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. While the underlying cause of Parkinson’s
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. While the underlying cause of Parkinson’s disease in most patients is unknown, the motor symptoms caused by the disease arise from a loss of neurons in the midbrain that produce the neurotransmitter dopamine. Declining levels of dopamine in this region of the brain lead to 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, which was discovered more than 40 years ago3, remains the standard of care treatment, and while patients are generally well-controlled with oral levodopa in the early stages of the disease, they become less responsive to treatment as the disease progresses. Patients experience longer periods of reduced mobility and stiffness, which is referred to as “off-time” (the time when medication is no longer providing benefit), and shorter periods of “on-time” when their medication is effective. Up to 15 percent of people with Parkinson’s disease, or approximately 100,000 U.S. patients, have motor fluctuations that are refractory, or not well-controlled, with levodopa.
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 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. 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/ct2/show/NCT01973543?term=AADC&rank=2.
The Phase 1b, open-label trial will treat up to 20 patients with advanced Parkinson’s disease and disabling motor fluctuations 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. Secondary objectives 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 December 2016, Voyager announced positive interim results from the ongoing Phase 1b trial. Results showed VY-AADC01:
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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
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.
VY-SOD101 is Voyager’s 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. VY-SOD101 is 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, VY-SOD101 has the potential to durably reduce the levels of toxic mutant SOD1 protein in the CNS to slow the progression of disease. Preclinical pharmacology and toxicology studies are now underway to support filing of an investigational new drug application for VY-SOD101 during the fourth quarter of 2017.
When selecting an AAV gene therapy candidate for a particular disease, Voyager considers a number of features of the overall candidate profile including optimization of the AAV vector capsid, the transgene and the dosing paradigm. The VY-SOD101 clinical candidate was selected after screening a series of capsids, microRNA expression cassettes and encoded payloads. Multiple rounds of optimization resulted in a candidate that is potent and selective. In addition, many construct configurations were evaluated toward the identification of one that would provide excellent yield and genome integrity for manufacturing scale-up in Voyager’s baculovirus AAV manufacturing system in insect-derived cells. Preclinical data in large mammals demonstrated that a single IT administration resulted in robust knockdown of SOD1 in motor neurons.
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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
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 approach for this program that has been used for VY-AADC01 delivery to the brain, allowing us to leverage prior clinical experience.
Our collaborators at Sanofi-Genzyme completed significant preclinical work focused on AAV gene therapy for Huntington’s disease. Sanofi-Genzyme’s preclinical studies in a mouse model of Huntington’s disease demonstrated the safety and efficacy of AAV gene therapy targeting the knockdown of the HTT gene in the CNS. Using an AAV vector delivered directly to the CNS, HTT gene expression was observed to be reduced by more than 50 percent, on average, in the treatment group as compared to the control group. No signs of toxicity were reported. In addition, significant functional benefit was observed in the treatment group, as measured by the rotarod test to assess motor function, and the Porsolt Swim Test to measure depressive behavior in mice.
Sanofi-Genzyme’s Huntington’s disease gene therapy program was combined with our efforts in connection with our collaboration agreement in February 2015. We are screening a series of microRNA expression cassettes and encoded payloads and multiple rounds of optimization have resulted in candidates that are potent and selective for knocking down HTT. In addition, many construct configurations were evaluated toward identifying one that would provide excellent yield and genome integrity for manufacturing scale-up in our baculovirus AAV manufacturing system in insect-derived cells. Preclinical data in large mammals have demonstrated that a single intrastriatal administration results in robust knockdown of HTT in the striatum.
Through our product engine efforts, we constructed and have screened multiple RNAi sequences within a number of miRNA cassettes. Multiple vector genome configurations have been compared as well. We are conducting the necessary experiments to evaluate these potential lead candidates based upon criteria that include safety, selectivity, potency and efficiency and precision of microRNA processing. This work leverages the learnings from the VY-SOD101 program, as we anticipate that the miRNA cassettes and vector genome configurations that we designed for that program will be applicable to all of our RNAi programs, including VY-HTT01.
We are also in the process of confirming in non-human primate studies that the current lead capsid is optimal for the VY-HTT01 program. The criteria include safety, overall level of transgene expression achieved, distribution of transgene expression, and the specific cell types transduced.
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.
Once we select a clinical candidate and dosing paradigm for this program, we plan to complete a number of preclinical studies to evaluate the safety, biodistribution, pharmacology and efficacy of our lead candidate, including studies in relevant animal models and IND-enabling studies. 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
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. We are in the process of identifying a lead candidate that will comprise an optimal capsid, promoter, and FXN transgene. We are completing several AAV capsid screening experiments to identify capsids that effectively distribute to disease target tissues in a desired manner. We are comparing capsids in non-human primates following intrathecal and intravenous injection, and evaluating these capsids based upon multiple criteria including safety, overall level of transgene expression achieved, distribution of transgene expression and the specific cell types transduced. In addition, we are optimizing the promoter and specific characteristics of the FXN transgene that we expect to use for VY-FXN01. To evaluate the therapeutic potential of our vectors, we have initiated testing in a new genetic mouse model of Friedreich’s ataxia. We are also focused on better understanding the clinical course of Friedreich’s ataxia and identifying potential clinical endpoints for future clinical trials.
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
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. With the VY-TAU01 program, using a variety of proprietary AAV capsids and routes of administrations, scientists at Voyager are optimizing the delivery of monoclonal antibodies directed against tau and other misfolded proteins to potentially treat a variety of neurodegenerative disorders.
 Liu W, et al. (2016) Journal of Neuroscience 36 (49): 12425-12435
Nav1.7 is a sodium ion channel that is required for transmission of pain signals to the CNS. We believe that an AAV gene therapy approach targeting the knockdown of Nav1.7
Nav1.7 is a sodium ion channel that is required for transmission of pain signals to the CNS. We believe that an AAV gene therapy approach targeting the knockdown of Nav1.7 in sensory neurons could be an effective treatment for certain forms of severe, chronic pain. A major challenge for the successful development of small molecules and antibodies targeting Nav1.7 has been the selective inhibition of Nav1.7 over closely related sodium channels such as Nav1.5 which are important for cardiac function. MicroRNAs, which work by harnessing the RNA interference pathway, can achieve a high level of specificity for their messenger RNA targets, and can inhibit Nav1.7 selectively over other sodium channel subtypes. Such an approach could avoid the dose-limiting side effects associated with the non-selective profile of many current drugs used to treat severe, chronic pain, and also achieve a durable clinical benefit following a single administration of the therapy. VY-NAV01 leverages our extensive experience designing novel microRNA knockdown cassettes and delivering them using AAV, an approach that we are using for our ALS (VY-SOD101) and Huntington’s disease (VY-HTT01) programs.
We are in the process of conducting proof-of-concept studies to establish the level of Nav1.7 knockdown needed to relieve pain in animal models. We will then identify a lead candidate which will comprise an optimal capsid, promoter, and microRNA targeting Nav1.7. We are completing several AAV capsid screening experiments to identify capsids that effectively distribute to pain sensory neurons in a desired manner. We are comparing capsids in non-human primates following intrathecal and intravenous injection, and evaluating these capsids based upon multiple criteria including safety, overall level of transgene expression achieved, distribution of transgene expression and the specific cell types transduced.