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KEBILIDI (eladocagene exuparvovec-tneq) is a gene therapy product that expresses the human aromatic L-amino acid decarboxylase enzyme (hAADC). It is a recombinant adeno-associated virus serotype 2 (rAAV2) based vector containing the complementary DNA of the human DDC gene under the control of the cytomegalovirus immediate-early promoter. Eladocagene exuparvovec-tneq is produced in human embryonic kidney cells by recombinant DNA technology.
KEBILIDI is a sterile suspension administered by bilateral intraputaminal infusion in one surgical session at two sites (anterior and posterior) per putamen. Each single-dose 2 mL vial contains 2.8×1011 vg in an extractable volume of 0.5 mL of suspension. Each mL of suspension contains 5.6×1011 vg. Patients will receive a total dose of 1.8×1011 vg delivered as four 0.08 mL (0.45×1011 vg) infusions (two per putamen).
KEBILIDI is provided in a single-dose 2 mL vial containing a clear to slightly opaque, colorless to faint white liquid, free of visible particulates following thaw from its frozen state. The excipients include potassium chloride (3 mM), sodium chloride (337 mM), potassium dihydrogen phosphate (2 mM), disodium hydrogen phosphate (8 mM), and poloxamer 188 (0.001%).
KEBILIDI (eladocagene exuparvovec-tneq) is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of adult and pediatric patients with aromatic L-amino acid decarboxylase (AADC) deficiency.
This indication is approved under accelerated approval based on the change from baseline in gross motor milestone achievement at 48 weeks post-treatment [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.
For single-dose intraputaminal infusion only.
Important Dosing Information
KEBILIDI is administered as four intraputaminal infusions in a single stereotactic neurosurgical procedure as per the recommended dose shown in Table 1.
Table 1: Recommended Dose of KEBILIDI
| Total Recommended Dose | 1.8x1011 vg (0.32 mL) |
| Total number of infusions | 4 |
| Volume (dose) per infusion | 0.08 mL (0.45X1011 vg) |
| Location of infusions | 2 in anterior putamen, 2 in posterior putamen |
| Infusion rate at each target point | 0.003 mL/min |
| Dose duration for infusion at each target point | 27 minutes |
Table 2: Supplies for KEBILIDI Preparation
| Component | Material of Construction |
| 1mL lubricated sterile Luer-lock syringe with elastomer plunger Or 5mL lubricated sterile Luer-lock syringe with elastomer plunger | Silicone, PC; Silicone, PP Silicone, PP |
| 18 or 19 G sterile needle with 5^m filter | Stainless steel, PC hub; Stainless steel, PP hub |
| Sterile Luer-lock syringe cap | - |
| Plastic bag for delivery into surgical unit | - |
| Secondary container for delivery into surgical unit | - |
| Abbreviations: PC=Polycarbonate; PP=Polypropylene | |
Notes:
Figure 1: Four Target Points within the Putamen for Infusion Sites
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Figure 2: Infusion Delivery System
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Administer KEBILIDI by bilateral intraputaminal infusion using a single infusion cannula in one surgical session at two sites (anterior and posterior) per putamen. The infusion cannula is placed and infusion performed separately for each target point (see Figure 2).
KEBILIDI is a sterile suspension for intraputaminal infusion. Each single-dose vial contains 2.8×1011 vg/0.5 mL (nominal concentration of 5.6×1011 vg/mL) of KEBILIDI and each 2 mL vial contains an extractable volume of 0.5 mL.
Following product thaw, the suspension for infusion is a clear to slightly opaque, colorless to faint white liquid, free of visible particulates [see HOW SUPPLIED/Storage And Handling].
KEBILIDI is supplied in a single-dose 2 mL vial containing sterile, clear to slightly opaque, colorless to faint white liquid free of visible particulates, following thaw from its frozen state. Each KEBILIDI (eladocagene exuparvovec-tneq) vial contains 2.8×1011 vg of eladocagene exuparvovec-tneq in an extractable volume of 0.5 mL of suspension. Each mL of suspension contains a nominal concentration of 5.6×1011 vg of eladocagene exuparvovec-tneq.
Package (carton): NDC Number 52856-601-01
Container (vial): NDC Number 52856-601-11
Store and transport frozen at ≤-65°C (-85°F). Keep the vial in the supplied carton.
Thaw KEBILIDI prior to administration. If not used immediately, store at room temperature (up to 25°C [77°F]) and use within 6 hours of starting product thaw [see DOSAGE AND ADMINISTRATION]. Do not refreeze vial once thawed.
Manufactured by: PTC Therapeutics, Inc. Warren, NJ 07059 USA. Revised: Nov 2024
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety data described in this section reflects exposure 246 to KEBILIDI in 13 pediatric patients with genetically confirmed AADC deficiency who received a single dose of 1.8×1011 vg. The median duration of follow-up was 72 weeks (range 23 to 109 weeks) [see Clinical Studies].
