Parkinson’s disease is a chronic, progressive and debilitating neurodegenerative disease that affects approximately 1 million people in the U.S. and 6 million people worldwide.1 Parkinson’s disease is characterized by a loss of dopamine and its function.
Parkinson’s disease is a chronic, progressive and debilitating neurodegenerative disease that affects approximately 1 million people in the U.S. and 6 million people worldwide.1 Parkinson’s disease is characterized by a loss of dopamine and its function. Dopamine is a chemical “messenger” that is produced in the brain and is involved in the control of movement. Some chemicals, like dopamine, are made from other chemicals by proteins called enzymes. Dopamine is made in the brain when the enzyme AADC (Aromatic l-amino acid decarboxylase) converts the chemical levodopa to dopamine. Levodopa, AADC, and dopamine are each present at normal levels in healthy people.
When dopamine levels decrease in the brain and there is no longer enough to control movement, the motor symptoms of Parkinson’s disease including tremors, slow movement or loss of movement, rigidity, and postural instability, may occur. When this happens, a doctor may prescribe a levodopa medication, which is converted into dopamine by the enzyme AADC in the same way that naturally occurring levodopa is converted to dopamine.
As Parkinson’s disease worsens, there is less AADC enzyme in parts of the brain where it is needed to convert levodopa to dopamine. Therefore, the amount of dopamine that is produced from each dose of levodopa medicine may be reduced. When this happens, patients’ motor function may worsen with a less predictable response to medications.
Voyager Therapeutics’ investigational gene therapy, in collaboration with Neurocrine Biosciences, is designed to put the AADC enzyme into brain cells where it can convert levodopa to dopamine. To do this, the AADC gene is delivered inside a transporter called “adeno-associated viral vector” (AAV), much like a letter that carries the instructions the brain needs to make the AADC enzyme with the AAV as the envelope that carries the letter.
About the Phase 2 RESTORE-1 Clinical Trial
Voyager and Neurocrine completed enrollment and monitoring in an open-label, dose-escalating Phase 1b trial of VY-AADC in fifteen patients with advanced Parkinson’s disease designed to evaluate the safety and efficacy of escalating doses of VY-AADC. Additionally, Voyager and Neurocrine completed enrollment and continue to monitor eight patients in a second Phase 1b trial of VY-AADC designed to explore a delivery route using a posterior trajectory. In these trials (link here) one-time administration of VY-AADC led to improvements in patients’ motor function. Patients were able to reduce their daily levodopa and other Parkinson’s disease medications. To date, infusions of VY-AADC have been well-tolerated. In patients treated in these trials, there were no vector-related serious adverse events reported.
The RESTORE-1, Phase 2, randomized, placebo-surgery controlled, double-blinded, multi-center, clinical trial was designed to evaluate the safety and efficacy of VY-AADC in patients who have been diagnosed with Parkinson’s disease for at least four years, are not responding adequately to oral medications, and have at least three hours of OFF time during the day as measured by a validated self-reported patient diary.
The primary endpoint of RESTORE-1 is ON time without troublesome dyskinesia, or good ON time, as measured by self-reported patient diary at 12 months. Secondary endpoints include diary OFF time, other motor function and quality of life measures from the United Parkinson’s Disease Rating Scales (UPDRS-II and III scores), the Parkinson’s Disease Questionnaire (PDQ-39), and patient’s global function as measured by the proportion of participants with improvement on the Clinical Global Impression (CGI) score. The trial will also measure non-motor symptoms from the Non-Motor Symptom Scale (NMSS), as well as safety.
The RESTORE-1 trial has been placed on clinical hold by the U.S. Food and Drug Administration following the submission of an IND Safety Report related to the observation of MRI abnormalities in some RESTORE-1 study participants. The trial originally paused screening, enrollment, and dosing due to the COVID-19 pandemic and as a result of the independent Data Safety Monitoring Board (DSMB)’s request to pause pending its review of patient level data.
Neurocrine has terminated the portion of the collaboration agreement related to VY-AADC for the treatment of Parkinson’s disease. The termination is effective on August 2, 2021. Voyager plans to support Neurocrine on any ongoing matters related to imaging and clinical assessments requested by the DSMB and other information requested by the FDA for the RESTORE-1 Phase 2 clinical trial.
 Michael J. Fox Foundation
Amyotropic Lateral Sclerosis (ALS) is a rare, rapidly progressive, fatal disease characterized by the degeneration of nerve cells in the spinal cord and brain resulting in severe muscle atrophy with loss of the ability to walk and speak,
Amyotropic Lateral Sclerosis (ALS) is a rare, rapidly progressive, fatal disease characterized by the degeneration of nerve cells in the spinal cord and brain resulting in severe muscle atrophy with loss of the ability to walk and speak, and premature death. The median survival is approximately three years, and 90 percent of people with ALS die within five years of symptom onset¹. ALS affects approximately 20,000 people in the U.S., with less than 10,000 new cases identified each year reflecting a high rate of mortality and short survival, relative to other diseases with similar incidences².
