Eladocagene Exuparvovec

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 ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. KEBILIDI 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 change from baseline in gross motor milestone achievement at 48 weeks post-treatment. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. ( 1 , 14 )

KEBILIDI is a sterile suspension for intraputaminal infusion. Each single-dose vial contains 2.8×10 11 vg/0.5 mL (nominal concentration of 5.6×10 11 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 (16) ] . KEBILIDI is a suspension for intraputaminal administration with a nominal concentration of 5.6×10 11 vg/mL. ( 3 ) KEBILIDI is supplied in a single-dose vial that contains 2.8×10 11 vg of eladocagene exuparvovec-tneq in an extractable volume of 0.5 mL of suspension. Each mL of suspension contains 5.6×10 11 vg of eladocagene exuparvovec-tneq. ( 3 , 16 )

KEBILIDI is contraindicated in patients who have not achieved skull maturity assessed by neuroimaging. Skull maturity is needed for stereotactic neurosurgical administration of KEBILIDI. Patients who have not achieved skull maturity assessed by neuroimaging. ( 4 )

Procedural complications: Monitor patients for procedural complications for neurosurgery, including events of respiratory and cardiac arrest after administration of KEBILIDI. ( 5.1 ) Dyskinesia: Monitor patients for dyskinesia after treatment with KEBILIDI. The use of dopamine antagonists can be used to control dyskinesia symptoms. ( 5.2 )

5.1 Procedural Complications 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 (6) ] . 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 continuous cardiorespiratory monitoring during hospitalization.

5.2 Dyskinesia Dyskinesia was reported after administration of KEBILIDI. All events were reported within 3 months of administration and 2 events required hospitalization [see Adverse Reactions (6) ] . 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.

Most common adverse reactions (incidence ≥15%) were dyskinesia, pyrexia, hypotension, anemia, salivary hypersecretion, hypokalemia, hypophosphatemia, insomnia, hypomagnesemia, and procedural complications. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PTC Therapeutics, Inc at toll-free phone 1 866 562 4620 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience 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 to KEBILIDI in 13 pediatric patients with genetically confirmed AADC deficiency who received a single dose of 1.8×10 11 vg. The median duration of follow-up was 72 weeks (range 23 to 109 weeks) [see Clinical Studies ( 14 )] . The most common adverse reactions (incidence ≥15%) are summarized in Table 3 . Table 3: Adverse Reactions in ≥15% of Patients in Study 1 * Procedural complications included respiratory and cardiac arrest. 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%) Other clinically significant adverse reaction includes worsening in duration and frequency of oculogyric crises during hospitalization following administration of KEBILIDI reported in one patient.

8.1 Pregnancy Risk Summary 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.

8.2 Lactation Risk Summary There is no data on the presence of KEBILIDI in human milk, the effects on the breastfed infant, or the effects on milk production.

8.3 Females and Males of Reproductive Potential Pregnancy Testing 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. Contraception There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with KEBILIDI. Infertility There is no data on the effects of KEBILIDI on fertility.

8.4 Pediatric Use 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 ( 6 ) and Clinical Studies ( 14 )] . The safety and effectiveness of KEBILIDI have not been studied in pediatric patients younger than 16 months.

8.5 Geriatric Use KEBILIDI has not been studied in patients 65 years of age and older.

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.