information: Presentation of results at a congress
Announcement: presentation of results at the 2019 American Academy of Neurology (AAN) Annual Meeting
Company: Voyager Therapeutics (USA-MA)
- gene therapy. VY-AADC, comprised of the adeno-associated virus-2 capsid and a cytomegalovirus promoter to drive aromatic L-amino acid decarboxylase (AADC) transgene expression, is designed to deliver the AADC gene directly into neurons of the putamen where dopamine receptors are located, bypassing the substantia nigra neurons and enabling the neurons of the putamen to express the AADC enzyme to convert levodopa into dopamine. The approach with VY-AADC, therefore, has the potential to durably enhance the conversion of levodopa to dopamine and provide clinically meaningful improvements by restoring motor function in patients and improving symptoms following a single administration.
Disease: Parkinson's disease
area: Neurological diseases - Neurodegenerative diseases
- The Phase 1b, open-label, dose-escalation trial included 15 patients with advanced Parkinson’s disease and disabling motor fluctuations, despite treatment with optimal anti-parkinsonian medications. Patients enrolled in the Phase 1b trial were, on average, 58 years of age with a Parkinson’s disease diagnosis for an average of 10 years.
- • On May 5, 2019, Neurocrine Biosciences and Voyager Therapeutics announced Phase I trial results for VY-AADC from eight patients with Parkinson’s disease who participated in the open-label trial to evaluate the safety and efficacy of VY-AADC and to further assess the posterior (i.e., from the back of the head) surgical delivery approach. These Phase I results have been presented as a poster presentation at the 2019 American Academy of Neurology (AAN) Annual Meeting. Treatment with VY-AADC improved good ON time (ON time without troublesome dyskinesia) by 1.7 hours from baseline and reduced OFF time by 2.2 hours at 12 months from baseline in patients with Parkinson’s disease. Exploratory analyses in four of the eight patients with low or no dyskinesia or absence of impulse control disorder (ICD) at baseline demonstrated a greater improvement in motor function including a 3.2-hour improvement in good ON time from baseline to 12 months. Infusions of VY-AADC were well tolerated with no serious adverse events (SAEs) reported. These Phase I results show that the posterior trajectory is an additional surgical delivery route in patients with Parkinson’s disease.
VY-AADC Motor Function Results from the Phase I (PD-1102) Trial
The PD-1102 trial includes eight patients with advanced Parkinson’s disease. On average, patients’ baseline characteristics in PD-1102 were consistent with patients’ baseline from a separate, ongoing Phase Ib trial (PD-1101) employing a frontal (i.e., from the top of the head) surgical delivery approach. Two patients in PD-1102 were identified as having impulse control disorder while no patients were identified as having impulse control disorder in PD-1101. At baseline, patients’ mean good ON time was 9.1 hours and mean OFF time was 6.8 hours.
Administration of VY-AADC with the posterior trajectory resulted in a mean coverage of the putamen of 54% and reduced the infusion time by approximately two hours (from 5.2 hours to 3.1 hours) compared to PD-1101. In PD-1102, treatment with VY-AADC increased AADC enzyme activity in the putamen as measured by positron emission tomography (PET) using [18F] fluorodopa (or 18F-DOPA) by 85%. AADC enzyme activity in the putamen as measured by PET using 18F-DOPA reflects the capacity of neurons in the brain to convert levodopa to dopamine.
Treatment with VY-AADC improved patients’ motor function from baseline to twelve months across multiple assessments. These assessments include patient self-reported diary entries of ON and OFF times (including good ON time), Unified Parkinson’s Disease Rating Scales, and activities of daily living measures. In addition, patients’ reported an ability to maintain motor function with less Parkinson’s disease medication, as patients’ reported a mean 28% reduction in the dosage of Parkinson’s disease medication (measured as levodopa equivalents) at six months and at 12 months from a baseline mean of 1,500 mg/day.
Treatment with VY-AADC improved patients’ good ON time by 1.7 hours from baseline and reduced OFF time by 2.2 hours from baseline to 12 months. Exploratory analyses in PD-1101 suggested that patients with high dyskinesia or an ICD at baseline may show different outcomes, especially in patient-reported diary measures. A clinical assessment of the subgroup of patients (n=4) with no or low baseline dyskinesia as measured by the Unified Dyskinesia Rating Scale score (? 30) and absence of ICD at baseline as determined by the investigator, indicated that VY-AADC improved good ON time from baseline by 3.2 hours and reduced OFF time by 3.2 hours in patients at 12 months.
In addition to motor function, VY-AADC improved patients’ quality of life as measured by the patient-reported 39-item Parkinson’s Disease Questionnaire (PDQ-39). For PDQ-39, VY-AADC improved (reduced) patients’ score by a mean change from baseline to 12 months of -7.6. Infusions of VY-AADC have been well tolerated in the eight patients treated in PD-1102 with no serious adverse events (SAEs) reported.
