Only 18 months after its initial licensing, Agilis Biotherapeutics‘ gene therapy for aromatic l-amino acid decarboxylase (AADC) deficiency has been deemed ready for submission to the U.S. Food and Drug Administration (FDA).
Given its rare disease status, with roughly 120 cases of AADC deficiency described to date, this is a “remarkable pace of successful drug development,” researchers say in the case study, “Acceleration of rare disease therapeutic development: a case study of AGIL-AADC,” published in Drug Discovery Today.
AADC deficiency is a rare genetic disorder caused by mutations in the DDC gene, which provides instructions to make the AADC enzyme. This enzyme is necessary for the production of neurotransmitters — chemical substances that allow communication between nerve cells — in the brain.
However, when AADC malfunctions, infants may experience severe developmental delays and movement impairments that usually emerge during the first year of life and remain forever.
One of the most promising therapeutic avenues for AADC patients is gene therapy, because it enables the correction of faulty genes in a specific and efficient manner.
Agilis — now part of PTC Therapeutics — in collaboration with the National Taiwan University (NTU) developed a new type of gene therapy (AGIL-AADC) aimed to increase the amount of AADC in the brains of patients with AADC deficiency. It uses an adeno-associated virus (AAV) to deliver healthy copies of the gene, in an attempt to normalize the production of neurotransmitters and improve patients’ neurological function.
“Once the Agilis team established the license agreement for AGIL-AADC with NTU in January 2016, it was clear that a considerable amount of time and resources would need to be invested to gain FDA approval,” the researchers wrote.
This involved the formation of a partnership between Agilis and the Therapeutics for Rare and Neglected Diseases (TRND) program of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) to facilitate the development of AGIL-AADC, and the announcements of promising and accurate data from clinical trials for AGIL-AADC.
The first proof-of-concept compassionate study for AGIL-AADC, including eight children younger than 8 years old with AADC, was the first evidence that long-term gene therapy might improve neurotransmitters’ production and children’s motor function.
This was followed by an open-label Phase 1/2 trial (NCT01395641) undertaken in Taiwan involving a total of 10 patients under 8 years old that confirmed AGIL-AADC was safe and highly effective for children with severe AADC deficiency.
“By July 2017, after a year of intensive work requiring sourcing data to the case records, database auditing, and further statistical analysis, a comprehensive data package was presented to an FDA review panel, which judged AGIL-AADC to be [ready for a biologics license application] ready. In merely 18 months, AGIL-AADC has been accelerated through a translational ‘Valley of Death’ and is now positioned for FDA submission and review and potential U.S. approval,” the investigators wrote.
“This case study of Agilis demonstrates the power of public-private partnerships and international collaboration orchestrated by a committed and focused small private biotech. With the proper alignment of stakeholders, the challenges of rare disease drug development can be addressed more successfully, and life-saving therapies need not fall through the cracks,” they concluded.
PTC is planning to submit a request for FDA approval in 2019 and begin AGIL-AADC’s commercialization upon approval.