The most common adverse reactions (incidence ≥15%) are summarized in Table 3.
Table 3: Adverse Reactions in ≥15% of Patients in Study 1
| Adverse Reaction | Patients Treated with KEBILIDI N=13 (%) |
| Dyskinesia | 10 (77%) |
| Pyrexia | 5 (38%) |
| Hypotension | 4 (31%) |
| Anemia | 4 (31%) |
| Salivary hypersecretion | 3 (23%) |
| Hypokalemia | 3 (23%) |
| Hypophosphatemia | 3 (23%) |
| Insomnia | 3 (23%) |
| Hypomagnesemia | 2 (15%) |
| Procedural complications* | 2 (15%) |
| *Procedural complications included respiratory and cardiac arrest. | |
Other clinically significant adverse reaction includes worsening in duration and frequency of oculogyric crises during hospitalization following administration of KEBILIDI reported in one patient.
No Information provided
Included as part of the PRECAUTIONS section.
Procedural complications have been reported after neurosurgery required for KEBILIDI administration. These events included respiratory and cardiac arrest which occurred within 24 hours of the neurosurgical procedure and during post-surgical care [see ADVERSE REACTIONS]. KEBILIDI administration has the potential risk for additional procedure related adverse events including cerebrospinal fluid (CSF) leak, intracranial bleeding, neuroinflammation, acute infarction, and infection.
Monitor patients for procedure related adverse events with KEBILIDI administration, including 233 continuous cardiorespiratory monitoring during hospitalization.
Dyskinesia was reported after administration of KEBILIDI. All events were reported within 3 months of administration and 2 events required hospitalization [see ADVERSE REACTIONS].
Monitor patients for signs and symptoms of dyskinesia after KEBILIDI treatment which may include involuntary movements of face, arm, leg, or entire body. These may present as fidgeting, writhing, wriggling, head bobbing or body swaying. The use of dopamine antagonists may be considered to control dyskinesia symptoms.
Carcinogenicity, genotoxicity, and fertility studies have not been performed with KEBILIDI.
There are no clinical data from the use of KEBILIDI in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted with KEBILIDI.
In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
There is no data on the presence of KEBILIDI in human milk, the effects on the breastfed infant, or the effects on milk production.
Pregnancy status of females with reproductive potential should be verified. Sexually active females of reproductive potential should have a negative pregnancy test before administering KEBILIDI.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with KEBILIDI.
There is no data on the effects of KEBILIDI on fertility.
The safety and effectiveness of KEBILIDI have been established in pediatric patients. The use of KEBILIDI was evaluated in a single-arm, open-label study that enrolled 13 pediatric patients aged 16 months to 10 years who had achieved skull maturity [see ADVERSE REACTIONS and Clinical Studies].
The safety and effectiveness of KEBILIDI have not been studied in pediatric patients younger than 16 months.
KEBILIDI has not been studied in patients 65 years of age and older.
No Information provided
KEBILIDI is contraindicated in patients who have not achieved skull maturity assessed by neuroimaging. Skull maturity is needed for stereotactic neurosurgical administration of KEBILIDI.
KEBILIDI is a recombinant adeno-associated virus serotype 2 (rAAV2) based gene therapy designed to deliver a copy of the DDC gene which encodes the AADC enzyme. Intraputaminal infusion of KEBILIDI results in AADC enzyme expression and subsequent production of dopamine in the putamen.
In Study 1, homovanillic acid (HVA), a downstream metabolite of dopamine, in cerebrospinal fluid (CSF) was measured at baseline, Week 8, and Week 48 using a high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In all patients of Study 1, an increase in CSF HVA levels from baseline was observed at Week 8 and Week 48 (Table 4).
Table 4: HVA Levels in CSF (Study 1)
| Timepoint | Observed Values (nmol/L) | Change from Baseline (nmol/L) | Percent Change from Baseline (%) |
| Baseline | |||
| N | 13 | - | - |
| Median (Min, Max) | 3.34 (1.00, 93.73) | - | - |
| Week 8 | |||
| N | 12 | 12 | 12 |
| Median (Min, Max) | 35.09 (15.09, 150.48) | 26.62 (12.49, 56.75) | 534.7 (57.4, 2810.0) |
| Week 48 | |||
| N | 9 | 9 | 9 |
| Median (Min, Max) | 29.16 (14.21, 125.84) | 24.7 (13.21, 58.02) | 773.1 (33.9, 3991.0) |
| Note: Lower limit of quantification (LLOQ) was 2 nmol/L, and values reported as <LLOQ were imputed as 0.5*LLOQ. Abbreviations: CSF=cerebrospinal fluid; HVA=homovanillic acid; N=number of subjects; Max=maximum; Min=minimum |
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18F-DOPA is a positron-emitting fluorine-labeled substrate of the AADC enzyme. Following administration of 18F-DOPA, its uptake into the putamen assessed by positron emission tomography (PET) imaging reflects AADC enzyme activity of dopaminergic neurons in the putamen. In Study 1, 18F-DOPA uptake in the putamen was assessed at baseline and followed up at Week 8 in 12 out 13 patients and at Week 48 in 10 out 13 patients indicating increased AADC 18F-DOPA uptake in all assessed patients. The median (range) percent increase from baseline was 259% (65% to 620%) at Week 8 and 271% (25% to 760%) at Week 48.
