As Treatments Await FDA Ruling, Researchers Discover ‘Key Players’ in Early-Onset Parkinson’s Disease

Parkinson's Disease

While pharma and biotech researchers have been driving forward with therapies aimed at helping Parkinson’s disease patients, medical researchers from two Texas hospitals have identified “unexpected new key players” in the development of early-onset Parkinson’s disease, called Parkinsonism.

Researchers at Baylor College of Medicine and Texas Children’s Hospital said the key players are ceramides, a family of lipid molecules that are found within cell membranes. Ceramides, according to the researchers, “are the linchpin that connects previously identified cellular defects and genes independently known to be associated with Parkinson’s disease and suggest a mechanism that can lead to the condition.”

Hugo Bellen, professor of molecular and human genetics and neuroscience at Baylor College of Medicine and an investigator at the Howard Hughes Medical Institute, noted that there are numerous genes that have been associated with Parkinson’s. However, he said there has been little understanding in how the genes can lead to Parkinson’s. Bellen said the new research can “provide a connection between previously unconnected genes and cellular defects observed in these diseases.”

The findings, which were published in Cell Metabolism, could be used to help develop new treatments for the debilitating disease. Bellen said the research is important because it points to a potential mechanism that can lead to Parkinsonism and, perhaps, Parkinson’s disease. Research shows that the loss of phospholipase PLA2G6 or a reduction in Vps35 can cause a disruption of retromer function. That then creates “an insidious stress for the cell and is potentially at the root of these conditions,” Bellen said.

Bellen went on to say that if retromer function is disrupted, then neurons are not able to reuse some ceramide-derived lipids.

Parkinson’s disease is a neurodegenerative disorder. It affects dopaminergic neurons in a part of the brain. Disease symptoms typically develop slowly and could begin with slight tremors in the hands, slowness of movement or limb rigidity. Symptoms include tremor, slowed movement, rigid muscles, impaired posture and balance, loss of automatic movements and speech changes. Several risk factors for Parkinson’s have been identified, including glucocerebrosidase (GBA1) gene mutation. The GBA1 mutation is the most common of Parkinson’s disease mutations. In advanced Parkinson’s the putamen’s dopamine levels are depleted as is the enzyme aromatic L-amino acid decarboxylase (AADC). It accounts for about 10 percent of all Parkinson’s disease cases in the United States. The disease affects more than 10 million people worldwide. While there is no cure for Parkinson’s disease, there are medications that can slow its progression.

There are also numerous treatments in the pipeline of companies that could provide hope to so many patients. Recent movement in the space includes three potential treatments awaiting approval by the U.S. Food and Drug Administration (FDA). In February the FDA accepted Acorda Therapeutics' New Drug Application for Inbrija (CVT-301), a treatment, an investigational inhaled levodopa treatment for symptoms of OFF periods in people with Parkinson’s disease taking a carbidopa/levodopa regimen. People diagnosed with Parkinson’s often deal with times classified as “ON” and “OFF.” OFF periods are characterized by the reemergence of Parkinson’s symptoms. In OFF times patients experience periods of decreased mobility. Acorda data showed patients taking CVT-301 showed a statistically significant improvement in motor function. The FDA is expected to make a decision on Acorda’s medication by Oct. 5.

Also in March, Mass.-based Sunovion Pharmaceuticals submitted a New Drug Application to the FDA for apomorphine sublingual film to treat OFF episodes in Parkinson’s. Apomorphine sublingual film is a novel formulation of a dopamine agonist. It hits its Phase III primary endpoint of Change in Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III Motor Examination at 30 minutes after dosing at the 12-week visit during the Maintenance Treatment Phase. This week the FDA accepted an NDA for apomorphine sublingual film for the on-demand treatment of OFF episodes associated with Parkinson’s disease. Apomorphine sublingual film is being developed as a fast-acting medicine for the on-demand treatment of all types of motor OFF episodes, including morning OFF, unpredictable OFF and end-of-dose wearing OFF. While OFF episodes are experienced by 40 to 60 percent of all people living with PD there are limited on-demand treatment options available, Sunovion said in its announcement.

One month before the acceptance of the two NDAs, San Diego-based Neurocrine Biosciences said it intends to file an NDA for opicapone, its investigational Parkinson’s drug. Opicapone is a once-daily, peripherally-acting, highly-selective catechol-o-methyltransferase (COMT) inhibitor being developed as an adjunct therapy to preparations of levodopa/DOPA decarboxylase inhibitors for adult patients with Parkinson's disease and motor fluctuations.

In March Voyager Therapeutics released longer-term data from its Phase Ib gene therapy trial for Parkinson’s disease. VY-AADC, Voyager’s gene therapy, is believed to have the potential to provide improved motor function and cut patients’ need for oral levodopa and other dopaminergic medications. The longer-term data released by the company shows durable, dose-dependent and time-dependent improvements in the patients’ motor function after a one-time treatment. 

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