AADC Deficiency
Conditions
Keywords
AADC Deficiency gene therapy
Brief summary
This study will have a trial phase, extension phase, and a long-term extension phase. The primary objectives of the trial phase are to assess the pharmacodynamics (PD) of eladocagene exuparvovec treatment by evaluation of homovanillic acid (HVA) levels and to assess the safety of the SmartFlow® magnetic resonance (MR) Compatible Ventricular Cannula for administering eladocagene exuparvovec to pediatric participants with aromatic L-amino acid decarboxylase (AADC) deficiency. The extension phase is designed to capture additional clinical information for eladocagene exuparvovec through study evaluations, changes in motor development, AADC-specific symptoms, and other PD measures. The long-term extension phase is designed to capture long-term safety and efficacy data from participants treated with eladocagene exuparvovec.
Interventions
GENETICEladocagene Exuparvovec
Four 0.08 milliliters (mL) infusions at a dose of 0.45×10\^11 vg and a volume of 80 microliters (μl) per site to 4 sites (2 per putamen), for the total dose of 1.8×10\^11 vg and a total volume of 320 μl per participant.
Sponsors
PTC Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric participants must have genetically-confirmed AADC deficiency with typical clinical characteristics and decreased AADC enzyme activity in plasma. * Cranium sufficiently developed to allow placement of ClearPoint® system for stereotactic surgery. * Persistent neurological defects secondary to AADC deficiency despite standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine, or other forms of vitamin B6) in the opinion of the investigator. * Unable to ambulate independently (with or without assistive device). * Baseline hematology, chemistry, and coagulation values within the normal pediatric laboratory value ranges, unless in the investigator's opinion the out of range values are not clinically significant with respect to the participant's suitability for surgery. * Participant must test negative for coronavirus disease of 2019 (COVID-19) a maximum of 72 hours prior to receiving gene therapy. * Participant must be on stable dosage for 3 months prior to baseline for all medications related to treatment of AADC deficiency, including dopamine agonists, monoamine oxidase inhibitors, anticholinergic drugs, and vitamin B6. * Females of childbearing potential must have a negative pregnancy test at screening and baseline and agree to abstinence or double-barrier form of contraception for the duration of the study following discharge from the hospital (acceptable methods will be determined by the site). * Males sexually active with females of childbearing potential must agree to use a barrier method of birth control during the study following discharge from the hospital. * Parent(s)/legal guardian(s) of the participant must agree to comply with the requirements of the study, including the need for frequent and prolonged follow up. * Parent(s)/legal guardian(s) with custody of the participant must give their consent for the participant to enroll in the study.
Exclusion criteria
* The participant has presence of other significant medical or neurological conditions that would create an unacceptable operative or anesthetic risk. * Participants with pyridoxine 5'-phosphate oxidase or tetrahydrobiopterin (BH4) deficiency. * Contraindication for imaging studies (computed tomography \[CT\] scan, PET or magnetic resonance imaging \[MRI\]), including sedation limitations or metal that would interfere with a brain MRI. * Anti-adeno-associated virus, serotype 2 (anti-AAV2) antibody titer higher than 1:1200 or \>1 optical density value by enzyme-linked immunosorbent assay. * Participants who have received treatment with other experimental therapies within the last 24 weeks prior to planned gene therapy administration, or any treatment ever with a gene therapy. * Evidence of a clinically active infection. * Females who are pregnant or breast feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HVA Metabolite Level at the End of the Trial Phase | Baseline (Day 1), Week 8 | HVA is a main metabolite of dopamine and HVA CSF levels are recognized as a proxy for dopamine levels in the brain. |
| Number of Participants With Adverse Events (AEs) Associated With the Surgical Administration of Eladocagene Exuparvovec Using the SmartFlow® MR-Compatible Ventricular Cannula | Baseline (Day 1) up to Week 8 | An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered related to the drug. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease in a study participant who was administered gene therapy in this study. Number of participants with AEs related to the SmartFlow MR-compatible ventricular cannula used to administer eladocagene exuparvovec to pediatric participants at the end of Trial Phase (8 weeks after administration) are reported. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module." |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in Neurotransmitter Cerebrospinal Fluid (CSF) Metabolite HVA at Week 48 | Baseline (Day 1), Week 48 |
| Change From Baseline in Positron Emission Tomography (PET) Imaging of Putaminal-Specific L-6-[18F] Fluoro-3,4-Dihydroxyphenylalnine (18F-DOPA) PET Uptake at the End of the Trial Phase (Week 8) and the Extension Phase (Week 48) | Baseline (Day 1), Week 8, Week 48 |
| Change From Baseline in Neurotransmitter CSF Metabolites 5-hydroxyindoleacetic Acid (5-HIAA), and 3-O-methyldopa (3-OMD) at Weeks 8 and 48 | Baseline (Day 1), Weeks 8 and 48 |
| Number of Participants Who Attain Motor Milestones | Baseline (Day 1) up to Week 260 |
| Change in Peabody Developmental Motor Scale, Second Edition (PDMS-2) | Baseline (Day 1), Week 260 |
| Change in Bayley Scale of Infant Development, Third Edition (Bayley-III) | Baseline (Day 1), Week 260 |
| Change in EuroQol-5 Dimensions Youth Version (EQ-5D-Y) | Baseline (Day 1), Week 260 |
| Change in Body Weight | Baseline (Day 1), Week 260 |
| Number of Participants With AADC-Specific Symptoms | Baseline (Day 1) up to Week 260 |
| "Number of Participants With Treatment-Emergent Adverse Events (TEAEs) " | Baseline (Day 1) up to Week 260 |
Countries
Israel, Taiwan, United States
Participant flow
Pre-assignment details
The study is ongoing. Only primary analysis results are reported. Final results will be reported after completion of study.
