Gene Therapy VY-AADC Improves Motor Function in Parkinson’s Patients, Studies Show

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by Diana Campelo Delgado |

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One-time treatment with investigational gene therapy VY-AADC (NBIb-1817) showed sustained improvement in motor function in patients with Parkinson’s, results from the Phase 1 PD-1102 clinical trial show.

These results were presented recently in two poster presentations at the MDS Virtual Congress 2020.

VY-AADC, a gene therapy being developed by Neurocrine Biosciences and Voyager Therapeutics, is made of a modified and harmless adeno-associated virus that delivers the DDC gene to brain cells. This gene provides instructions for making the AADC enzyme, where it can promote levodopa’s conversion into dopamine, a chemical “messenger” that is involved in movement control and is gradually lost in Parkinson’s patients.

By increasing the levels of dopamine directly where it is needed, VY-AADC could potentially help in easing disease symptoms.

In the scientific poster, “AADC gene therapy administered via a posterior approach: 24-month results from the PD-1102 trial in advanced Parkinson’s disease,” researchers presented 24-month results from an ongoing three-year Phase 1b clinical trial (NCT03065192) evaluating the safety and efficacy of a single dose of VY-AADC.

The PD-1102 study included eight patients with a mean age of 56.8 years with advanced Parkinson’s (mean disease duration of 9.2 years). The gene therapy was administered directly to the putamen — a brain region involved in movement control — using a neurosurgical approach aided by real-time magnetic resonance imaging to monitor its delivery.

Data from seven of these eight patients revealed that the gene therapy reduced daily “off” time by an average of 3.2 hours, increasing daily good “on” time by 2.1 hours.

Off periods in Parkinson’s are characterized by the reappearance or worsening of symptoms — such as tremors and dyskinesia, or abnormal involuntary movements — due to a gradual decline in levodopa’s therapeutic effectiveness. These symptoms become more frequent and severe as the disease progresses.

Importantly, average daily doses of medications were substantially reduced, and study participants showed sustained improvement in motor function after two years of treatment.

The therapy was well-tolerated, and no serious adverse events were observed.

VY-AADC’s safety and efficacy was also evaluated in the PD-1101 two-year Phase 1b clinical trial (NCT01973543).

Three-year results from this study were presented in the poster titled “Three-year safety and clinical outcomes from the PD-1101 trial of AADC gene therapy for advanced Parkinson’s disease.”

This study evaluated the safety and efficacy of ascending doses of VY-AADC, administered in a similar fashion as in the other clinical trial, in 15 patients with Parkinson’s disease.

Participants were divided into three groups, each receiving ascending doses of the therapy: group 1 received up to 7.5×1011 vector genomes (vg); group 2 up to 1.5×1012 vg; and group 3 up to 4.7×1012 vg.

Preliminary safety data from groups 2 and 3 revealed that one-time treatment with the gene therapy reduced daily “off” time by an average of 0.15 to 1.91 hours, while improving daily “on” time without troublesome dyskinesia by an average of 0.26 to 2.23 hours.

Sustained improvement in motor function was also observed, with patients requiring substantially less antiparkinsonian medications.

The researchers found VY-AADC was well-tolerated, with no drug-related serious adverse events.

“Parkinson’s disease patients’ motor function would be expected to worsen over three years, making these results very encouraging,” Chad Christine, MD, a lead investigator of the study and neurology professor at the University of California, San Francisco Weill Institute for Neurosciences, said in a press release.

Omar Khwaja, MD, PhD, chief medical officer and head of research and development at Voyager Therapeutics, added: “We are encouraged by the congruence of long-term data, including clinician- and patient-reported clinical outcomes in our clinical studies. These results are promising and show that the approach has the potential to transform the treatment of Parkinson’s disease, and help improve the lives of patients and their families.”

Based on the positive results of both trials, researchers have launched the RESTORE-1 Phase 2 clinical trial (NCT03562494) assessing the efficacy, safety, and tolerability of VY-AADC in Parkinson’s patients who failed to respond to oral medications.

The study had been temporarily paused last April due to the COVID-19 pandemic, and will resume enrollment later this year. It will include patients who have been diagnosed with Parkinson’s for at least four years and are not responding adequately to oral medication.

RESTORE-2, a Phase 3 clinical trial, is expected to start during the first half of 2021.