Parkinson's Innovative Drug Gene Therapy Improves Dopamine Levels
December 12, 2016 Source: WuXi PharmaTech
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Yesterday, gene therapy company Voyager Therapeutics announced an ongoing phase 1b clinical trial for patients with advanced Parkinson's disease, with positive results at 6 months and 12 months of follow-up. The interim data from Groups 1 and 2 of the trial indicated that the new drug VY-AADC01 was well tolerated; the dose-increasing treatment delivered by precise MRI-guided delivery increased the putamen The degree of coverage, increased AADC enzymatic activity and enhanced response to levodopa ultimately resulted in clinically meaningful improvements in various measurement parameters of the patient's motor function. This is especially evident in the second group at higher doses. These good effects have been maintained in some patients during the 12-month follow-up period.
Parkinson's disease is a chronic neurodegenerative disease with approximately 700,000 patients in the United States and between 7 and 10 million patients worldwide. It is estimated that up to 15% of the Parkinson's disease patient population (approximately 1 million in the United States) has levodopa refractory or uncontrolled exercise fluctuations. Although the underlying cause of Parkinson's disease is unknown in most patients, the motor symptoms of the disease are derived from the loss of midbrain neurons that produce the neurotransmitter dopamine. Decreased levels of dopamine in this particular region of the brain lead to motor symptoms associated with Parkinson's disease, including tremors, slow or lost motion, stiffness, and postural instability. Motor symptoms in the late stages of the disease include falls, gait stiffness, speech and difficulty swallowing, and patients often require daily assistance from a caregiver.
There are currently no therapies that effectively slow or reverse the progression of Parkinson's disease. Levodopa is still the standard of care, and its beneficial effects on symptom control have been discovered more than 40 years ago. Patients usually use oral levodopa in the early stages of the disease to achieve good control, but become less responsive to the treatment as the disease progresses.
The degenerative motor symptoms of Parkinson's disease are mainly due to the death of dopamine neurons in the substantia nigra. The substantia nigra is part of the midbrain region that converts levodopa to dopamine, a single biochemical step catalyzed by aromatic L-amino acid decarboxylase (AADC). Neurons in the substantia nigra release dopamine into the putamen where the dopamine receptor is located. In advanced Parkinson's disease, neurons in the substantia nigra degenerate and AADC enzymes are significantly reduced in the putamen, which limits the brain's ability to convert levodopa to dopamine.
VY-AADC01 is Voyager's innovative gene therapy vector, which contains a gene encoding the AADC enzyme. It includes the adeno-associated virus-2 capsid and cytomegalovirus promoter to drive AADC gene expression, designed to deliver the AADC gene directly into the putamen where the dopamine receptor is located, thus bypassing the substantia nigra neurons and Neurons of the putamen express the AADC enzyme to efficiently convert levodopa to dopamine. Thus, the method principle of VY-AADC01 has the potential to continuously enhance the conversion potential of levodopa to dopamine and provide a clinically significant improvement in motor symptoms after a single administration.
This phase 1b, open-label trial enrolled more than 20 patients with advanced Parkinson's disease and disability movements, and received a single treatment with VY-AADC01. The primary objective of this trial was to assess the safety and surgical coverage of the escalating dose of VY-AADC01, a brain region associated with motor function in Parkinson's disease, in the nucleus of the brain. Secondary objectives of the trial included the use of [18 F]fluorodopa (or 18 F-DOPA) labeled positron emission tomography (PET) measurements to assess the expression and activity of AADC in the putamen. Furthermore, by controlled intravenous infusion of levodopa, the daily needs of levodopa and related drugs can be measured to determine changes in motor response to levodopa. Secondary goals for other motor function assessments include unified Parkinson's Disease Rating Scale (UPDRS) and Patient Completion (Hauser) log measurements. UPDRS is the standard clinical rating scale for Parkinson's disease.
“VY-AADC01 treatment promoted a 14-point or 44% improvement in the drug-free UPDRS-III index at 12 months of follow-up in Group 2, with a 9-point or 55% improvement in the UPDRS-III index,†Dr. Bernard Ravina, vice president of clinical development at Voyager Therapeutics, said, "It is very important that these improvements in motor function have been maintained in Group 2 for 12 months. This is a striking finding and is consistent with the mechanism of action of VY-AADC01. The dose escalation portion of the trial will continue, we plan to complete Group 3 (higher dose group) enrollment in early 2017, report 6 months of data for this cohort, and report Group 1 and Group 2 in mid-2017 Long-term data.
Xi'an XJeson Biotech Co., Ltd , https://www.xjesonbio.com