Participants by arm
| Arm | Count |
|---|---|
| Eladocagene Exuparvovec Participants received eladocagene exuparvovec intraoperatively at 1.8×10\^11 vg via SmartFlow® MR Compatible Ventricular Cannula in a single operative session. Participants received standard of care for their AADC deficiency during the study. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Eladocagene Exuparvovec |
|---|---|
| Age, Continuous | 45.2 months STANDARD_DEVIATION 29.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Homovanillic Acid (HVA) Metabolite Level | 22.54 nanomoles (nmol)/liter (L) STANDARD_DEVIATION 32.34 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 1 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 9 / 13 |
Outcome results
Primary
Change From Baseline in HVA Metabolite Level at the End of the Trial Phase
HVA is a main metabolite of dopamine and HVA CSF levels are recognized as a proxy for dopamine levels in the brain.
Time frame: Baseline (Day 1), Week 8
Population: The safety population included all participants enrolled in the study who have received any amount of study drug. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eladocagene Exuparvovec | Change From Baseline in HVA Metabolite Level at the End of the Trial Phase | 29.53 nmol/L | Standard Deviation 12.93 |
Primary
Number of Participants With Adverse Events (AEs) Associated With the Surgical Administration of Eladocagene Exuparvovec Using the SmartFlow® MR-Compatible Ventricular Cannula
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered related to the drug. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease in a study participant who was administered gene therapy in this study. Number of participants with AEs related to the SmartFlow MR-compatible ventricular cannula used to administer eladocagene exuparvovec to pediatric participants at the end of Trial Phase (8 weeks after administration) are reported. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline (Day 1) up to Week 8
Population: The safety population included all participants enrolled in the study who have received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eladocagene Exuparvovec | Number of Participants With Adverse Events (AEs) Associated With the Surgical Administration of Eladocagene Exuparvovec Using the SmartFlow® MR-Compatible Ventricular Cannula | 0 Participants |
Secondary
Change From Baseline in Neurotransmitter Cerebrospinal Fluid (CSF) Metabolite HVA at Week 48
Time frame: Baseline (Day 1), Week 48
Secondary
Change From Baseline in Neurotransmitter CSF Metabolites 5-hydroxyindoleacetic Acid (5-HIAA), and 3-O-methyldopa (3-OMD) at Weeks 8 and 48
Time frame: Baseline (Day 1), Weeks 8 and 48
Secondary
Change From Baseline in Positron Emission Tomography (PET) Imaging of Putaminal-Specific L-6-[18F] Fluoro-3,4-Dihydroxyphenylalnine (18F-DOPA) PET Uptake at the End of the Trial Phase (Week 8) and the Extension Phase (Week 48)
Time frame: Baseline (Day 1), Week 8, Week 48
Secondary
Change in Bayley Scale of Infant Development, Third Edition (Bayley-III)
Time frame: Baseline (Day 1), Week 260
Secondary
Change in Body Weight
Time frame: Baseline (Day 1), Week 260
Secondary
Change in EuroQol-5 Dimensions Youth Version (EQ-5D-Y)
Time frame: Baseline (Day 1), Week 260
Secondary
Change in Peabody Developmental Motor Scale, Second Edition (PDMS-2)
Time frame: Baseline (Day 1), Week 260
Secondary
Number of Participants Who Attain Motor Milestones
Time frame: Baseline (Day 1) up to Week 260
Secondary
Number of Participants With AADC-Specific Symptoms
Time frame: Baseline (Day 1) up to Week 260
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time frame: Baseline (Day 1) up to Week 260