KEBILIDI vector DNA levels in various tissues and secretions were determined using a validated quantitative polymerase chain reaction (qPCR) assay.
Nonclinical Data
Biodistribution of eladocagene exuparvovec-tneq was evaluated in rats at Days 7, 30, 90, and 180 after single-dose intraputaminal infusion at dose levels up to 7.5×109 vg/animal (21-fold higher than the recommended human dose based on relative brain weight). At Day 7, vector DNA was observed in the putamen, cerebellum, cerebrum, and spinal cord. Vector DNA levels declined from Day 7 to Day 90, with DNA levels primarily sustained in the putamen at Day 180.
Clinical Data
Following administration of KEBILIDI at a total dose for each patient of 1.8×1011 vg in Study 1, biodistribution and viral shedding in CSF, blood, and urine were evaluated in 13 patients. CSF was collected at Weeks 8 and 48, and blood and urine were collected from Day 3 up to Week 48. Five (38%) patients showed detectable vector DNA levels in blood at Day 3 ranging from 4.0×103 to 6.5×103 copies/mL, which became below the limit of detection (<3.1×103 copies/mL) by Week 3. No vector was detected in CSF or urine.
The observed incidence of anti-AAV2 antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-AAV2 antibodies in the studies described below with the incidence of anti-AAV2 antibodies in other studies.
There is no clinical experience with KEBILIDI in patients with pre-existing anti-AAV2 neutralizing antibody at titers >1:1200.
In Study 1, anti-AAV2 total binding antibodies and anti-AAV2 neutralizing antibodies were assessed from Day 3 up to Week 48 following administration of KEBILIDI. In all patients  (N=13), titers of total binding antibody and neutralizing antibody increased from Week 3 and remained elevated, as measured at Week 48 (N=9). The highest titers in each patient ranged from 1:800 to 1:204,800 for total binding antibodies and from 1:80 to 1:10,240 for neutralizing antibody. Because of the small sample size of Study 1, there is insufficient data to determine the effect of anti-AAV2 antibody on the pharmacokinetics, pharmacodynamics, safety, or effectiveness.
The efficacy of KEBILIDI was evaluated in one open-label, single arm study (Study 1;
NCT04903288). The study enrolled pediatric patients with genetically confirmed, severe AADC deficiency who had achieved skull maturity assessed with neuroimaging. The main efficacy outcome measure was gross motor milestone achievement evaluated at week 48 and assessed using the Peabody Developmental Motor Scale, Second Edition (PDMS-2). Patients treated with KEBILIDI were compared to an external untreated natural history cohort of 43 pediatric patients with severe AADC deficiency who had at least one motor milestone assessment after 2 years of age.
A total of 13 patients received a single total dose of 1.8×1011 vg of KEBILIDI given as four intraputaminal infusions in a single stereotactic neurosurgical procedure. The demographic characteristics of the population were as follows: the median age was 2.8 years (1.3 to 10.8 years), 7 patients (54%) were female, 10 patients (77%) were Asian, 2 patients (15%) were White, and 1 patient was of “other” race. Twelve of the 13 patients had the severe phenotype of AADC deficiency, defined as having no motor milestone achievement at baseline and no clinical response to standard of care therapies. The one remaining patient had a “variant” of the severe disease phenotype, with the ability to sit with assistance but with lack of head control.
Gross motor milestone achievement at Week 48 was assessed in 12 of the 13 patients treated in Study 1 (one patient dropped out of the study prior to Week 48).
Eight (67%) of the 12 treated patients achieved a new gross motor milestone at week 48: 3 patients achieved full head control, 2 patients achieved sitting with or without assistance, 2 patients achieved walking backwards and the patient with the “variant” severe phenotype was able to sit unassisted. The two patients who achieved walking backwards at week 48 were treated before 2 years of age. The four patients who were unable to achieve new gross motor milestones at week 48 were treated between the ages of 2.8 and 10.8 years. In comparison, none of the 43 untreated patients with the severe phenotype had documented motor milestone achievement at last assessment at a median age of 7.2 years (range 2 to 19 years).
