#AANAM – PTC-AADC Gene Therapy Can Improve Patient Motor Function

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The investigational gene therapy PTC-AADC improved motor function in children with aromatic l-amino acid decarboxylase (AADC) deficiency in several clinical studies, new data show.

These findings were presented at this year’s American Academy of Neurology annual meeting by Mark Pykett, PhD, the chief scientific officer of PTC Therapeutics, which is developing PTC-AADC and helped fund the studies. The AAN virtual meeting is being held online April 17-22.

AADC deficiency is caused by mutations in the gene DDC, which result in the body being unable to make a functional AADC enzyme. Without enough AADC enzyme, the brain cannot make enough of the hormones serotonin and dopamine, which leads to physical and mental developmental delays from a young age.

PTC-AADC is a gene therapy that uses an engineered viral vector to deliver a non-mutated version of the DDC gene to cells in the body.

“The purpose of gene therapy is to replace the faulty gene with a functional one,” Pykett said. “Because the DDC gene is mutated, the gene therapy adds a healthy gene to compensate for the mutated one, thus restoring AADC enzyme activity.”

Pykett presented data from three clinical studies of PTC-AADC in children with AADC deficiency: a Phase 2 trial, a Phase 1/2 trial, and a compassionate use study.

All of these trials enrolled children with confirmed AADC deficiency, and in all of the studies, the therapy was surgically injected into the putamen, a brain region responsible for producing most of the dopamine.

Interim data from the Phase 2 trial (NCT02926066) were shared at the AAN meeting in a poster titled “Improved Motor Function in Children With Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Treated With Eladocagene Exuparvovec (PTC-AADC): Interim Findings From a Phase 2 Trial.”

In this trial, eight children with AADC deficiency were given one of two doses of the gene therapy, based on age. Specifically, five children younger than 3 were given 2.4 × 1011 viral genomes (vg), while the other three children, who were ages 3 or older, were given 1.8 × 1011 vg. The mean follow-up was 11.5 months, or just less than one year.

The interim data showed that half of the children achieved the motor milestone of head control within a year of treatment. This included three of the five participants given the higher dose, as well as one of the three participants given the lower dose. One child, who received the higher dose, was able to sit unassisted within a year of treatment.

Improvements in cognitive and language development also were noted after one year, particularly in the high dose group.

“While achievement of key motor milestones was more frequent in the higher dose group, further assessments are needed to determine whether this finding was due to the dose or to the younger age at treatment,” Pykett said.

In the Phase 1/2 clinical trial (NCT01395641), the investigational gene therapy was given to 10 children, ages 2 and older, with AADC deficiency.

Interim data from that trial were shared in a poster, titled “Improved Motor Function in Children With Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Treated With Eladocagene Exuparvovec (PTC-AADC): Interim Findings From a Phase 1/2 Study.”

All of the participants in this trial received a dose of 1.8 × 1011 vg. Among the 10, nine completed two years in the study. The remaining participant died due to an infection unrelated to treatment.

Two years post-treatment, half of the children had achieved full head control, a third were able to sit unassisted, and nearly a quarter (22%) could stand with support. Patients also experienced significant improvements in motor function and fine motor skills.

Pykett highlighted imaging data that indicated that dopamine was present in the brains of treated patients.

This finding “means that dopamine is being produced due to the production and availability of the AADC enzyme,” Pykett said. In other words, the therapy appears to be working as intended.

In a final poster, “Improved Motor Function in Children With Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Treated With Eladocagene Exuparvovec (PTC-AADC): Compassionate Use Study,” Pykett shared findings from a compassionate use study in which eight children with AADC deficiency, all older than age 2, were dosed with 1.8 × 1011 vg of PTC-AADC.

The mean follow-up time was 62.5 months, or about 5 years. While none of the patients had full head control at the study’s start, half of the children achieved that milestone and could sit unassisted at five years post-treatment. Two of the participants also were able to stand with support. Similar to the Phase 1/2 findings, imaging studies indicated that functional AADC enzyme was being produced in the participants’ brains.

Across all three of these studies, standardized measurements of motor function, development, and cognition generally showed substantial improvements following treatment. In addition, the children’s body weights increased following treatment, and their symptoms of AADC deficiency — for example, oculogyric crises, a common eye movement disorder in patients with AADC — were less frequent after treatment.

Safety data also were generally positive across the studies, with no new safety concerns identified and no reported differences in the therapy’s safety profile based on dosage. Most reported adverse events (side effects) were mild in severity and deemed unrelated to treatment. No serious adverse events deemed related to the therapy were reported. The most common treatment-associated adverse event was dyskinesia, or abnormal, involuntary muscle movements.

Pykett concluded that “children with AADC deficiency achieved sustained improvements in motor function after treatment with PTC-AADC.”

An application seeking approval of PTC-AADC in the European Union is currently under review. PTC has announced that it is expecting to submit an application to the U.S. Food and Drug Administration this year.