Synonyms: VY-AADC01, VY-AADC02
Therapy Type: DNA/RNA-based
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Discontinued)
Company: Neurocrine Biosciences, Voyager Therapeutics
VY-AADC is an AAV-based gene therapy that was developed by Voyager Therapeutics and evaluated clinically in partnership with Neurocrine Biosciences. It aims to restore the treatment benefit of oral levodopa for people with advanced Parkinson's disease whose treatment response has started fluctuating. VY-AADC attempts to supply transgenic L-amino acid decarboxylase (AADC), the enzyme that converts levodopa to dopamine, directly into the putamen area of the brain. As dopaminergic neurons in the brain's substantia nigra degenerate in PD, dopamine levels decrease in their projection area, the striatum encompassing the putamen, where medium spiny neurons survive and maintain expression of dopamine receptors long into PD progression (Braak et al., 2004). The treatment rationale is that local expression of transgenic AADC will boost dopamine levels in the putamen, reducing motor "off" time and prolonging "on" time for the patient.
VY-AADC uses the adeno-associated virus 2 capsid as a vector encoding AADC; expression is driven by a cytomegalovirus promoter. This renewed attempt at CNS gene therapy employs MRI-guided cannula placement to the putamen, convection-enhanced infusion of larger volumes of transgene solution to increase exposure, and 18F-DOPA PET to quantify local transgene expression and activity. The goal is to achieve long-term expression with a single treatment. Proof of concept, as well as safety and tolerability of this delivery mode, were reported in nonhuman primates (Su et al., 2010; Hadaczek et al., 2010; San Sebastian et al., 2012; San Sebastian et al., 2014).
In 2013, Voyager started enrolling 15 people who had had PD for at least five years and were on levodopa therapy, into an open-label trial. It compared three ascending doses of VY-AADC, delivered once by MRI-guided neurosurgical infusion into the putamen on both sides of the brain. The primary outcome, assessed over a three-year period, was safety and tolerability; secondary outcomes included PD symptoms as recorded in participant diaries and assessed by a neurologist, as well as quality-of-life surveys, changes to Parkinson's medications, and PET scanning six months after gene transfer. Conducted at the University of California, San Francisco, and the University of Pittsburgh, the trial ended in January 2020.
Interim results were reported in December 2016, September 2017, and March 2018. Injection of up to 900 microliters of VY-AADC into the putamen was well-tolerated, distributed better throughout the putamen than previous gene therapies, and correlated with increased F-DOPA PET signal. The higher-dose cohort had higher putamen coverage, and a 79 percent increase in AADC enzyme activity. There were also dose-dependent changes in imaging responsiveness to levodopa, and clinical measures. Thus far, the trial showed a 2.1-hour lengthening in patient-reported on-time without dyskinesia from baseline to three years for patients in Cohort 1; 3.5 hours more on-time from baseline to 18 months in Cohort 2; and 1.5 hours more up to 12 months in Cohort 3. Participants needed less oral levodopa, and VY-AADC still appeared safe at three years out. One patient had a pulmonary embolism from a venous thrombosis during the procedure, which resolved (Mar 2018 news; Christine et al., 2017). Results for all cohorts through one year post-treatment have been published (Christine et al., 2019).
According to subsequently published trial results, the need for PD medications was reduced by 21 to 30 percent, respectively, in the two highest dose cohorts after three years. Outcomes related to movement and quality of life were generally stable or improved (Christine et al., 2022). In terms of serious adverse events, a second patient experienced a bowel obstruction; it occurred more than two years after the procedure and was considered unrelated to treatment. The most common side effects deemed related to treatment were postoperative headache and dyskinesia; both were mild and transient. The dyskinesias resolved with PD medication adjustments. In a sub-study, investigators determined that VY-AADC improved motor responses to an intravenous levodopa dose given six months after surgery (Nutt et al., 2020).
In May 2017, a second open-label trial started enrolling 16 people with advanced PD who had a fluctuating levodopa response with a defined minimum of time spent in the "off" state. These participants received 9.4 x 1012 vector genomes of VY-AADC01, twice the highest dose than in the first trial, also infused once directly into the putamen. This trial evaluates delivery via an occipital, i.e., posterior, trajectory, along the long axis of the putamen, to see if that increases coverage of the putamen relative to the frontal trajectory used in the first trial. Primary outcomes include adverse events, brain abnormalities on MRI scans, routine physical exams and labs, as well as change on the Columbia-Suicide Severity Rating Scale—all recorded for up to three years after gene transfer. Secondary outcomes monitor changes in PD medications, motor function using both participant diaries and neurologist assessment, changes in dyskinesia, as well as changes in transgene expression, sleep, compulsive behavior, cognition, quality of life, and other parameters. This trial was conducted at four U.S. sites; it finished in August 2021.
