Homozygous Familial Hypercholesterolemia (HoFH)
Conditions
Keywords
LDL Receptors, Gene therapy, Metabolic Diseases, Rare diseases, Genetic Diseases, Atherosclerosis, cardiovascular disease
Brief summary
This first-in-human study is intended to evaluate the safety and preliminary effectiveness of AAV (Adeno-associated virus)-based liver-directed gene therapy in the treatment of adults with Homozygous Familial Hypercholesterolemia (HoFH).
Detailed description
Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic metabolic disorder characterized by absent or severely reduced capacity to catabolize circulating LDL (Low density lipoprotein) particles by the hepatic LDL receptor. As a consequence, HoFH subjects present abnormal total plasma cholesterol (LDL-C) levels, resulting in severe atherosclerosis often leading to early onset of cardiovascular disease. Early initiation of aggressive treatment for these patients is therefore essential. Unfortunately, despite existing therapies, treated LDL-C (Low density lipoprotein cholesterol) levels could remain well above acceptable levels. Thus, the functional replacement of the defective LDLR via AAV-based liver-directed gene therapy may be a viable approach to treat this disease and improve response to current lipid-lowering treatments. This first-in-human study is intended to evaluate the safety of this gene therapy investigational product and assess preliminary evidence of efficacy using plasma LDL-C levels as a surrogate biomarker for human LDLR transgene expression. Subjects may be asked to participate in an optional kinetics study to assess the metabolic mechanism by which LDL-C is reduced.
Interventions
GENETICAAV directed hLDLR gene therapy
AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
REGENXBIO Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
dose escalation
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female ≥ 18 years of age. * Untreated and/or treated LDL-C levels and clinical presentation consistent with the diagnosis of homozygous FH (Familial hypercholesterolemia) * Molecularly defined LDLR mutations at both LDLR alleles. * A baseline serum AAV8 NAb (Neutralizing antibody) titer ≤ 1:10.
Exclusion criteria
* Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period: 1. niacin \> 250 mg/day: within 6 weeks of baseline 2. fibrates: within 4 weeks of baseline 3. lomitapide: within 8 weeks of baseline 4. mipomersen: within 24 weeks of baseline * History of cirrhosis or chronic liver disease based on documented histological evaluation or non-invasive imaging or testing. * Abnormal liver function tests (LFTs) at screening (AST (Aspartate aminotransferase) or ALT (Alanine aminotransferase) \> 2 × upper limit of normal (ULN) and/or Total Bilirubin of \> 1.5 × ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With IP (Investigational Product) Related Adverse Events | Up to 24 weeks | Physical examinations; Clinical laboratory parameters; and adverse event reporting |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in LDL-C | 18 weeks, 12 weeks for cohort 1 only, compared to baseline | Percent change in LDL-C compared to baseline |
| Percent Change in Lipid Parameters Compared to Baseline Values | 18 weeks, 12 weeks for cohort 1 only, compared to baseline | total cholesterol (TC); non-high density lipoprotein cholesterol (non-HDL-C); HDL-C; fasting triglycerides (TG); overflow density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); apolipoprotein B (apoB) and apolipoprotein A-I (apo A-I) |
| Number of Participants With IP Related Adverse Events | up to 104 weeks | Physical examinations; Clinical laboratory parameters; and adverse event reporting |
| Amount of Vector Shedding, Urine | up to 104 weeks | Amount of virus secreted in urine |
| Amount of Vector Shedding, Plasma | up to 104 weeks | Amount of virus secreted in plasma |
Countries
Canada, Italy, Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 2.5E12 GC/kg body weight
Single intravenous (IV) dose of human Low Density Lipoprotein Receptor (LDLR) Gene Therapy
AAV directed hLDLR gene therapy: a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene | 3 |
| Cohort 2 7.5E12 GC/kg body weight
Single intravenous (IV) dose of human Low Density Lipoprotein Receptor (LDLR) Gene Therapy
AAV directed hLDLR gene therapy: a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene | 3 |
| Cohort 2 Expansion 7.5E12 GC/kg body weight
DSMB (Data Safety Monitoring Board) approved expansion of Dose 2 cohort, 3 additional subjects enrolled and received prophylactic corticosteroids
Single intravenous (IV) dose of human Low Density Lipoprotein Receptor (LDLR) Gene Therapy
AAV directed hLDLR gene therapy: a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 2 Expansion | Cohort 2 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 7 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Canada | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Italy | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Netherlands | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 3 Participants | 5 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 3 |
| other Total, other adverse events | 2 / 3 | 3 / 3 | 2 / 3 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 1 / 3 |
Outcome results
Primary
Number of Participants With IP (Investigational Product) Related Adverse Events
Physical examinations; Clinical laboratory parameters; and adverse event reporting
Time frame: Up to 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants With IP (Investigational Product) Related Adverse Events | 1 Participants |
| Cohort 2 | Number of Participants With IP (Investigational Product) Related Adverse Events | 3 Participants |
| Cohort 2 Expansion | Number of Participants With IP (Investigational Product) Related Adverse Events | 2 Participants |
Secondary
Amount of Vector Shedding, Plasma
