Gaucher Disease, Type 1
Conditions
Brief summary
This study is a first-in-human, open-label, safety, tolerability, and efficacy study in adult patients with Gaucher disease Type 1. The aims are to investigate the safety/tolerability and efficacy of FLT201, and to investigate the relationship of FLT201 dose to augmentation of residual glucocerebrosidase (GCase) expression (activity and concentration), and its potential to improve the clinical phenotype by reduction and prevention of cellular accumulation of GCase substrate.
Interventions
GENETICFLT201
FLT201 is a replication-incompetent single-stranded (ss) recombinant adeno-associated virus (AAV) vector. The vector is composed of a ss DNA genome packaged in an AAV-derived protein capsid.
Sponsors
Spur Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult ≥ 18 years of age. 2. Diagnosis of Gaucher disease Type 1 with deficient GCase enzyme activity ≤30% of normal in leukocytes at diagnosis. 3. All female patients of childbearing potential must not be lactating and must have a negative serum pregnancy test at screening and confirmed negative by urine testing prior to dosing on Day 1. Female patients of childbearing potential and male patients must be willing to follow protocol guidelines for barrier protection/contraception. 4. Able to give full informed consent for the trial. 5. Treatment status at screening (screening period is 16 weeks): Treated with either enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) and started this treatment at least 2 years prior to dosing with no change in regimen for the prior 3 months. ERT dose ≥15 U/kg and ≤60 U/kg every other week.
Exclusion criteria
1. Diagnosed or suspected Type 2 or Type 3 Gaucher disease (including any patient with eye movement abnormality on clinical examination). 2. Positive for neutralising antibodies to AAVS3 at screening. 3. Evidence of significant and persistent liver dysfunction at Screening defined as \>1.5 x upper limit of normal (ULN) in alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin. 4. Evidence of any of the following at screening: 1. Hb \<8 g/dL. 2. Platelets \<45,000/mm3. 3. Pulmonary hypertension. 4. New osteonecrosis within 12 months of screening. 5. Fragility fracture or bone crisis within 12 months of screening. 5. Hepatitis B surface antigen (HBsAg) positive at screening. 6. Hepatitis C antibody (Hep C Ab) positive and hepatitis C RNA polymerase chain reaction (PCR) (as follow-up test if Hep C Ab-positive)-positive at screening. 7. Cytomegalovirus (CMV) immunoglobulin G (IgG) and CMV DNA PCR-positive at screening. 8. Human immunodeficiency virus (HIV)-1 or -2 antibody positive at screening. 9. Patient has received live attenuated vaccination within 12 weeks prior to screening or intends to receive such vaccination during the study. 10. History of clinically-advanced liver disease e.g. cirrhosis, portal hypertension. 11. History of bone marrow transplant. 12. History of splenectomy (partial or total). 13. History of splenic infarct within 12 months of screening. 14. History of receiving any gene transfer medicinal product. 15. History of receiving any investigational therapy for Gaucher disease within 60 days of screening. 16. Participation in any other clinical study of an investigational medicinal product (IMP), and/or receiving any other IMP during the study. 17. History of idiopathic thrombocytopaenic purpura, thrombotic thrombocytopaenic purpura, thrombocytopaenia, anaemia, hepatomegaly, splenomegaly, and/or osteoporosis, unrelated to Gaucher disease. 18. History of, or active neoplastic disease within 5 years of screening (except for basal or squamous cell carcinoma of the skin or carcinoma in situ which has been definitively treated). 19. Subjects with uncontrolled cardiac failure, unstable angina, myocardial infarction, pulmonary hypertension or cardiac presentations including cardiac instability deemed significant by the investigator in the past 6 months 20. History of acute myocarditis or presence of acute myocarditis during screening. 21. History of substance abuse, including alcohol abuse or alcohol dependence. 22. Known or suspected intolerance, hypersensitivity or contraindication to the investigational medicinal product (IMP) and non-investigational medicinal products (NIMPs) or their excipients. 23. History of anaphylaxis or infusion related reactions to ERT. 24. Contraindication(s) to MRI. (e.g. ferromagnetic metallic implants, some types of pacing and defibrillator devices, nerve stimulators). 25. Any clinical condition (medical or psychiatric) that, in the opinion of the investigator, could jeopardise safety or compromise ability of the patient to participate in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events Over Time | Day 1 (dosing) through transfer to the long-term follow-up (LTFU) study, which was up to 15 months. | Treatment-emergent adverse events (including dose-limiting toxicities), with AEs graded as mild/moderate/severe. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Lyso-Gb1 in Plasma | From baseline to week 38/9 months. | Change from baseline to week 38/month 9 of lyso-Gb1 in plasma. |
| Change From Baseline in Spleen Volume Measured by MRI | From baseline to week 38/9 months. | Change from baseline to week 38/month 9 in spleen volume measured by MRI. |
| Change From Baseline in Liver Volume Measured by MRI | From baseline to week 38/9 months. | Change from baseline to week 38/month 9 in liver volume measured by MRI. |
| Change From Baseline in Hemoglobin | From baseline to week 38/9 months. | Change from baseline to week 38/month 9 in hemoglobin. |
| Change From Baseline in Platelet Count | From baseline to week 38/9 months. | Change from baseline to week 38/month 9 in platelet count. |
Countries
Brazil, Germany, Israel, Spain, United Kingdom, United States
Participant flow
Recruitment details
This was a multicenter study with 15 study sites in USA, Brazil, Paraguay, Spain, Germany, UK, and Israel. Ten participants met all the inclusion criteria for the trial and were enrolled, with 6 participants ultimately being dosed with FLT201 at 4 trial sites in Brazil, Spain, UK, and USA.
Pre-assignment details
Participants were to undergo screening assessments for up to 16 weeks prior to Day 1 (gene therapy infusion). Treatment-eligible participants reported to the infusion trial site on the day prior to receiving the gene therapy infusion (Day -1).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 32.7 Years STANDARD_DEVIATION 13.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment Brazil | 2 Participants |
| Region of Enrollment Spain | 1 Participants |
| Region of Enrollment United Kingdom | 1 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 |
Outcome results
None listed