An investigational gene therapy being developed for the treatment of Parkinson’s disease was well- tolerated and eased patients’ motor fluctuations in a dose-dependent manner after a one-time administration, according to interim results.
The study, “Magnetic Resonance Imaging-Guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson’s Disease,” was published in Annals of Neurology.
VY-AADC01 is a gene therapy being developed by Neurocrine Biosciences and Voyager Therapeutics. It uses a viral vector (AAV) to deliver the AADC gene — which codes for an enzyme called L-amino acid decarboxylase (AADC) and mediates the conversion of levodopa into dopamine — directly into a specific brain area called the putamen, a large structure filled with dopamine receptors.
Death of dopaminergic neurons and a reduction in AADC enzyme levels are two fundamental mechanisms underlying Parkinson’s disease. By delivering the AADC enzyme into brain cells, researchers aim to restore the conversion of levodopa and increase dopamine production.
The open-label, Phase 1b study (NCT01973543) enrolled 15 people (13 men and two women, mean age 57.7 years) with moderately advanced Parkinson’s disease and fluctuating responses to levodopa. Subjects were divided into three groups and treated with ascending doses of VY-AADC01 (7.5 × 1011vector genomes (vg); 1.5 × 1012vg; 4.7 × 1012vg).
The therapy was administered in a single-dose infusion using magnetic resonance imaging (MRI) to guide its delivery. Group 1 (lower dose) was followed for up to three years, group 2 through two years, and group 3 (higher dose) for up to 1.5 years. During the study, patients kept taking their antiparkinsonian medications, including levodopa.
The trial’s primary goals were the safety, tolerability, and distribution of ascending doses of VY-AADC01. Secondary objectives included AADC activity changes in response to levodopa, clinical outcomes over a year, and the durability of those changes after 12 months.
Results showed that large-volume administrations of VY-AADC01 were well-tolerated. At six months post-treatment, the MRI-guided delivery approach increased the coverage area reached by the gene therapy: coverage of 21% in group 1, 34% in group 2 and 42% in group 3. This was found to be closely correlated with increases in AADC activity: 13%, 56%, and 79%, respectively. The increase in putaminal coverage was also related to reductions in the patients’ medication regimen: 15% less in group 1, 33% less in group 2 and 42% less in group 3.
A year after treatment, investigators observed VY‐AADC01 dose-dependent improvements in motor fluctuations, motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS part III) and patients’ quality of life, despite reductions in antiparkinsonian medications.
Patients reported increases in their “on” periods (when medication does not wear off and motor symptoms are controlled) without experiencing troublesome abnormal involuntary movements (dyskinesia).
“The interim results from this Phase 1b trial demonstrated that administration of [VY-AADC01] to the putamen using a novel technique, which included intraoperative monitoring with magnetic resonance imaging guidance, facilitated targeted delivery of the investigational gene therapy,” Chad Christine, MD, professor of neurology, University of California, San Francisco and investigator in this trial, said in a news release.
“Additionally, administration of [VY-AADC01] resulted in dose-dependent increases in AADC enzyme expression and improvements in clinical measures and has been well-tolerated to date,” he said.
Based on these open-label results, researchers have initiated the RESTORE-1 Phase 2 trial (NCT03562494) to evaluate the safety and efficacy of VY-AADC01 and understand “its efficacy relative to optimal medical management alone,” they said.
The trial, which is recruiting, will randomize patients with advanced Parkinson’s disease who have not responded adequately to oral therapy to either optimized medical management plus VY-AADC01 or continued optimized medical management — including levodopa — plus placebo-surgery. Researchers plan to enroll 42 participants.