Voyager Therapeutics, a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases, announced positive results from its ongoing Phase 1b trial of VY-AADC01 in advanced Parkinson’s disease. The results demonstrated durable, dose-dependent and time-dependent improvements across multiple measures of patients’ motor function after a one-time administration of the gene therapy. These measures include patient-reported diaries, Parkinson’s disease rating scales, and activities of daily living.
“We are very pleased with the updated results from our dose-escalation trial. By six months in Cohort 3, patients achieved the clinically meaningful improvements in motor symptoms that were observed in Cohort 2 and with even lower doses of their oral Parkinson’s medications, including levodopa,” said Bernard Ravina, M.D., M.S., chief medical officer of Voyager Therapeutics. “These data suggest that higher doses of VY-AADC01 result in greater AADC activity, increasing the patient’s capacity to produce dopamine and, therefore, reducing their need for oral Parkinson’s medications. As a result, patients in the trial are spending more time during the day with good motor function, less time with poor motor function, and are experiencing less disability. For patients in Cohort 2 at 12 months, this meant an average increase during the day of four hours of on-time without dyskinesia, which is a very meaningful change. We believe the distinct mechanism of action of VY-AADC01 that allows patients to achieve this motor function improvement while markedly reducing their Parkinson’s medications to this extent and duration reflects a pattern that has not been seen in previous Parkinson’s gene therapy trials and does not exist with current or emerging treatments.”
Steven Paul, M.D., Voyager’s president and chief executive officer added, “These encouraging results continue to de-risk the program and support the use of either dose of VY-AADC01 administered in Cohort 2 or Cohort 3 for our planned pivotal trial. We continue to be impressed with the Cohort 2 data out to 12 months, namely, the increase in diary on-time of four hours without dyskinesia, decrease in off-time of 54%, supported by a 56% reduction in UPDRS-III motor scores while on medication. In addition, preliminary results from our posterior delivery trial suggest that even greater coverage of the putamen, the brain region we are targeting, can be achieved and with shorter administration times. We are excited to continue to follow the patients in this Phase 1b trial, particularly patients in Cohort 3 from six to 12 months, and those in the posterior delivery trial, as we approach the start of the pivotal Phase 2-3 program later this year.”
About the Phase 1b Trial
In advanced Parkinson’s disease, the putamen is depleted of dopamine and of the enzyme aromatic L-amino acid decarboxylase (AADC) that is responsible for converting levodopa to dopamine. VY-AADC01 is Voyager’s gene therapy vector that contains the gene that encodes the AADC enzyme. A single administration of VY-AADC01 into the putamen could offer advanced patients’ improved motor function while reducing their requirements for oral levodopa and other dopaminergic medications and their associated behavioral and motor side effects.
- The Phase 1b, open-label trial includes 15 patients with advanced Parkinson’s disease and disabling motor fluctuations, treated with a single administration of VY-AADC01.
- The primary objective of the trial is to assess the safety and distribution of ascending doses of VY-AADC01 administered under magnetic resonance imaging (MRI) guidance to the putamen, a region of the brain associated with impaired motor function in Parkinson’s disease.
- Secondary objectives include assessment of AADC expression and activity in the putamen measured by positron emission tomography (PET) using [18F] fluorodopa (or 18F-DOPA), which reflects the capacity to convert levodopa to dopamine. Other secondary measures include assessments of motor function and activities of daily living, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS-III and UPDRS-II, respectively), quality of life, and a patient-completed (Hauser) diary. Daily requirements for levodopa and related medications are also measured.
Biomarker and Clinical Results Summary
Today’s interim results include data from all 15 patients treated in Cohorts 1, 2 and 3 (five patients in each Cohort) including data from patients in Cohort 1 at 24 months, Cohort 2 at 12 months and Cohort 3 at six months. Patients enrolled in Cohort 3 received similar infusion volumes of VY-AADC01 compared to Cohort 2 (up to 900 µL per putamen), but three-fold higher vector genome concentrations. This volume and concentration for Cohort 3 represents up to a three-fold higher total dose of up to 4.5×1012 vector genomes (vg) of VY-AADC01 compared to patients in Cohort 2 who received a total dose of up to 1.5 × 1012 vg. Patients in Cohort 1 received lower volumes (up to 450 µL per putamen) and lower vector genome concentrations for at a total dose of up to 7.5×1011 vg.
Patients enrolled in Cohorts 1, 2 and 3 were:
- On average, 58 years of age with a Parkinson’s disease diagnosis for an average of 10 years.
- Candidates for surgical intervention including deep-brain stimulation due to disabling motor complications despite treatment with optimal anti-Parkinsonian medication.
- At baseline, the average patient diary on-time without troublesome dyskinesia was 10.5 hours, average UPDRS-III on medication score was 13.5, average diary off-time was 4.6 hours and average UPDRS-II activities of daily living off medication score was 16.5.
- At baseline, patients were treated with maximal levels of multiple dopaminergic medications including, in many cases, amantadine for the treatment of dyskinesia, or uncontrolled or involuntary movements. Patients’ average amount of Parkinson’s disease medications at baseline was 1,526 mg of oral levodopa equivalents per day.
Putamen Coverage, AADC Activity and Daily Doses of Oral Levodopa
- The use of real-time, MRI-guided delivery and increasing infusion volumes resulted in 21% mean coverage of the volume of the putamen with VY-AADC01 in Cohort 1, 34% mean coverage in Cohort 2, and 42% mean coverage in Cohort 3.
- VY-AADC01 treatment resulted in a 13% increase, a 56% increase, and a 79% increase in mean putaminal AADC enzyme activity in Cohort 1, 2, and 3, respectively at six months relative to baseline as measured by 18F-DOPA PET scans (Figure 1). Coverage of the putamen and AADC enzyme activity were highly correlated (r=0.84, p=0.0002)
- VY-AADC01 treatment resulted in reduced daily doses of oral levodopa and related medications to achieve optimal motor control, suggesting a greater capacity for patients to make more dopamine but with less need for oral levodopa. Patients’ Parkinson’s medications were reduced by a mean of 208 mg (14%), 553 mg (34%) and 618 mg (42%) for Cohorts 1, 2 and 3, respectively, at six months compared with baseline (Figure 1).
Filed Under: Drug Discovery