ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by , was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.
“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author , said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”
According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used 18F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”
The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 1011 vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 1011 vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 1012 vg/mL and were followed for 12 months.
At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.
In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.
“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”
He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.
Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.
Source: Christine et al. ANA 2018,.