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

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Randomized, Open-label Study To Assess the Safety and Tolerability of AT2101 in Treatment-naive Adult Patients With Type 1 Gaucher Disease

Conditions
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Gaucher Disease, Type 1 Gaucher Disease, Gaucher Disease, Type 1

Intervention / Treatment
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* Drug: afegostat tartrate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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: Afegostat Tartrate Treatment Regimen 1<br>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. | Drug: afegostat tartrate<br> <br> * Other names: AT2101;|
| Experimental: Afegostat Tartrate Treatment Regimen 2<br>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. | Drug: afegostat tartrate<br> <br> * Other names: AT2101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 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. | Day 1 (after dosing) through Day 183 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline To End Of Treatment In β-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | 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. | Baseline, Day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amicus Therapeutics, afegostat tartrate, isofagomine tartrate, AT2101