New drug candidate improves Parkinson's treatment in animal models

For many people with Parkinson's disease, the body stops moving the way it used to. A hand may tremble at rest. Muscles may stiffen. Walking can become slower and balance more uncertain. The most effective treatment remains L-dopa, also called levodopa, a medication that can dramatically improve movement and quality of life. But the relief often comes with a caveat: over time, the drug's benefits can become less reliable, and it can cause erratic, involuntary movements known as dyskinesia.

Now, researchers led by Sinopia Biosciences - a startup that grew out of University of California San Diego - have reported preclinical results that could help change that equation. In animal models of Parkinson's disease, their drug candidate, SB-0110, boosted L-dopa's benefits while reducing dyskinetic side effects.

The paper was published in Science Translational Medicine on July 15.

Virtually every Parkinson's patient takes levodopa. But patients face two major problems with the drug: the reappearance of Parkinson's symptoms and dyskinesia. There is no drug that can can be added to L-dopa to address both simultaneously in a robust manner, and that's what our drug candidate is doing."

UC San Diego alumnus Aarash Bordbar, chief executive officer, chief scientific officer and co-founder of Sinopia Biosciences

The need is growing. The World Health Organization estimates that more than 8.5 million people worldwide were living with Parkinson's disease in 2019, and that the disease's prevalence has doubled globally over the past 25 years. For many of those patients, the benefits of levodopa become harder to manage over time: after nine or more years of treatment, about 70% develop motor fluctuations - periods when symptoms return between doses - and about 90% develop dyskinesia.

Where computation meets biology

Bordbar ('08, '14) conducted his graduate studies in the UC San Diego laboratory of Bernhard Palsson, who is the Y.C. Fung Endowed Professor of Bioengineering at the Shu Chien-Gene Lay Department of Bioengineering (Jacobs School of Engineering), Qualcomm Institute affiliate and professor of pediatrics. There, Bordbar worked on building computational approaches to quickly develop novel experimental and clinical strategies from large biological datasets.

Bordbar and Palsson founded Sinopia Biosciences in 2014 to carry that approach into drug development, particularly the problem of avoiding and managing side effects. The company's strategy was to use tools for "biologically coherent data analysis" and connect findings back to biochemical mechanisms.

They chose to launch their new company at the UC San Diego Qualcomm Institute (QI) Innovation Space, where Sinopia Biosciences became one of the first tenants. For Bordbar, QI offered more than office space: it provided a collaborative environment where the Sinopia Biosciences team could easily consult with UC San Diego experts, including experts in intracellular signaling, computational chemistry, movement disorders and pharmacokinetics. The location also made it easy to hire UC San Diego interns.

Funded primarily by Small Business Innovation Research grants from the National Institutes of Health with additional support from the Michael J. Fox Foundation, Sinopia moved forward to identify candidates for drug development. One was SB-0110.

Putting the candidate to the test

In the new study, published in Science Translational Medicine, Bordbar and collaborators set out to test, in rodent and non-human primate models of Parkinson's disease, SB-0110's effects.

They had reasons to think the compound was worth investigating. Their computer analysis suggested SB-0110 could preserve the gene-activity patterns tied to L-dopa's benefits while counteracting the biological changes associated with dyskinesia.

The compound also had a practical advantage. It was based on an older heart drug with a history of use outside the United States, which gave the team some confidence about its safety. And its target, a brain signaling system called PKA-II, was already connected to movement and dopamine responses - exactly the biology they hoped to influence.

To conduct the study, Sinopia Biosciences collaborated with both private and academic partners, drawing on specialized UC San Diego expertise via Distinguished Professor of Pharmacology, Chemistry and Biochemistry Susan Taylor and Distinguished Professor of Pharmacology Emeritus J. Andrew McCammon, along with Parkinson's disease model specialists at Atuka and Motac Neuroscience.

When the results came in, they showed that the compound did more than produce a modest improvement. It significantly reduced dyskinesia and, in animals that were not getting full benefit from L-dopa alone, improved movement to a degree comparable to increasing the L-dopa dose, but without the usual worsening of involuntary movements.

Looking ahead

While pre-clinical results don't always translate seamlessly to humans, Bordbar said, "We're really excited that there's a high chance that this could work clinically."

For patients and families eager for new options, a new treatment is not around the corner, but it is moving in the right direction. Sinopia is completing the toxicology studies needed for regulatory review and hopes to begin first-in-human testing next year.

If all goes well, Bordbar estimates the drug could be available to patients in six to seven years.