Trials Data Predict PTC-AADC Gene Therapy to Result in Long-term Benefits

PTC Therapeutics’ investigational gene therapy PTC-AADC is expected to result in long-term and durable therapeutic benefits in children with aromatic l-amino acid decarboxylase (AADC) deficiency, long-term data from three clinical trials suggest.

These findings, along with data from a review study highlighting the increasingly high disease burden of AADC deficiency, were presented in seven company-sponsored posters at the Virtual ISPOR Europe 2020 Conference, held Nov. 16–19.

“PTC has been working with the rare disease community to better understand the impact of rare diseases on patients and their families for over 20 years,” Stuart W. Peltz, PhD, PTC’s CEO, said in a press release.

“These insights are critical so that the best treatments can be made available to patients,” he added, noting that the company “is committed to ensuring patients can access clinically differentiated treatments such as our gene therapy for AADC deficiency which, if approved, promises to become the standard of care.”

A rare genetic disorder, AADC deficiency is caused by mutations in the DDC gene, resulting in reduced activity of AADC, an enzyme necessary for the production of two neurotransmitters called dopamine and serotonin. Neurotransmitters are chemical messengers used by nerve cells to communicate with each other.

Lower levels of dopamine and serotonin trigger a number of symptoms with varying degrees of severity that typically appear early in life. These include developmental delay, intellectual disability, movement disorders, muscle weakness, and problems in the autonomic nervous system — which controls functions such as blood pressure, heart and respiratory rate, body temperature, and digestion.

In the poster “Age at onset and frequency of clinical signs and symptoms in patients with AADC Deficiency: A systematic literature review,” researchers presented data from a review study that included 66 cases of AADC deficiency.

Results showed that symptoms contributing to high disease burden started early in life — since birth in 29% of cases — and accumulated over time. Notably, 28% of these patients were severely disabled by age 6, showing symptoms in all six core domains: developmental delays, movement disorders, problems with muscle tone, behavior and sleeping problems, and autonomic dysfunction.

These findings reveal a high and accumulating disease burden of AADC deficiency, highlighting the urgent need of effective disease-modifying therapies.

The gene therapy PTC-AADC (formerly known as GT-AADC and AGIL-AADC) is on the verge of becoming the first of such therapies to be approved for AADC deficiency.

An application requesting its approval is currently being reviewed by the European Medicines Agency, with a final recommendation from its Committee for Medicinal Products for Human Use expected by the first half of 2021. Of note, the committee’s recommendations are usually followed by the European Commission, which makes the final decision.

A similar request to the U.S. Food and Drug Administration is expected to be submitted by the end of the year.

PTC-AADC uses a modified and harmless adeno-associated virus (AAV) to deliver a working version of the DDC gene to brain nerve cells. The one-time therapy is delivered directly into the putamen — a brain region that provides most of the dopamine that the brain requires — through a surgical procedure.

As such, the therapy is expected to restore dopamine levels in the brain, improving or restoring some functions and preventing further damage.

Previous data showed that PTC-AADC dropped the frequency of oculogyric crises (involuntary upward eye movement characteristic of the disease) over a five-year period in 26 children with AADC deficiency (age range from 21 months to 8.5 years) in three open-label clinical trials (NCT01395641, NCT02926066, and NCT02852213).

PTC-AADC also led to a recovery of the children’s weight, and improved their ability to sit, walk, and talk — milestones often delayed or unachieved in this patient population. Benefits in motor, language, and cognitive milestones were maintained for up to five years after treatment, and all children showed sustained dopamine production.

No new safety concerns were identified during long-term evaluations.

Now, further data from 28 PTC-AADC-treated patients in these trials were presented at the conference in a poster, “Estimating the long-term effects of therapy for patients with Aromatic l-amino acid decarboxylase deficiency (AADC-d) using individual participant data.”

Using one to nine years of follow-up data, the researchers estimated the potential long-term and durable benefits of PTC-AADC in children with AADC deficiency. Among these benefits were improvements in motor milestone achievement, assessed with the peabody developmental motor scales – second edition (a measure of motor development in children).

The other posters presented at the meeting focused on potential tools to evaluate the impact of AADC deficiency in health-related quality of life.