- • On March 28, 2019, Neurocrine Biosciences and Voyager Therapeutics announced the publication of interim results from the Phase 1b trial of VY-AADC, an investigational gene therapy treatment for Parkinson’s disease, in Annals of Neurology. The publication titled “Magnetic Resonance Imaging-Guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson's Disease,” reports data from patients in this trial who were followed for up to three years (Cohort 1), two years (Cohort 2), or 18 months (Cohort 3) as reported in November 2018. “The interim results from this Phase 1b trial demonstrated that administration of VY-AADC to the putamen using a novel technique, which included intraoperative monitoring with magnetic resonance imaging guidance, facilitated targeted delivery of the investigational gene therapy,” said Chad Christine, M.D., Professor of Neurology, University of California, San Francisco and Investigator in the Phase 1b trial of VY-AADC. “Additionally, administration of VY-AADC resulted in dose-dependent increases in AADC enzyme expression and improvements in clinical measures and has been well-tolerated to date.”
- • On November 7, 2018, Voyager Therapeutics announced positive longer-term results from the open-label, dose-escalating Phase 1b trial of VY-AADC demonstrating sustained improvements in patients’ motor function. Patients in the two highest dose cohorts (Cohorts 3 and 2) experienced mean improvements in diary on-time without troublesome dyskinesia (good ON time) of 1.7 hours per day at 18 months and 2.7 hours per day at two years, respectively.
- Having selected a dose for the Phase 2 trial between the two highest dose cohorts from the Phase 1b trial, Voyager performed a combined analysis of the outcomes from the ten patients in Cohorts 2 and 3. This combined analysis demonstrated an increase from baseline in good ON time of 2.4 hours per day at 12 months, the timepoint for the primary endpoint in the Phase 2 trial, and 2.6 hours per day at 18 months, the latest timepoint measured for both cohorts. Of the combined ten patients in Cohorts 2 and 3, seven patients would be eligible for the Phase 2 trial based on limits in severity of dyskinesia and minimum OFF time at baseline. For these seven patients, the Phase 2 trial relevant group, the improvements in good ON time were 2.8 hours at 12 months and 2.5 hours at 18 months. These results were achieved with clinically meaningful and sustained reductions in daily oral levodopa and related medications.
- VY-AADC Motor Function Results from the Phase 1b Trial
- At baseline, patients’ average good ON time was 10.5 hours and average OFF time was 4.6 hours. At baseline, patients were treated with optimal levels of multiple dopaminergic medications including, in many cases, amantadine for the treatment of dyskinesia, or uncontrolled or involuntary movements. On average, patients were receiving 1,526 mg of oral levodopa equivalent antiparkinsonian medications per day at baseline. Today’s results included data from all 15 patients treated in Cohorts 1, 2 and 3 (five patients in each Cohort) with data from patients in Cohort 1 at three years (as an update from four of five patients at three years as previously reported), Cohort 2 at two years and Cohort 3 at 18 months (Table 1).
- Table 1: VY-AADC Mean Improvement in Good ON Time per Normalized 16-Hour Day
|Good ON time: hour improvement from baseline (SE)
|Cohort 1, n=5
|Cohort 2, n=5
|Cohort 3, n=5
|Cohorts 2-3, n=10
|Cohorts 2-3 and Phase 2 trial eligible, n=7
- (1) Protocol amended to include 18-month data collection after Cohort 1 reached this timepoint
- One-time administration of VY-AADC resulted in reduced daily doses of oral levodopa and related medications. This included a 42.5% (standard error [SE], 5.7%) reduction from baseline for Cohort 3 at 18 months, a 21.2% (10.6%) reduction from baseline for Cohort 2 at two years, and a 14.7% (17.3%) increase from baseline for the low-dose Cohort 1 at three years.
- Measured against the unmet disease burden at baseline, which is the time patients record as OFF time and ON time with troublesome dyskinesia, VY-AADC reduced this combined time by 46% from baseline at 12 months and 47% at 18 months for Cohorts 2 and 3 combined. Similar reductions were observed in the seven of ten patients who would have been eligible for the Phase 2 trial (Table 2).
- Table 2: VY-AADC Mean Reduction in OFF Time and ON Time with Troublesome Dyskinesia
|OFF time and ON time w/ troublesome dyskinesia hour per day (SE)
||Mean % change from baseline (1)
||Mean % change from baseline (1)
|Cohorts 2-3, n=10
|Cohorts 2-3 and Phase 2 trial eligible, n=7
- (1) Mean % change from baseline is calculated as the mean of all individual patient’s percent change from baseline
- Infusions of VY-AADC have been well-tolerated in all 15 patients treated in these Cohorts with no reported vector-related serious adverse events (SAEs) and fourteen of the 15 patients were discharged from the hospital within two days following surgery.
- Voyager has identified 24 clinical trial sites (including neurosurgical and neurology patient referral and management sites) for participation in the Phase 2 randomized, placebo-controlled trial. Institutional review board approvals, site activation and patient screening efforts are underway. Voyager expects to announce when the first patient has been dosed.
