Gene therapy to boost levodopa conversion enzyme shows benefit in Parkinson’s

Patients with advanced Parkinson’s disease were able to reduce daily levodopa doses in phase Ib testing of an experimental gene therapy from Voyager Therapeutics of Cambridge, Mass.

The company packed the gene for aromatic L-amino acid decarboxylase (AADC) – the enzyme that converts levodopa to dopamine – into a benign adenovirus capsid, then injected it directly into the putamen of 10 patients under MRI-guidance. The idea was to counter the decline in AADC as Parkinson’s progresses. For now, the name of the AADC vector is VY-AADC01.

After one-time treatment, the five patients in cohort 1 had 21% coverage of the volume of the putamen and, at 6 months, a 13% increase in putaminal AADC activity, assessed by [18F] fluorodopa PET scan. Increased infusion volumes led to 34% putamen coverage and a 56% increase in AADC activity in cohort 2. Patients in cohorts 1 and 2 received a single administration of VY-AADC01 at a total dose of up to 7.5 x 1011 and 1.5 × 1012 vector genomes, respectively.

Due to symptom improvement, cohort 1 patients were able to reduce daily levodopa and related medications by 14%, and cohort 2 patients by 34%, at 6 months. The “reduction in oral medication was generally maintained at 12 months,” the company said in an announcement. The results have not been published in a peer-reviewed journal.

“VY-AADC01 treatment prolonged the duration and markedly increased the motor symptom response to levodopa measured following a controlled intravenous infusion of levodopa [at] 6 months … when compared to baseline.” There were no serious treatment-related adverse events, and patients went home within 2 days, Voyager said.

“We are excited about the data,” but “we think we have to be as good [as deep brain stimulation]; ideally, we’d obviously like to be better,” Voyager President and CEO Steven Paul, MD, said in a conference call Dec. 7. “We are optimistic that we can at least be equivalent with a onetime treatment, no indwelling hardware, no stimulators, and possibly even beat [deep brain stimulation], but that’s to be determined.” A placebo-controlled trial is scheduled to begin in late 2017 “so we can establish this really does work well against placebo.”

At 6 months, cohort 1 patients had a 15.6-point, off-medication improvement on the 56-point motor exam section of the Unified Parkinson’s Disease Rating Scale (UPDRS-III), which further improved to 16.4 points over baseline at 12 months. Cohort 2 patient improved 17.8 points at 6 months, but declined to 14.3 points over baseline at 12 months.

On medication, cohort 1 worsened 1.6 points on the UPDRS-III at 6 months, and remained there at month 12. Cohort 2 improved 9.6 points over baseline at 6 months, and kept the gain at 1 year.

Cohort 1 lost 0.3 hours in diary on-time over baseline at 6 months, but gained 1.6 hours at 12 months, a 16% improvement. Cohort 2 had a 2.2-hour increase at 6 months, and a further increase to 4.1 hours at 1 year, a 43% improvement over baseline.

Patients had Parkinson’s for an average of 10 years, after being diagnosed at a mean age of 58 years.

Voyager’s stock jumped more than 20% when the results were announced, but lost much of the gain in subsequent trading; VY-AADC01 is one of several gene therapies under development for Parkinson’s.