Gene Therapy Candidate Found to Provide Clinical Benefits for Up to 5 Years

PTC Therapeutics‘ gene therapy candidate PTC-AADC (formerly AGIL-AADC) provided clinically meaningful and sustained improvements in motor, cognitive, and language milestones in children with aromatic l-amino acid decarboxylase (AADC) deficiency up to five years following the one-time treatment, trial analyses show.

A single dose of PTC-AADC delivered into the brain lowered the number of oculogyric crises (involuntary upward eye movement) and recovered children’s weight, as well as improved their ability to sit, walk, and talk over a five-year period.

PTC Therapeutics will request marketing approval soon, with plans to submit a Biologics License Application (BLA) to the U.S. Food and Drug Administration later this year.

The new findings were shared at the 48th Annual Meeting of the Child Neurology Society (CNS), held recently in Charlotte, NC. Data were presented in two posters titled “AGIL-AADC gene therapy results in sustained improvements in motor and developmental milestones through 5 years in children with AADC deficiency” (page S136), and “Safety and Improved Efficacy Outcomes in Children With AADC Deficiency Treated with AGIL-AADC Gene Therapy: Results From Three Clinical Trials” (page S148).

“We are excited to see the transformational effects in AADC deficiency patients in this long-term study as patients with severe AADC deficiency never achieve the ability to sit, walk or talk,” Stuart Peltz, PhD, PTC Therapeutics’ CEO, said in a news release.

“We are on track to submit a BLA to the FDA by the end of the year and are proud to be on the verge of bringing the first commercial treatment for AADC deficiency patients which is in line with our mission of bringing clinically differentiated treatments to patients with rare disorders,” he added.

PTC-AADC is an investigational gene therapy designed to deliver a healthy copy of the DDC gene — the faulty gene in patients with AADC deficiency — to nerve cells. The goal is to restore the production of AADC enzyme which is missing because of this genetic defect and counter the symptoms caused by this deficiency.

A working copy of DDC is passed on to cells through an adeno-associated virus that is modified to be non-infectious.

The gene therapy is injected via a surgical procedure into an area of the brain called the putamen. This region is crucial for producing chemical messengers (neurotransmitters) such as dopamine and serotonin, which are involved in movement control but fail to be produced in patients with the disease.

In one of its presentations, PTC Therapeutics provided the most extensive study of PTC-AADC’s efficacy and safety to date. It conducted a joint analysis of three open-label clinical trials, which together enrolled 26 children with AADC deficiency, ranging in age from 21 months to 8.5 years.

At the beginning of these studies, children had no full head control and were unable to sit, stand, or walk. They were given a single dose of PTC-AADC (total dose, 1.8×10¹¹ vector genomes, vg) which was injected into the patient’s putamen during a single surgery session.

One year after treatment, the patients’ mean body weight had increased from 12.0 kg to 15.2 kg, and there was a reduction in the frequency of involuntary upward eye movements characteristic of the disease (oculogyric crises).

Dyskinesia (uncontrolled erratic movements) was a common adverse event, affecting 23 of 26 patients, but most events were mild or moderate in severity, and all cases had resolved within 10 months from dosing.

“In addition to failing to reach key developmental milestones, such as walking and talking, children with AADC deficiency can experience severe symptoms that affect their everyday lives. These symptoms can include episodes of oculogyric crises, which can last for minutes or hours and involve sustained upward movement of the eyes, involuntary movements of the neck, tongue protrusions and jaw spasms, which can be very distressing for patients and their families,” said Claudio Santos, MD, senior vice president of global medical affairs at PTC Therapeutics.

“The post-treatment data presented at CNS confirm reductions in the number of patients experiencing oculogyric crises, suggesting that this gene therapy treatment has the potential to make a real difference in the lives of patients with AADC deficiency,” he added.

A second analysis demonstrated that PTC-AADC’s benefits can hold up to five years after treatment, the longest data available for any investigational therapy for AADC deficiency.

The findings came from the latest follow-up data of two open-label clinical studies: AADC-1601 (NCT02926066), a trial in which patients were enrolled under individual compassionate use consents, and AADC-010 (NCT01395641).

Together, the studies enrolled 18 patients who were 21 months to 8.5 years old. None had full head control or could sit unassisted or stand. In this update, all patients had two years of follow-up data, and eight of these patients had five years of post-treatment data.

Prior results shared by PTC Therapeutics showed that at two years, eight patients (44%) had achieved full head control, six (35%) were able to sit unassisted, and three (17%) could stand without support. Among the eight patients followed for five or more years, four (50%) had full head control, four (50%) could sit unassisted, and two (25%) could stand without support.

The latest results continue to support these meaningful improvements in motor, cognitive, and language skills, and importantly, show that effects from a single dose of PTC-AADC can last at least five years post-treatment.

In addition, all treated patients continued to demonstrate sustained production of dopamine in the body, one of the neurotransmitters missing in patients with AADC deficiency.

No new safety signals were observed during these long-term evaluations.