Patients with ALS typically develop weakness in one body region (upper or lower limb or bulbar) and then develop symptoms and signs of progressive dysfunction of motor neurons. The majority of ALS cases occur sporadically and with unknown cause, but in approximately 10 percent of patients, the cause is familial and can be linked to an identifiable genetic defect. An estimated 20 percent of familial cases can be attributed to mutations in superoxide dismutase 1 gene (SOD1). SOD1 is the first mutant gene discovered to cause the development of ALS, through a toxic gain of function mechanism leading to motor neuron pathogenesis³. Riluzole is the only drug approved by the U.S. Food and Drug Administration for the treatment of ALS. In controlled trials, riluzole delayed the time to onset of tracheostomy or death by approximately two to three months, but did not improve muscle strength or neurological function.
Voyager is generating a lead clinical candidate for the treatment of ALS due to mutations in SOD1. Multiple studies have demonstrated that mutant SOD1 is toxic to motor neurons, and leads to their progressive loss. The lead candidate would be composed of a proprietary adeno-associated virus (AAV) capsid and transgene with a micro RNA (miRNA) expression cassette that harnesses the RNAi pathway to selectively silence, or knockdown, the production of SOD1 messenger RNA. With a single intrathecal (IT) injection, this lead candidate would have the potential to durably reduce the levels of toxic mutant SOD1 protein in the CNS to slow the progression of disease.
 Sorenson EJ, et al. (2002) Neurology 59:280-282.
 Rosen D, et al. (1993) Nature 362:59-62.
Huntington’s disease is a fatal, inherited neurodegenerative disease that results in the progressive decline of motor and cognitive functions and a range of behavioral and psychiatric disturbances. The disease affects approximately 30,000 individuals in the U.S.,
Huntington’s disease is a fatal, inherited neurodegenerative disease that results in the progressive decline of motor and cognitive functions and a range of behavioral and psychiatric disturbances. The disease affects approximately 30,000 individuals in the U.S., according to the Huntington’s Disease Society of America, with symptoms usually appearing between the ages of 30 to 50, and worsening over a 10 to 25-year period. Huntington’s disease is caused by mutations in the huntingtin, or HTT, gene. While the exact function of the HTT gene in healthy individuals is unknown, it is essential for normal development before birth and mutations in the HTT gene ultimately lead to the production of abnormal intracellular huntingtin protein aggregates that cause neuronal cell death. Huntington’s disease is an autosomal dominant disorder, which means that every child of a parent with Huntington’s has a 50/50 chance of inheriting the faulty HTT gene. Currently, there are no approved treatments targeting the underlying cause of the disease and only one drug, tetrabenazine, has been approved for the treatment of the specific motor symptoms of Huntington’s disease.
Because HTT mutations that cause Huntington’s disease are toxic gain-of-function mutations, we believe that we can employ an AAV gene therapy approach designed to knock down expression of the HTT gene. VY-HTT01 works by knocking down HTT expression in neurons and astrocytes in the striatum and cortex (discrete regions in the brain that can be targeted with AAV gene therapy delivered directly into the brain), thereby reducing the level of toxicity associated with mutated protein in these brain regions, and slowing the progression of cognitive and motor symptoms. We believe that we can use the same surgical delivery approach to the brain for this program that has been used for VY-AADC for our Parkinson’s disease program, allowing us to leverage prior clinical experience.
We are evaluating direct injection into the brain for the best distribution and delivery to the regions relevant to Huntington’s disease – striatum and cortex. We are studying parameters such as site of administration, volume of administration and rate of infusion to identify the dosing paradigm that we believe will translate into an effective therapy in patients.
We are in the process of completing a number of preclinical studies to evaluate the safety, biodistribution, pharmacology and efficacy of our lead candidate, including studies in relevant animal models to support an investigational new drug (IND) application. We expect that the first clinical trial of VY-HTT01 will enroll Huntington’s disease patients.
Friedreich’s ataxia is a debilitating neurodegenerative disease resulting in poor coordination of the legs and arms, progressive loss of the ability to walk, generalized weakness, loss of sensation, scoliosis, diabetes and cardiomyopathy as well as impaired vision,
Friedreich’s ataxia is a debilitating neurodegenerative disease resulting in poor coordination of the legs and arms, progressive loss of the ability to walk, generalized weakness, loss of sensation, scoliosis, diabetes and cardiomyopathy as well as impaired vision, hearing and speech. The typical age of onset is 10 to 12 years, and life expectancy is severely reduced with patients generally dying of neurological and cardiac complications between the ages of 35 and 45. According to the Friedreich’s Ataxia Research Alliance, there are approximately 6,400 patients living with the disease in the United States and no FDA-approved treatments.
