Gene Therapy Seen to Raise Response to Levodopa Given as IV Infusion in Trial

An investigational gene therapy, called VY‐AADC01, boosts motor responses to levodopa that is given intravenously —particularly at a low dose — in people with Parkinson’s disease, a sub-study within a Phase 1b trial shows.

These findings, along with positive data from the main PD-1101 study (NCT01973543), support the potential benefits of this approach and further clinical development of VY‐AADC01.

The study, “Aromatic L‐Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson’s Disease,” was published in the journal Movement Disorders.

Parkinson’s is characterized by the death of dopamine-producing neurons, resulting in lower dopamine levels and affecting how muscle movement and coordination are regulated.

In addition, as the disease progresses, patients are thought to produce less of L-amino acid decarboxylase (AADC), an enzyme that mediates the conversion of levodopa into dopamine. This loss would make a dose of levodopa, one of the main therapies for Parkinson’s symptoms, less effective.

VY-AADC01, being developed by Neurocrine Biosciences and Voyager Therapeutics, consists of a modified and harmless adeno-associated virus (AAV) that delivers the AADC gene — which contains the instructions to produce the AADC enzyme — directly into the putamen, a large brain structure filled with dopamine receptors and involved in movement control.

By providing AADC to these brain cells, VY-AADC01 is thought to promote levodopa’s conversion into dopamine, increasing its levels directly where it is needed and potentially easing disease symptoms.

The open-label, Phase 1b PD-1101 study evaluated the safety and preliminary effectiveness of a single administration of ascending doses of VY-AADC01 (7.5 × 10¹¹ vector genomes (vg), 1.5 and 4.7 × 10¹² vg) in 15 people with moderately advanced Parkinson’s disease and fluctuating responses to levodopa treatment.

VY-AADC01 was administered directly into the striatum (a brain area that includes the putamen) via a surgical procedure through the top of the head, aided by real-time magnetic resonance imaging (MRI).

Participants — 13 men and two women — had a mean age of 57.7 and a Parkinson’s diagnosis for 10 years. During the study, patients continued their antiparkinsonian medications, including levodopa.

Interim results showed that VY-AADC01, given as a single administration, was well-tolerated and resulted in robust and durable dose-dependent improvements in patients’ motor function, quality of life, and a reduction of antiparkinsonian medications — and for up to three years.

Now, researchers evaluated VY‐AADC01 in the context of patients’ motor response to levodopa (administered intravenously, or directly into a vein, rather than orally) within the PD-1101 study, which concluded in January.

A total of 13 patients participated in this sub-study: all 10 from the lower and intermediate dose groups, and three of the five given the higher dose.

Patients’ response to two different doses of levodopa (0.6 mg/mL and 1.2 mg/mL; only the higher dose was expected to almost certainly lead to clinical responses) was assessed before and six months after VY‐AADC01 administration.

Changes in AADC enzymatic activity, motor function — measured by the Unified Parkinson’s Disease Rating Scale Part III — and dyskinesia (abnormal involuntary movements that characterize advanced Parkinson’s) were assessed before and after levodopa was administered.

Patients’ responses to levodopa (in both motor and dyskinesia scores) were seen to be greater when levodopa was given after VY‐AADC01 administration, indicating that VY‐AADC01 boosted levodopa’s responses.

The researchers noted that greater levodopa responses after VY‐AADC01 administration were a result of increases in AADC activity associated with the gene therapy’s use, and not because of an increase in levodopa blood levels (which was not detected after gene therapy administration).

Notably, VY‐AADC01-associated improvements were more pronounced with the lower dose of levodopa. The scientists noted this suggests that clinically relevant dopamine levels may be reached with lower levodopa doses, which is consistent with the previously reported reductions in medication use by these patients.

Furthermore, after receiving VY‐AADC01, patients showed a trend toward better motor function and lesser dyskinesia during an off-period (when patients had been without levodopa and other antiparkinsonian medications overnight).

This observation was consistent with data from previous studies, the researchers said, and may be a result of greater dopamine production from the brain’s own levodopa.

“A lingering question is whether the administration of [into-the-vein] levodopa at a clinical research center translates to the clinical setting with oral levodopa and the use of other antiparkinsonian medications,” the researchers wrote.

They also concluded that this sub-study provides further evidence that this type of gene therapy may be of meaningful therapeutic benefit to Parkinson’s patients, and supports further clinical development of VY‐AADC01.

A Phase 2 trial (NCT03562494), called the RESTORE-1  study, was opened based on PD-1101’s positive results and those of another open-label Phase 1 trial (NCT03065192).

The new trial, which is still recruiting at sites across the U.S., is evaluating the gene therapy’s safety and effectiveness against a placebo in up to 42 people with advanced Parkinson’s, who have failed to respond properly to levodopa treatment.

Main efficacy goals include changes in motor fluctuations in gene therapy patients, against placebo, one year after a single treatment, and changes in AADC enzyme activity.

The AAV vector used in this trial is slightly different (adeno-associated viral vector serotype 2), and as such the therapy has been designated VY‐AADC02.