Gaucher Disease, Gaucher Disease, Type 1, Type 1 Gaucher Disease
Conditions
Keywords
Amicus Therapeutics, afegostat tartrate, isofagomine tartrate, AT2101
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).
Interventions
Sponsors
Amicus Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Israel, South Africa, United Kingdom, United States
Participant flow
Pre-assignment details
Confirmatory β-glucosidase (GBA) genotype testing was done at screening to confirm reported genotype (with the exception of participants enrolled in Israel).19 participants received at least 1 dose of study drug. All participants were eligible for inclusion in both the safety and the pharmacodynamics (PD) populations.
Participants by arm
| Arm | Count |
|---|---|
| Afegostat Tartrate Treatment Regimen 1 For the first 2 weeks, 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. 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. | 11 |
| Afegostat Tartrate Treatment Regimen 2 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. | 8 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Afegostat Tartrate Treatment Regimen 1 | Afegostat Tartrate Treatment Regimen 2 | Total |
|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 16.27 | 39.1 years STANDARD_DEVIATION 17.62 | 41.4 years STANDARD_DEVIATION 16.48 |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 11 | 8 / 8 |
| serious Total, serious adverse events | 0 / 11 | 0 / 8 |
Outcome results
Primary
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.
Time frame: Day 1 (after dosing) through Day 183
Population: Safety Population: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Afegostat Tartrate Treatment Regimen 1 | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
| Afegostat Tartrate Treatment Regimen 2 | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
Secondary
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.
Time frame: Baseline, Day 169
Population: PD Population: all participants who were included in the Safety Population and had a baseline and at least 1 post-baseline PD measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afegostat Tartrate Treatment Regimen 1 | Change From Baseline To End Of Treatment In β-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | 10.2 picomole/minute/mg | Standard Deviation 15.87 |
| Afegostat Tartrate Treatment Regimen 2 | Change From Baseline To End Of Treatment In β-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | 3.9 picomole/minute/mg | Standard Deviation 4.12 |