of reproductive potential were required to practice an acceptable method of contraception
• Provided written informed consent to participate in the study

Exclusion Criteria

• A clinically significant disease other than Gaucher disease, severe complications from Gaucher disease, or serious intercurrent illness that precluded participation in the study in the opinion of the investigator
• During the screening period, had any clinically significant findings as deemed by the investigator
• Partial or total splenectomy
• Documentation of moderate or severe pulmonary hypertension, defined as pulmonary arterial pressure >35 millimeters of mercury (mmHg) or significant Gaucher-related lung disease
• History of allergy or sensitivity to the study drug or any excipients, including any prior serious allergic reaction to iminosugars
• Pacemaker or other contraindication for magnetic resonance imaging (MRI) scanning
• Pregnant or breast-feeding
• Current/recent drug or alcohol abuse
• Treatment with any investigational product in the last 90 days before study entry
• Treatment in the previous 90 days with any drug known to have a well-defined potential for toxicity to a major organ
• Presence of symptoms of gastrointestinal, liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Afegostat Tartrate Treatment Regimen 1	afegostat tartrate	For the first 2 weeks, afegostat tartrate was administered orally at a dose of 225 milligrams (mg) once daily (QD) for 7 consecutive days, followed by no study medication for 7 consecutive days. After 2 weeks, participants then took 225 mg afegostat tartrate QD for 3 consecutive days, followed by no study medication for 4 consecutive days. This 3-days-on/4-days-off treatment regimen was followed for 22 weeks.
Afegostat Tartrate Treatment Regimen 2	afegostat tartrate	Afegostat tartrate was administered orally at a dose of 225 mg QD for 7 consecutive days, followed by no study medication for 7 consecutive days. This 7-days-on/7-days-off treatment regimen was followed for 24 weeks.

Primary Outcome Measures

Name	Time	Method
Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs)	Day 1 (after dosing) through Day 183	A TEAE was defined as any adverse event (AE) with start date on or after administration of study drug or pre-existing conditions that worsened on or after the start of the first study drug administration (on Day 1). A severe AE defined as an AE that was incapacitating and required medical intervention. The number of participants who experienced 1 or more severe TEAEs after dosing on Day 1 through the end of follow-up (Day 183) is presented. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline To End Of Treatment In β-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC)	Baseline, Day 169	GCase is a biomarker used to assess the PD effects of afegostat tartrate. Blood samples were collected to assess GCase levels in WBC. The baseline value was defined as the last non-missing value before the start of study drug.