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Voyager Therapeutics Initiates Third Cohort in Ongoing Phase 1b Clinical Trial of VY-AADC01 in Advanced Parkinson’s Disease
“We are pleased with the progress of this ongoing Phase 1b trial and the initiation of the planned third cohort in this trial of up to 20 patients,” said
About the Phase 1b Study of VY-AADC01 in Advanced Parkinson’s Disease
Patients enrolled in Cohorts 1 and 2 received a single administration of VY-AADC01 at a total dose up to of 7.5 × 1011 vector genomes (vg) and 1.5 × 1012 vg, respectively. Patients enrolling in Cohort 3 (up to five patients) will receive up to a three-fold higher total dose (4.5×1012 vg) than Cohort 2. A final, additional cohort (Cohort 4) could increase the total dose six-fold higher than Cohort 2.
The primary objective of the study is to assess the safety at ascending dose levels of VY-AADC01. Secondary objectives include an assessment of the surgical coverage of the putamen and the assessment of aromatic L-amino acid decarboxylase (AADC) expression and activity in the putamen before and after VY-AADC01 treatment using 18-fluorodopa and positron emission tomography (PET). Changes in patients’ sensitivity to levodopa treatment will be measured by assessing their motor function in response to an intravenous infusion of levodopa, their doses of levodopa, and related medications pre- versus post-treatment with VY-AADC01. Clinical motor symptoms including patients’ off-time, or the time when medication is no longer providing benefit with regard to mobility, slowness, and stiffness, will be measured using a validated patient diary developed to assess Parkinson’s disease motor symptoms. Additional tests will measure patients’ motor symptoms including use of the Unified Parkinson’s Disease Rating Scale (UPDRS), as well as tests of cognitive function, mood, and quality of life. These primary and secondary objectives will be measured systematically from baseline over a 36-month period post-treatment, with PET scans and intravenous levodopa infusions at six months after treatment. Additional details about the Phase 1b study can be found using the following link: https://clinicaltrials.gov/ct2/show/NCT01973543?term=AADC&rank=2
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. and seven to 10 million people worldwide. 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 disease arises 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 ago. 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, the neurons in the substantia nigra degenerate and the enzyme AADC is markedly reduced, which limits the brain’s ability to convert oral levodopa to dopamine. The neurons in the putamen do not degenerate in Parkinson’s disease,. VY-AADC01, comprised of the adeno-associated virus-2 capsid and a cytomegalovirus promotor 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.
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