- • On March 9, 2018, Voyager Therapeutics announced longer-term data from its ongoing dose-ranging Phase 1b trial of VY-AADC in advanced Parkinson’s disease.
- The results continue to demonstrate 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 quality of life, with diary on-time without troublesome dyskinesia at twelve months as the proposed primary endpoint of the planned pivotal program. The update of results from the ongoing Phase 1b trial of VY-AADC include a durable 2.1-hour improvement in patient-reported diary on-time without troublesome dyskinesia from baseline to three years for patients in Cohort 1, a durable and clinically meaningful 3.5-hour improvement from baseline to 18 months in Cohort 2, and an improvement from baseline to six months of 1.5 hours that plateaued from six to 12 months in Cohort 3.
- Clinical Results Summary
- These 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 three years, Cohort 2 at 18 months and Cohort 3 at one year. Patients enrolled in Cohort 3 received similar infusion volumes of VY-AADC delivered with the transfrontal, or top of the head, approach compared to Cohort 2 (up to 900 µL per putamen), but three-fold higher vector genome (vg) concentrations. This volume and concentration for Cohort 3 represents up to a three-fold higher total dose of up to 4.5×1012 vg of VY-AADC 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 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. Patients in Cohort 3 entered the trial with approximately 50% more severe dyskinesia at baseline than patients in Cohorts 1 and 2 based on the Unified Dyskinesia Rating Scale, with a mean score of 30.2 for Cohort 3 compared with a mean score of 19.2 and 17.4 for Cohorts 1 and 2, respectively.
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.
During the trial, patients were instructed to reduce their daily doses of oral levodopa and related medications, or levodopa equivalent doses (LEDs), to achieve optimal motor control in response to severe dyskinesia observed post-treatment with VY-AADC. In this trial, patients’ Parkinson’s disease LEDs were reduced by a mean of 15%, 33% and 42% for Cohorts 1, 2 and 3, respectively, from baseline to six months. LED reductions were sustained for Cohorts 1 and 2 to eighteen months and for Cohort 3 to 12 months (Figure 1).
- Clinical Motor Function Data Summary
- Treatment with VY-AADC resulted in a durable 2.1-hour improvement in patient-reported diary on-time without troublesome dyskinesia from baseline to three years for patients in Cohort 1, a durable and clinically meaningful 3.5-hour improvement from baseline to 18 months in Cohort 2, and an improvement from baseline to six months of 1.5 hours that plateaued from six to 12 months in Cohort 3 (Figure 2). Cohort 3 patients had higher levels of severe dyskinesia at baseline than patients in Cohorts 1 and 2. This, coupled with treatment with a higher dose of VY-AADC, resulted in patients in Cohort 3 reducing their LEDs to a greater extent than patients in Cohorts 1 and 2 and may have resulted in less robust control of motor function as measured by on-time without troublesome dyskinesia compared to Cohort 2 by 12 months. Voyager intends to apply these learnings to the protocols for the pivotal Phase 2-3 program.
- VY-AADC also generated durable improvements in this trial in other measures of motor function including decreases in both diary off-time and diary on-time with troublesome dyskinesia and increases in both diary on-time without dyskinesia and diary on-time with non-troublesome dyskinesia. In Cohort 2 at 18 months, patients had a mean increase of 5.1 hours a day of on-time without any dyskinesia and experienced 65% less off-time (Figure 3).
- In addition to motor function, VY-AADC improved patients’ quality of life as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II activities of daily living section and the patient-reported 39-item Parkinson’s Disease Questionnaire (PDQ-39), demonstrating dose-dependent and clinically meaningful improvements in these scores. For PDQ-39, VY-AADC improved (reduced) patients’ score by a mean change from baseline to 12 months of -8.4 and -9.1 for Cohorts 2 and 3, respectively (Figure 4).
- Safety Data from Cohorts 1, 2 and 3
- Infusions of VY-AADC have been well-tolerated in all fifteen patients treated in these Cohorts with no vector-related serious adverse events (SAEs). Fourteen of the 15 patients were discharged from the hospital within two days following surgery. As previously reported, one patient experienced two SAEs: a pulmonary embolism or blood clot in the lungs, and related heart arrhythmia or irregular heartbeat. The patient was treated with an anti-coagulant and symptoms associated with the SAEs have completely resolved. Investigators determined that this was most likely related to immobility during the administration and subsequent formation of a blood clot, or deep vein thrombosis (DVT), in the lower extremity. Consequently, DVT prophylaxis was added to the protocol and no subsequent events have been observed.
- Pivotal Phase 2-3 Program on Track to Begin Dosing Patients in Mid-2018
- Voyager plans to meet with the FDA during a Type C meeting to discuss the current Phase 1b data and designs for the pivotal program. Voyager expects to include information from this meeting, as well as data from Cohorts 1, 2 and 3 and the Phase 1 posterior trajectory trial, into the final design of the Phase 2-3 pivotal program, which remains on track to dose the first patient during mid-2018.