CHARLOTTESVILLE, VA (CVILLE RIGHT NOW) – The U.S. Food and Drug Administration has approved a groundbreaking drug developed by UVA Health researchers to treat Parkinson’s Disease, according to a UVA Health release.

The drug tavapadon, now branded Juvmo, was pioneered by University of Virginia School of Medicine Professor of Pharmacology and Neuroscience Richard B. Mailman, PhD. UVA Health’s Xuemei Huang, MD, PhD, chair of the Department of Neurology, also played a vital role in the first successful clinical trial with a drug of this class. 

“The current standard of care for the last sixty years has been the drug levodopa, and it works very, very well because it’s converted in the body and the brain to dopamine and this is what’s missing in Parkinson’s disease is the depth of dopamine nerve cells,” Mailman told Cville Right Now. “The problem is the cells that are degenerating in Parkinson’s are also the ones that are needed to convert that drug into dopamine.”

That means, according to Mailman, the more these nerve calls degenerate, the more levodopa needs to be administered during the day.

“What we investigated many years ago was exactly which of the targets for dopamine is really important in Parkinson’s and the idea we came up with was different than the field believed and we began focusing on a drug to target only one of the dopamine receptors we thought was important and tavapadon was the endpoint after decades from us and several pharmaceutical companies of a drug that does that,” said Mailman.

Juvmo, however, can selectively activate D1 dopamine receptors in the brain, providing relief from some of the disease’s motor symptoms, according to the UVA Health release.

“We figured out the specific mechanism that made levodopa effective and developed the first drug that could turn on that mechanism,” Mailman said. “Juvmo itself was made by a brilliant chemist and team who made a similar drug that could be given as a pill only once or twice a day.” 

Early drugs in the class, called D1 agonists, could only be injected, but Juvmo is taken as a pill once per day. The current gold-standard Parkinson’s medication, levodopa, requires multiple doses per day at increasingly frequent intervals as the disease progresses.

“More than 11 million people around the world live with Parkinson’s, one of the fastest-growing age-related neurological conditions,” according to UVA Health. “Parkinson’s causes tremor – shaking – as well as stiffness, slowness and difficulty moving. It increases the risk of falls and can come with symptoms such as fatigue, insomnia, memory loss and impaired ability to concentrate.” 

About 70% of patients taking levodopa need to have their dose increased within the first year. But 93% of clinical trial participants receiving Juvmo had not increased their dose of levodopa after 85 weeks, while 94% with early Parkinson’s had not needed to start levodopa.

Mailman has spent decades on the research that led to Juvmo. His big breakthrough came in 1984, when he realized all the existing “dopamine agonists” targeted a specific subset of receptors called “D2-like.” His experiments suggested that the other type of dopamine receptor (“D1-like”) actually was responsible for most of levodopa’s beneficial effects. He also suspected targeting D1-like receptors would not have many of the side effects of the approved dopamine-agonist drugs. 

UVA Health’s Xuemei Huang, MD, PhD, chair of the Department of Neurology, also played a vital role in the first successful clinical trial with a drug of this class. He joined the research team in the late 1990s, designing a clinical study that showed that D1 agonists could be administered in a way that avoided blood pressure problems that had plagued previous attempts.

Mailman over the decades has been on an odyssey, at one point having his idea almost snuffed out when an earlier drug targeting these receptors actually didn’t work because it was first administered along with another drug to compliment the dopamine effect but in reality competed with it because it was too weak.

“It made the patients worse,” he said. “And everybody thought this receptor is no use. But we realized from a variety of other (clues) that that was a misinterpretation and if you had a drug at a higher percentage of activity and you used it alone, it could be very, very effective.”

They did develop a drug that, by 1991, that worked for humans, but was short-acting and could only be given by injection. There was a lack of interest from people who invest in drug discovery or startup companies because it could not be taken orally.

Mailman persisted despite an overall feeling within the industry that the Parkinson’s market was too small to be worth the investment. A key breakthrough was finding a team at Pfizer led by David L. Gray, PhD, who was convinced by Mailman’s data. Their efforts led to the success of Juvmo.

Juvmo will be marketed by the drug company AbbVie and is expected to become available this month.

 “It has been frustrating to think that we had a breakthrough for Parkinson’s patients and could not get others to see this vision. A key early collaborator for his work was Professor Steven Wyrick, who was diagnosed with Parkinson’s but never lived to try a drug in which he believed,” Mailman said. “It would have made the long journey worthwhile if this helps begin a new era of Parkinson’s treatment.”

Mailman and Huang continue to research other possible applications for tavapadon and other D1 drugs beyond the scope now approved by the FDA.