Gaucher Disease, Gaucher Disease, Type 1, Type 1 Gaucher Disease
Conditions
Keywords
afegostat tartrate, isofagomine tartrate, AT2101, Amicus Therapeutics
Brief summary
This study was conducted to test the safety and tolerability of afegostat tartrate in participants with type 1 Gaucher disease already receiving enzyme replacement therapy.
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 14-day screening period, a 28-day treatment period, and a 7-day wash-out period. Participants received 1 of 4 dosing regimens for afegostat tartrate.
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
* Had a confirmed diagnosis of type 1 Gaucher disease with a known documented missense gene mutation in at least 1 of the 2 gene-encoding β-glucosidase alleles * Clinically stable * Male or female participants, 18 to 74 years old inclusive * All participants of childbearing potential used adequate birth control * Provided written informed consent to participate in the study
Exclusion criteria
* Clinically significant disease, severe complications from Gaucher disease, or serious illness that precluded participation in the study in the opinion of the Investigator that compromised the safety of the participant or precluded the participant from completing the study * During the screening period, any clinically significant findings, as deemed by the Investigator * Partial or total splenectomy (removal of spleen) within the 2 years prior to study entry * History of pulmonary hypertension or Gaucher related lung disease * History of allergy or sensitivity to the study drug or any excipients, including any prior serious adverse reaction to iminosugars (for example, N-butyldeoxynojirimycin or miglustat) * Pregnant or breast-feeding * Current/recent drug or alcohol abuse * Treatment with any investigational product in the 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 or 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 35 | TEAEs were defined as any adverse event (AE) with a start date on or after administration of the study drug (on Day 1). A severe AE was 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 7 days after the last dose of study drug (Day 35) 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 Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Baseline, Day 28 | 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
United States
Participant flow
Pre-assignment details
Participants were screened for evaluation of eligibility to participate in the study. Confirmatory β-glucosidase genotype testing was done at screening to confirm reported genotype. Thirty participants received at least 1 dose of study drug. All participants were eligible for inclusion in the safety and 29 in the pharmacodynamics (PD) populations.
Participants by arm
| Arm | Count |
|---|---|
| Afegostat Tartrate 25 mg Once Per Day Afegostat tartrate was administered orally during the 4-week treatment period. | 7 |
| Afegostat Tartrate 150 mg Once Per Day Afegostat tartrate was administered orally once per day during the 4-week treatment period. | 7 |
| Afegostat Tartrate 150 mg Once Every Four Days Afegostat tartrate was administered orally once every 4 days during the 4-week treatment period. | 9 |
| Afegostat Tartrate 150 mg Once Every Seven Days Afegostat tartrate was administered orally once every 7 days during the 4-week treatment period. | 7 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Afegostat Tartrate 25 mg Once Per Day | Afegostat Tartrate 150 mg Once Per Day | Afegostat Tartrate 150 mg Once Every Four Days | Afegostat Tartrate 150 mg Once Every Seven Days | Total |
|---|---|---|---|---|---|
| Age, Continuous | 41.4 years STANDARD_DEVIATION 15.1 | 43.4 years STANDARD_DEVIATION 18 | 36.7 years STANDARD_DEVIATION 12 | 45.0 years STANDARD_DEVIATION 12.3 | 41.3 years STANDARD_DEVIATION 14.01 |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 7 Participants | 5 Participants | 22 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 7 | 2 / 7 | 4 / 9 | 1 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 0 / 9 | 0 / 7 |
Outcome results
Primary
Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as any adverse event (AE) with a start date on or after administration of the study drug (on Day 1). A severe AE was 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 7 days after the last dose of study drug (Day 35) 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 35
Population: Safety Population: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Afegostat Tartrate 25 mg Once Per Day | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
| Afegostat Tartrate 150 mg Once Per Day | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
| Afegostat Tartrate 150 mg Once Every Four Days | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
| Afegostat Tartrate 150 mg Once Every Seven Days | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
Secondary
Change From Baseline To End Of Treatment In Beta-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 28
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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afegostat Tartrate 25 mg Once Per Day | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Baseline | 8.732 pmol/mg/min | Standard Deviation 3.1079 |
| Afegostat Tartrate 25 mg Once Per Day | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Change from Baseline to Day 28 | 10.226 pmol/mg/min | Standard Deviation 16.4 |
| Afegostat Tartrate 25 mg Once Per Day | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Day 28 | 19.148 pmol/mg/min | Standard Deviation 17.021 |
| Afegostat Tartrate 150 mg Once Per Day | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Baseline | 8.543 pmol/mg/min | Standard Deviation 4.156 |
| Afegostat Tartrate 150 mg Once Per Day | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Change from Baseline to Day 28 | 15.013 pmol/mg/min | Standard Deviation 11.2934 |
| Afegostat Tartrate 150 mg Once Per Day | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Day 28 | 23.557 pmol/mg/min | Standard Deviation 14.697 |
| Afegostat Tartrate 150 mg Once Every Four Days | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Day 28 | 14.687 pmol/mg/min | Standard Deviation 4.4901 |
| Afegostat Tartrate 150 mg Once Every Four Days | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Baseline | 9.371 pmol/mg/min | Standard Deviation 3.5133 |
| Afegostat Tartrate 150 mg Once Every Four Days | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Change from Baseline to Day 28 | 4.686 pmol/mg/min | Standard Deviation 3.1759 |
| Afegostat Tartrate 150 mg Once Every Seven Days | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Baseline | 12.035 pmol/mg/min | Standard Deviation 5.4742 |
| Afegostat Tartrate 150 mg Once Every Seven Days | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Change from Baseline to Day 28 | -1.028 pmol/mg/min | Standard Deviation 3.8147 |
| Afegostat Tartrate 150 mg Once Every Seven Days | Change From Baseline To End Of Treatment In Beta-glucocerebrosidase (GCase) Levels In White Blood Cells (WBC) | Day 28 | 13.026 pmol/mg/min | Standard Deviation 8.7286 |