For decades, treatment of Parkinson’s disease has centered on replacing dopamine, the neurotransmitter whose decline drives the disease’s hallmark motor symptoms. But while therapies such as levodopa can temporarily restore movement, they do little to address the underlying neurodegeneration, and often introduce complications of their own.
BioVie Inc (NASDAQ:BIVI, NASDAQ:BIVIW) is now advancing a different hypothesis: that Parkinson’s may be driven as much by inflammation and insulin resistance in the brain as by dopamine loss itself. Its lead drug candidate, bezisterim (NE3107), is designed to target both.
Rethinking Parkinson’s: Beyond dopamine
Parkinson’s disease affects roughly one million people in the United States, and its prevalence is expected to rise with aging populations. Yet treatment has changed little in more than 50 years.
BioVie’s approach reframes the disease at a cellular level. According to CEO Cuong Do, insulin resistance may sit at the center of multiple damaging processes in the brain.
“We believe it is insulin resistance that drives neurodegeneration and neuronal dysfunction,” Do told Proactive. “When insulin resistance occurs, it interferes with insulin’s normal signaling function in virtually every cell, including—very importantly—the brain.”
This disruption has far-reaching consequences. Impaired insulin signaling reduces glucose metabolism, depriving neurons of energy and compromising their survival. It also affects dopamine production and regulation, contributing directly to the motor symptoms associated with Parkinson’s.
“Insulin resistance is harmful to cells, period. It impairs the production of dopamine and disrupts the ability to transmit and reabsorb it,” Do said.
Beyond dopamine, insulin resistance is also linked to the buildup of alpha-synuclein, a misfolded protein that aggregates in the brains of Parkinson’s patients. It contributes to mitochondrial dysfunction and oxidative stress, both key drivers of neuronal damage.
Taken together, these pathways suggest that dopamine loss may be a downstream effect, rather than the root cause.
“This is a different way of looking at Parkinson’s,” Do said.
The limits of levodopa
Despite its effectiveness, levodopa presents significant challenges for patients. Its short half-life requires frequent dosing, creating disruptions to daily life and leaving patients vulnerable during “off” periods when symptoms return.
“Levodopa is a highly effective drug for helping restore muscle control in Parkinson’s patients. However, it has several significant limitations,” Do said. “One is its short half-life… patients must take it multiple times a day—often three, four, or even five doses.”
These fluctuations can be particularly difficult overnight, when the drug wears off and patients may wake up unable to move. Over time, levodopa’s effects wane and thus higher doses are needed to achieve muscle control. At higher doses, the drug can lead to levodopa-induced dyskinesia, causing involuntary movements that can be as debilitating as the disease itself.
Managing Parkinson’s becomes a delicate balance between maintaining mobility and limiting side effects without ever slowing the progression of the disease.
Bezisterim: Targeting inflammation and insulin resistance
Bezisterim is an oral small molecule designed to cross the blood-brain barrier, reduce inflammation, and improve insulin sensitivity without suppressing the immune system. By targeting TNF-alpha–mediated inflammation and reversing insulin resistance, the drug aims to protect neurons and preserve brain function.
“The rationale is that bezisterim targets inflammation that causes insulin resistance,” Do said. “By reversing insulin resistance, we hope to prevent the cellular damage it causes, thereby preserving neuronal function and extending the survival of brain cells.”
In earlier Phase 2 studies, bezisterim was tested in combination with levodopa. The results showed improved motor control and better “morning on” function compared with levodopa alone—an encouraging signal that the drug may enhance standard therapy.
“We evaluated bezisterim in patients in combination with levodopa… it led to improved muscle control,” Do said.
Those findings laid the groundwork for the company’s current strategy: testing bezisterim as a standalone therapy earlier in the disease course.
The SUNRISE-PD trial
BioVie has now completed enrollment in its 60-patient Phase 2 SUNRISE-PD trial, which is evaluating bezisterim in patients diagnosed within the past four years who have not yet begun levodopa treatment.
The study is designed to assess both motor and non-motor symptoms, using measures such as the Unified Parkinson’s Disease Rating Scale (UPDRS), asleep and various biomarkers.
“The clinically meaningful outcome we are targeting is the ability to help treated patients maintain or improve their UPDRS scores—specifically Parts II and III, as well as various nonmotor endpoints,” Do said.
Unlike traditional trials, SUNRISE-PD uses a hybrid, decentralized model, allowing patients to participate either from home or at clinical sites. The approach is intended to reduce barriers related to mobility and access, while improving recruitment and retention.
The trial also incorporates biomarker analysis to support future development.
“We are also assessing a range of biomarkers, which will provide the data needed to inform study powering and support the design and execution of a Phase 3 trial,” Do said.
What comes next
Topline results from SUNRISE-PD are expected in the first half of 2026, with the company targeting a readout around mid-year.
If successful, the study could mark a turning point not only for BioVie, but for Parkinson’s treatment more broadly.
“In the Phase 2 trial, we aim to measure the magnitude of therapeutic impact – to see how much better patients treated with bezisterim perform on motor and nonmotor endpoints compared with those receiving a placebo,” Do said. “The Phase 2 results will allow to design the Phase 3 trial – particularly the size of the trial – where we aim to show symptomatic relief as well as delaying disease progression.”
The ultimate goal is to demonstrate, for the first time, that a therapy can slow the progression of Parkinson’s disease.
“If we're successful, this may be the first drug to demonstrate that we can delay the progression of disease,” Do said. “This may be the first new therapeutic for Parkinson's in over five decades.”
BioVie envisions bezisterim as a first-line therapy that could be introduced early, potentially delaying the need for levodopa by years.
“When developed and available on the market, we envision a world in which Parkinson’s patients are treated differently,” Do said. “We see bezisterim becoming a first-line treatment.”
As an oral capsule taken twice daily, potentially even a once-daily version, the drug could also simplify treatment regimens compared with the frequent dosing required for levodopa.
For now, the focus remains on the upcoming data. But if BioVie’s hypothesis holds, it could redefine how Parkinson’s is understood and treated, shifting the focus from managing symptoms to addressing the disease at its source.