Eladocagene exuparvovec for the treatment of Aromatic L-amino acid decarboxylase (AADC): Regulatory Update


- Eladocagene exuparvovec is an investigational drug for the treatment of Aromatic L-amino acid decarboxylase (AADC)
- Developed by PTC Therapeutics
- Currently under EMA Review, the MMA application, decision delayed due to COVID
- Decision Expected by Q2 2020
- Planned BLA submission to FDA by H1 2021

Aromatic L-amino acid decarboxylase (AADC)

AADC deficiency is a rare genetic condition caused by a mutation in the dopa decarboxylase (DDC) gene, resulting in a lack of functioning AADC enzyme, which is responsible for the final step in the synthesis of key neurotransmitters dopamine and serotonin.

AADC deficiency results in delays or failure to reach developmental milestones such as head control, sitting, standing, walking, or talking, low muscle tone (also known as muscular hypotonia), severe, seizure-like episodes involving involuntary eye movement (also known as oculogyric crises), autonomic abnormalities, and the need for life-long care. Given this neurologically devastating illness, patients with severe AADC deficiency have a high risk of death during childhood. There are currently no approved therapies that address the underlying cause.

Eladocagene exuparvovec is a type of gene replacement therapy that involves the transfer of the gene encoding the production of the enzyme needed by the brain for the formation of dopamine and serotonin. The gene therapy is injected via a surgical procedure into an area of the brain called the putamen. By increasing the production of the AADC-enzyme, this therapy increases dopamine production in the target area of the brain and improves motor and cognitive symptoms in patients. If licensed, eladocagene exuparvovec will provide the first medicinal treatment option for adult and child patients with AADC-deficiency, a disease of very high unmet clinical need

Regulatory Status 

PTC expects the EMA's Committee for Medicinal Products for Human Use final opinion for the AADC deficiency application in the first half of 2021

PTC expects the biologics license application (BLA) for AADC deficiency to be submitted to the FDA in the first half of 2021

Clinical Study Update

Eladocagene exuparvovec is in phase I/II clinical development (NCT02926066, NCT01395641) for the treatment of AADC-deficiency. Eladocagene exuparvovec dosing is 1.8 × 10^11 vector genomes (vg) delivered as four 0.080 mL (0.45 × 10^11 vg) infusions (two per putamen).

Efficacy for Phase 2 Study (NCT01395641)
  • All patients achieved meaningful gains in motor function
  • An improvement in movement disorders (floppiness, OGC episodes and limb dystonia) was observed 1 year after treatment.
  • Anti-AAV2 antibody titres had little impact on efficacy as measured by change from baseline in PDMS-2 total score for patients in the 1.8 × 10^11vg dose group. 
  • Increased dopamine metabolites in the CSF of treated patients demonstrates that the noted clinical effects are due to eladocagene exuparvovec gene therapy.
Safety for Phase 2 Study (NCT01395641)
  • A total of 130 AEs were reported during the 12 month study as follows: 
  •  43 AEs in 3 patients (37.5%) in the 1.8 × 10^11 vg dose group and 87 AEs in 5 patients (62.5%) in the 2.4 × 1011 vg dose group. 
  • All 3 patients in the 1.8 × 10^11 vg dose group reported AEs of pyrexia, dehydration, and dyskinesia and 2 of the 3 patients in this group reported AEs of upper gastrointestinal haemorrhage, gastroenteritis, pneumonia, upper respiratory tract infection, and breath sounds abnormal. 
The most common AEs experienced by the 2.4 × 10^11 vg dose group were pyrexia and breath sounds abnormal (5 of 5 patients), upper respiratory tract infection and anaemia (4 of 5 patients) and dyskinesia, gastroenteritis, hypotension, and irritability (3 of 5 patients).

Comprehensive Analysis of Clinical Studies 
New analysis evaluated outcomes of 26 patients with AADC deficiency across three separate clinical trials, making it the most comprehensive analysis of patients treated with PTC-AADC to date. Specifically, these results showed that 12 months post-treatment with PTC-AADC, patients' mean body weight had increased from 12.0 kg to 15.2 kg, and the frequency of oculogyric crises (involuntary upward eye movement) was reduced. Dyskinesia (involuntary movements) was the most frequently recorded adverse event, however, most events were mild or moderate and all cases resolved by 10 months post-treatment.

  • http://www.io.nihr.ac.uk/wp-content/uploads/2020/04/13410-TSID_10313-Eladocagene-Exuparvo-for-AADC-V1.0-MARCH-2020_NON-CONF.pdf
  • https://www.ptcbio.com/