Amount of virus secreted in plasma
Time frame: up to 104 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Amount of Vector Shedding, Plasma | 50.0 GC/ μg (microgram) DNA | Standard Deviation 0 |
| Cohort 2 | Amount of Vector Shedding, Plasma | 50.0 GC/ μg (microgram) DNA | — |
| Cohort 2 Expansion | Amount of Vector Shedding, Plasma | 0.0 GC/ μg (microgram) DNA | — |
Secondary
Amount of Vector Shedding, Urine
Amount of virus secreted in urine
Time frame: up to 104 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Amount of Vector Shedding, Urine | 25.0 GC/12 μL (microliter) specimen) (urine) | Standard Deviation 0 |
| Cohort 2 | Amount of Vector Shedding, Urine | 25.0 GC/12 μL (microliter) specimen) (urine) | — |
| Cohort 2 Expansion | Amount of Vector Shedding, Urine | 0 GC/12 μL (microliter) specimen) (urine) | — |
Secondary
Number of Participants With IP Related Adverse Events
Physical examinations; Clinical laboratory parameters; and adverse event reporting
Time frame: up to 104 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants With IP Related Adverse Events | 1 Participants |
| Cohort 2 | Number of Participants With IP Related Adverse Events | 3 Participants |
| Cohort 2 Expansion | Number of Participants With IP Related Adverse Events | 2 Participants |
Secondary
Percent Change in LDL-C
Percent change in LDL-C compared to baseline
Time frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Percent Change in LDL-C | 7.21 percentage of change from baseline | Standard Deviation 12.24 |
| Cohort 2 | Percent Change in LDL-C | 27.35 percentage of change from baseline | Standard Deviation 32.51 |
| Cohort 2 Expansion | Percent Change in LDL-C | 8.98 percentage of change from baseline | Standard Deviation 31.34 |
Secondary
Percent Change in Lipid Parameters Compared to Baseline Values
total cholesterol (TC); non-high density lipoprotein cholesterol (non-HDL-C); HDL-C; fasting triglycerides (TG); overflow density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); apolipoprotein B (apoB) and apolipoprotein A-I (apo A-I)
Time frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | apolipoprotein B (apoB) | 4.53 percentage of change from baseline | Standard Deviation 9.61 |
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | total cholesterol (TC) | 7.89 percentage of change from baseline | Standard Deviation 15.72 |
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | overflow density lipoprotein cholesterol (VLDL-C) | 32.63 percentage of change from baseline | Standard Deviation 85.34 |
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | fasting triglycerides (TG) | 7.92 percentage of change from baseline | Standard Deviation 26.43 |
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | HDL-C | 9.10 percentage of change from baseline | Standard Deviation 22.58 |
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | non-high density lipoprotein cholesterol (non-HDL-C) | 8.43 percentage of change from baseline | Standard Deviation 15.93 |
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | lipoprotein(a) (Lp(a)) | -0.3 percentage of change from baseline | Standard Deviation 26.31 |
| Cohort 1 | Percent Change in Lipid Parameters Compared to Baseline Values | apolipoprotein A-I (apo A-I) | -2.71 percentage of change from baseline | Standard Deviation 15.18 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | overflow density lipoprotein cholesterol (VLDL-C) | 54.17 percentage of change from baseline | Standard Deviation 135.53 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | lipoprotein(a) (Lp(a)) | -31.4 percentage of change from baseline | Standard Deviation 16.08 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | fasting triglycerides (TG) | -9.16 percentage of change from baseline | Standard Deviation 8.23 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | HDL-C | 7.92 percentage of change from baseline | Standard Deviation 21.68 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | non-high density lipoprotein cholesterol (non-HDL-C) | 27.06 percentage of change from baseline | Standard Deviation 36.63 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | apolipoprotein B (apoB) | 21.15 percentage of change from baseline | Standard Deviation 25.21 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | total cholesterol (TC) | 24.91 percentage of change from baseline | Standard Deviation 34.45 |
| Cohort 2 | Percent Change in Lipid Parameters Compared to Baseline Values | apolipoprotein A-I (apo A-I) | 12.25 percentage of change from baseline | Standard Deviation 18.9 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | overflow density lipoprotein cholesterol (VLDL-C) | -5.46 percentage of change from baseline | Standard Deviation 111.43 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | total cholesterol (TC) | 7.17 percentage of change from baseline | Standard Deviation 37.35 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | apolipoprotein B (apoB) | 11.36 percentage of change from baseline | Standard Deviation 26.43 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | fasting triglycerides (TG) | 15.60 percentage of change from baseline | Standard Deviation 10.46 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | lipoprotein(a) (Lp(a)) | 30.3 percentage of change from baseline | Standard Deviation 17.83 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | non-high density lipoprotein cholesterol (non-HDL-C) | 8.26 percentage of change from baseline | Standard Deviation 38.16 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | HDL-C | -10.07 percentage of change from baseline | Standard Deviation 25.12 |
| Cohort 2 Expansion | Percent Change in Lipid Parameters Compared to Baseline Values | apolipoprotein A-I (apo A-I) | -16.18 percentage of change from baseline | Standard Deviation 11.04 |