Preliminary results of the second open-label trial were presented at AAN in May 2019. In eight patients with advanced PD injected via the posterior route, the virus spread across half of the putamen; AADC activity, as judged by 18F-DOPA PET, increased by 85 percent. Compared with the original approach through the top of the head, time in surgery was shorter by two to three hours. A year after surgery, patients reported 1.7 hours longer on-time on levodopa, and required 28 percent less levodopa to maintain motor function than they did presurgery. Other measures of motor function and quality of life also improved. Exploratory analysis suggested that patients with high dyskinesia or impulse control disorder responded less well to the treatment (company press release; see also Nov 2019 news). According to additional data from both trials that has since been presented at meetings, improved motor function and reduced need for medication has persisted out to two and three years (Sept 2020 press release). A comparison of the two surgical approaches, and their effects on vector delivery and expression, is published (Richardson et al., 2020).
People from both Phase 1 studies are eligible to join an eight-year, observational follow-up safety study.
In June 2018, RESTORE-1, a Phase 2 study, began enrolling 42 people with advanced Parkinson’s disease who were responding poorly to medications. They received a single dose of VY-AADC via the occipital route, or a placebo sham surgery that involved drilling through the skull without entering the brain. Similarly to Phase 1, primary endpoints included patient rating of motor fluctuations after one year, viral coverage of putamen, change in AADC enzyme activity, and measures of safety. Secondary outcomes included change in activities of daily living, quality of life, global function, non-motor symptoms, and response to levodopa. The trial was scheduled to run to the end of 2020.
In January 2019, Voyager announced that, after consulting with the FDA, it would increase the number of patients in this trial to 85, and undertake a Phase 3 of similar size and design (company release) with funding from San Diego-based Neurocrine Biosciences (company release).
The company paused screening of new participants in April 2020 due to the COVID pandemic. The pause was extended in November 2020, after the safety and data monitoring board raised concerns about imaging data. A month later, the company announced that the FDA had imposed a formal clinical hold, pending more information on MRI abnormalities in trial participants (press release).
For all VY-AADC trials, see clinicaltrials.gov.
Clinical Trial Timeline
Last Updated: 19 Aug 2022
- So Far, So Good for Parkinson’s Gene Therapy
- Time to Try Again: Gene-Based Therapy for Neurodegeneration
- Christine CW, Bankiewicz KS, Van Laar AD, Richardson RM, Ravina B, Kells AP, Boot B, Martin AJ, Nutt J, Thompson ME, Larson PS. Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease. Ann Neurol. 2019 May;85(5):704-714. Epub 2019 Mar 26 PubMed.
- Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004 Oct;318(1):121-34. Epub 2004 Aug 24 PubMed.
- Su X, Kells AP, Salegio EA, Salegio EA, Richardson RM, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Forsayeth J, Bankiewicz KS. Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther. 2010 Aug;18(8):1490-5. Epub 2010 Jun 15 PubMed.
- Hadaczek P, Eberling JL, Pivirotto P, Bringas J, Forsayeth J, Bankiewicz KS. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol Ther. 2010 Aug;18(8):1458-61. Epub 2010 Jun 8 PubMed.
- San Sebastian W, Richardson RM, Kells AP, Lamarre C, Bringas J, Pivirotto P, Salegio EA, Dearmond SJ, Forsayeth J, Bankiewicz KS. Safety and tolerability of magnetic resonance imaging-guided convection-enhanced delivery of AAV2-hAADC with a novel delivery platform in nonhuman primate striatum. Hum Gene Ther. 2012 Feb;23(2):210-7. Epub 2012 Jan 26 PubMed.
- San Sebastian W, Kells AP, Bringas J, Samaranch L, Hadaczek P, Ciesielska A, Macayan M, Pivirotto PJ, Forsayeth J, Osborne S, Wright JF, Green F, Heller G, Bankiewicz KS. SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE. Mol Ther Methods Clin Dev. 2014 Oct 15;3 PubMed.
- Nutt JG, Curtze C, Hiller A, Anderson S, Larson PS, Van Laar AD, Richardson RM, Thompson ME, Sedkov A, Leinonen M, Ravina B, Bankiewicz KS, Christine CW. Aromatic L-Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson's Disease. Mov Disord. 2020 May;35(5):851-858. Epub 2020 Mar 9 PubMed.
- Kang UJ, Nakamura K, Zhuang X. Reader Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology. 2022 Aug 9;99(6):258-259. PubMed.
- Christine CW, Richardson RM, Fine EM, Khwaja OS, Liang GS, Meier A, Roberts EW, Bankiewicz K, Larson PS. Author Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology. 2022 Aug 9;99(6):259. PubMed.
- Palma JA. Reader Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology. 2022 Aug 9;99(6):260. PubMed.
- Christine CW, Richardson RM, Van Laar A, Fine EM, Khwaja OS, Liang GS, Bankiewicz K, Larson PS. Author Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology. 2022 Aug 9;99(6):260-261. PubMed.