Developing life-changing gene therapies for fatal and debilitating diseases of the central nervous system
Voyager’s product pipeline includes programs for Parkinson’s disease, a monogenic form of amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia, Huntington’s disease, frontotemporal dementia, Alzheimer’s disease and severe, chronic pain. For each of these diseases, there is a dire need for new therapies. Depending on the disease, our gene therapies will use either gene replacement or gene knockdown techniques. By significantly increasing or decreasing production of relevant proteins at targeted sites within the central nervous system, the goal is to address the underlying biology of the disease and make a meaningful difference for patients.
About Parkinson’s Disease and VY-AADC01
Parkinson’s disease is a chronic, progressive and debilitating neurodegenerative disease that affects approximately 700,000 people in the U.S.1 and seven to 10 million people worldwide2. It is estimated that up to 15% of the prevalent population with Parkinson’s disease, or approximately 100,000 patients in the U.S., have motor fluctuations that are refractory, or not well-controlled, with levodopa. While the underlying cause of Parkinson's disease in most patients is unknown, the motor symptoms of the disease arise from a loss of neurons in the midbrain that produce the neurotransmitter dopamine. Declining levels of dopamine in this particular region of the brain leads to the motor symptoms associated with Parkinson’s disease including tremors, slow movement or loss of movement, rigidity, and postural instability. Motor symptoms during the advanced stages of the disease include falling, gait freezing, and difficulty with speech and swallowing, with patients often requiring the daily assistance of a caregiver.
There are currently no therapies that effectively slow or reverse the progression of Parkinson’s disease. Levodopa remains the standard of care treatment, with its beneficial effects on symptom control having been discovered over 40 years ago3. Patients are generally well-controlled with oral levodopa in the early stages of the disease, but become less responsive to treatment as the disease progresses. Patients experience longer periods of reduced mobility and stiffness termed off-time, or the time when medication is no longer providing benefit, and shorter periods of on-time when their medication is effective.
The progressive motor symptoms of Parkinson’s disease are largely due to the death of dopamine neurons in the substantia nigra, a part of the midbrain that converts levodopa to dopamine, in a single step catalyzed by the aromatic L-amino acid decarboxylase (AADC) enzyme. Neurons in the substantia nigra release dopamine into the putamen where the receptors for dopamine reside. In advanced Parkinson’s disease, neurons in the substantia nigra degenerate and the enzyme AADC is markedly reduced in the putamen, which limits the brain’s ability to convert oral levodopa to dopamine4. The neurons in the putamen do not degenerate in Parkinson’s disease5,6. VY-AADC01, comprised of the adeno-associated virus-2 capsid and a cytomegalovirus promoter to drive AADC transgene expression, is designed to deliver the AADC gene directly into the putamen where the 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-AADC01, therefore, has the potential to durably enhance the conversion of levodopa to dopamine and provide clinically meaningful improvements in motor symptoms following a single administration.
About the Phase 1b trial with VY-AADC01
Voyager is currently conducting an ongoing Phase 1b trial in patients with advanced Parkinson’s disease. Additional details about the Phase 1b study can be found using the following link: https://clinicaltrials.gov/
The Phase 1b, open-label trial includes up to 20 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 surgical coverage of ascending doses of VY-AADC01 in the putamen, a region of the brain associated with motor function in Parkinson’s disease. The secondary objectives of the trial include the assessment of AADC expression and activity in the putamen measured by positron emission tomography (PET) using [18F] fluorodopa (or 18F-DOPA). In addition, changes in motor responses to levodopa are measured by a controlled intravenous infusion of levodopa and by measuring daily requirements for levodopa and related medications. Other secondary objectives include assessment of motor function as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) and a patient-completed (Hauser) diary.
The UPDRS is a standard clinical rating scale for Parkinson’s disease. Part III of this scale measures motor function by physician examination. The UPDRS is conducted when patients are taking their Parkinson’s disease medications (referred to as “on” medication) and when patients are not taking their Parkinson’s disease medications (referred to as “off” medication). In the patient-completed diary, patients record their motor response over the course of several days as on-time, or time when they have good mobility with or without non-troublesome dyskinesia, off-time when they have poor mobility, and on-time with troublesome dyskinesia when they have uncontrolled movements.
In early December, Voyager announced positive interim results from the ongoing Phase 1b trial. VY-AADC01 dose-dependently improved measures of motor function and enhanced response to levodopa at six and twelve months; administration of VY-AADC01 was well-tolerated. The interim data from Cohorts 1 and 2 of this ongoing trial demonstrated that accurate MRI-guided delivery of escalating doses of VY-AADC01 were well tolerated and resulted in increased coverage of the putamen, increased AADC enzyme activity, enhanced response to levodopa, and dose-related, clinically meaningful improvements in various measures of patients’ motor function.
 Willis et al, Neuroepidemiology.2010;34:143–
 Poewe W, et al, Clinical Interventions in Aging.2010;5:229-238.
 Lloyd, J Pharmacol Exp Ther. 1975;195:453-464, Nagatsu, J Neural Transm Suppl.2007
 Cold Spring Harb Perspect Med 2012;2:a009258
 Braak et al, Cell Tissue Res.2004;318:121-134
ALS is a fatal neurodegenerative disease that leads to muscle weakness, loss of mobility, impaired speech, and difficulty breathing and swallowing. ALS patients live an average of three years after initial symptoms appear, and it is estimated that as many as 30,000 patients in the United States and 450,000 worldwide are living with the disease. Familial ALS accounts for 10 percent of ALS cases, and an estimated 20 percent of familial ALS is caused by toxic gain of function mutations in the SOD1 gene.
By knocking down SOD1, our goal is to reduce the level of mutated SOD1 protein in the CNS and have a meaningful impact on the progression of the disease.
Friedreich's ataxia is the most common hereditary ataxia, with approximately 8,000 patients living with the disease in the United States and Europe. Friedreich's ataxia patients have a genetic mutation in the FXN gene, which limits the production of the protein frataxin, causing a variety of debilitating symptoms and complications, including muscle weakness, impaired vision, hearing and speech, aggressive scoliosis, diabetes, heart disease and difficulty breathing.
By delivering a functional version of the FXN gene to targeted cells in the CNS, our goal is to increase levels of frataxin and have a meaningful impact on the progression of the disease.
Huntington's disease is an inherited neurodegenerative disorder that results in the progressive decline in motor and cognitive function and a range of behavioral disturbances. Toxic gain-of-function mutations in the HTT gene affect an estimated 70,000 Huntington's disease patients in the U.S. and Europe.
By knocking down HTT, our goal is to reduce the level of mutated HTT protein in the CNS and have a meaningful impact on the progression of the disease.
Pathological and aggregated tau protein is believed to play a key role in the severe CNS disorders frontotemporal dementia (FTD) and Alzheimer’s disease. FTD affects approximately 45,000 patients and Alzheimer’s disease affects over 5 million patients in the U.S.
Our goal is to treat FTD, Alzheimer’s disease, and potentially other tauopathies with an AAV vectorized version of an anti-tau monoclonal antibody delivered to the CNS.
Severe, chronic pain affects millions of people worldwide. Nav1.7 is a sodium ion channel that is required for pain transmission. By suppressing Nav1.7 selectively in sensory neurons, our goal is to treat certain forms of severe, chronic pain with a single administration of AAV gene therapy while avoiding the side effects and addictive potential associated with many current pain drugs.