Antioxidant Urate Fails to Slow Early Disease Progression

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by Steve Bryson, PhD |

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The antioxidant urate failed to slow Parkinson’s disease progression in newly diagnosed patients over two years, according to data from a Phase 3 clinical trial.

“While our study did not rule out a protective effect of urate in Parkinson’s, it clearly showed that increasing urate did not slow disease progression based on clinical assessments and serial bran scan biomarkers of neurodegeneration,” Michael Schwarzschild, MD, PhD, said in a MGH press release. Schwarzschild is a neurologist at Massachusetts General Hospital (MGH) in Boston, and senior author of the study.

The findings were published in the Journal of the American Medical Association, in the study “Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression.”

Oxidative stress is the imbalance between the production and removal of toxic oxygen reactive species that are harmful to cells and are thought to play an important role in neurodegenerative diseases such as Parkinson’s.

Urate is an end product of human metabolism and is the primary antioxidant circulating in the bloodstream. It has been shown to protect nerves in cellular and animal models of Parkinson’s, and at higher concentrations urate was associated with the slower progression of motor and non-motor disability.

These findings supported the launch of the SURE-PD Phase 2 study (NCT00833690) that evaluated the oral supplement inosine — the metabolic precursor to urate — in 75 people with early Parkinson’s. The treatment effectively raised urate levels in the body, showed a dose-dependent increase in antioxidant capacity, and was associated with favorable clinical outcomes.

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“The convergence of epidemiological, biological, and clinical data from past research made a compelling argument that elevating urate, the main antioxidant circulating in the blood, could protect against the oxidative damage thought to play a role in Parkinson’s disease,” Schwarzschild said.

The multicenter SURE-PD3 Phase 3 clinical trial (NCT02642393) was designed to further evaluate urate in a larger population of 298 people recently diagnosed with Parkinson’s.

Patients were eligible if they had urate levels in the bloodstream below the median expected level in the general population (less than 5.8 mg per deciliter, mg/dL), as low urate has been associated with faster disability progression.

Participants were assigned randomly to receive up to two 500 mg oral capsules of inosine, three times daily, for two years, or a placebo. Researchers adjusted inosine doses to maintain a blood urate level between 7.1 and 8.0 mg/dL, above the median population level (5.8 mg/dL).

The study’s primary goal was a change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), a composite scale of patient- and clinician-reported outcomes that measures the rate of disease progression; higher scores reflect greater disability (0–236 points). Based on study design, a reduction in the two-year expected increase in MDS-UPDRS by 6.3 points was considered clinically meaningful.

Along with adverse events to monitor safety, secondary measures included urate levels in the blood as well as assessments of disability, quality of life, cognition, mood, bodily function, and a biomarker of nerve cell health.

A total of 273 (92%) of the randomized participants, with a mean age of 63 years, of whom 49% were women, completed the study. Within three months, the urate in the bloodstream increased by 44% from a mean pre-treatment level of 4.6 mg/dL to the targeting levels.

However, results revealed the rate of MDS-UPDRS change did not significantly differ between patients treated with inosine supplement and those given placebo — 11.1 vs. 9.9 points per year.

There also were no significant differences between treatment and placebo in disease progression, or changes in patient-reported sub-scores in secondary clinical outcomes.

By one year, a similar proportion of patients who developed symptomatic disability required medication to replace missing dopamine — the signaling molecule lacking in Parkinson’s patients due to the loss of specific nerve cells in the brain. In the inosine group, 59% required this treatment compared to 56% in the placebo group.

The composite quality-of-life scores did not significantly differ between treatment or placebo groups. The biomarker for nerve cell health also showed no significant differences between inosine and placebo participants. No sex-specific differences were seen.

Overall, adverse events during treatment were comparable between the two groups. However, fewer participants treated with inosine experienced serious adverse events (12% vs. 17% in the placebo group).

Participants taking inosine, however, had an increased rate of kidney stones. Of note, high concentrations of urate have been associated with the development of kidney stones.

Although inosine was well-tolerated over several months, its tolerability declined over time, as 93% of the inosine group were tolerant to the therapy at 12 weeks (three months) and 76% by one year. In comparison, 99% of those who received a placebo were tolerant by three months and 91% at one year.

Based on the results, the team concluded: “Among patients recently diagnosed as having [Parkinson’s disease], treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early [Parkinson’s disease].”

Nonetheless, Schwarzschild noted that “the findings were very helpful in providing a reality check that now allows the field to move on to other therapeutic approaches.”