Friedreich’s ataxia patients have mutations of the FXN gene that reduce production of the frataxin protein, resulting in the degeneration of sensory pathways and a variety of debilitating symptoms. Friedreich’s ataxia is an autosomal recessive disorder, meaning that a person must obtain a defective copy of the FXN gene from both parents in order to develop the condition. One healthy copy of the FXN gene, or 50 percent of normal frataxin protein levels, is sufficient to prevent the disease phenotype. We therefore believe we may be able to achieve success by restoring FXN protein levels to approximately 50 percent of normal levels using AAV gene therapy.
We are developing an AAV gene therapy approach that delivers a functional version of the FXN gene to the sensory pathways through intrathecal or intravenous injection. We believe this approach has the potential to improve the balance, ability to walk, sensory capability, coordination, strength and functional capacity of Friedreich’s ataxia patients. Most Friedreich’s ataxia patients produce very low levels of the frataxin protein, which, though insufficient to prevent the disease, exposes the patient’s immune system to frataxin, thus reducing the likelihood that the FXN protein expressed by AAV gene therapy would trigger a harmful immune response.
We conducted preclinical studies in non-human primates and achieved high FXN expression levels within the target sensory ganglia, or clusters of neurons, along the spinal region following intrathecal injection. FXN expression was normalized as a fold increase relative to FXN expression in a human brain reference sample. The levels of FXN expression observed using an AAVrh10 vector were, on average, greater than FXN levels present in normal human brain tissue. The increased levels of FXN were achieved in cervical, thoracic, lumbar and sacral levels. Relatively low, but measurable, levels of FXN expression were also observed in the cerebellar dentate nucleus, another area of the CNS that is often affected in Friedreich’s ataxia, and that is often considered difficult to target therapeutically.
VY-FXN01 is currently in preclinical development. Once we identify a lead candidate for this program, we plan to complete preclinical studies to evaluate the safety and efficacy of our lead candidate, including studies in a relevant animal model of Friedreich’s ataxia and IND-enabling studies. We expect that the first clinical trial of VY-FXN01 will enroll Friedreich’s ataxia patients.
Pathological and aggregated tau protein is believed to play a key role in severe CNS diseases. In healthy individuals, tau is an abundant soluble cytoplasmic protein that binds to microtubules to promote microtubule stability and function.
Pathological and aggregated tau protein is believed to play a key role in severe CNS diseases. In healthy individuals, tau is an abundant soluble cytoplasmic protein that binds to microtubules to promote microtubule stability and function. In Alzheimer’s disease (AD) and other tauopathies, tau aggregates and becomes hyper-phosphorylated, forming insoluble tau-containing neurofibrillary tangles (NFTs). The progressive spread of tau pathology along distinct anatomical pathways in the brain closely correlates with disease progression and severity in a number of tauopathies, including AD, frontotemporal lobar degeneration (FTD), Pick’s disease, progressive supranuclear palsy (PSP) and corticobasal degeneration. Because the extent of tau pathology in AD and other tauopathies closely correlates with the severity of neurodegeneration, synapse loss, and cognitive deficits, attempts to prevent, reduce or slow the development of tau pathology have become important therapeutic strategies for these diseases.
In previous preclinical studies, despite high, weekly or biweekly infusions of anti-tau monoclonal antibodies over three to six months, only very low levels of antibody reach the brain parenchyma from the systemic circulation resulting in modestly reduced tau pathology. This incomplete and modest reduction in tau pathology following treatment with very high and frequent systemic doses of these antibodies may pose therapeutic challenges in humans with various tauopathies.
To address these limitations, scientists at Voyager Therapeutics, working in collaboration with colleagues at Weill Cornell Medical College, carried out a study demonstrating that a single injection of an AAV vector to deliver an anti-tau antibody, PHF1, resulted in very high antibody expression in hippocampal and cortical neurons and reduced tau pathology by up to 90 percent in a robust tauopathy animal model as compared to 40-50 percent reductions in tau pathology reported by others in preclinical models using weekly, systemic infusions of anti-tau antibodies¹.
These preclinical studies provide proof of principle in a robust animal model that AAV vectors can be used to deliver monoclonal antibodies to misfolded pathological proteins like tau to increase brain antibody levels beyond what can be achieved by traditional passive immunization and to potentially enhance their therapeutic effects.
 Liu W, et al. (2016) Journal of Neuroscience 36 (49): 12425-12435