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October 27th, 2014

Oral Inosine a Potential Disease-Modifying Therapy for Parkinson’s

Oral Inosine a Potential Disease-Modifying Therapy for Parkinson's

December 24, 2013

NEW YORK - In a study of patients with early Parkinson's disease (PD), oral inosine treatment raised serum and cerebrospinal fluid (CSF) urate levels, demonstrated nonfutility for slowing disability and was generally safe and well tolerated.

Results of the Safety of Urate Elevation in PD (SURE-PD) study "support the development of a more definitive trial to investigate the ability of inosine treatment to slow clinical progression among persons with early PD who have lower urate," researchers say.

In JAMA Neurology online December 23, they note that the urate precursor inosine has been shown to be neuroprotective in rodent models of PD. In prospectively followed cohorts of healthy people, higher blood urate levels have correlated with lower PD risk. In patients with early PD, higher serum or CSF urate levels at baseline have predicted slower rates of clinical or radiographic progression.

The SURE-PD trial had the "broader purpose of determining whether and how inosine should be pursued as a urate-elevating strategy in any subsequent phase 3 trials of its disease-modifying potential in PD," Dr. Michael Schwarzschild of the MassGeneral Institute for Neurodegenerative Disease in Boston and the SURE-PD team note in their paper.

Study participants included 75 men and women with early PD not yet requiring symptomatic treatment and a serum urate concentration less than the population median of 6 mg/dL.

They were randomized to placebo or oral inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation and followed for up to 25 months (median, 18 months).

The researchers say inosine treatment was clinically safe and well tolerated at doses that elevated serum urate concentrations from 4.5 mg/dL on average to 6 to 7 and 7 to 8 mg/dL in the mild and moderate dosing groups, respectively. "In observational studies, these higher but still relatively normal urate levels were predictive of favorable outcomes in PD," they point out.

Serum urate rose by 2.3 and 3.0 mg/dL in the two inosine groups (p<0.001 for each) compared with placebo, and the CSF urate level was greater in both inosine groups (p=0.006 and p<0.001, respectively).

The investigators say there was no increase in the risk of serious adverse events associated with urate elevation in this population, which, to their knowledge, is the oldest to date (mean age 62 years) to be exposed to long-term urate-elevating treatment.

"Our data strengthen the evidence against a hypertensive effect of urate elevation by inosine and do not support the contention that chronically elevated urate contributes to the hypertensive, hyperglycemic, dyslipidemic, and obesity components of metabolic syndrome, or to other cardiovascular disease associated with higher urate level," they say.

"Although overall safety of urate-elevating inosine treatment of 50 participants for an average of 1.5 years appeared at least as good as that of control participants, a small or delayed increase in risk of SAEs related to the cardiovascular system remains a possibility," they note.

In contrast, the risk of urate-related crystallopathies appears to increase with increasing urate concentration in blood or urine. No patient developed gout during the study, but three taking inosine developed symptomatic urolithiasis. "Exploratory data suggest that monitoring for both uric acid crystal formation and urine acidity in addition to close monitoring of serum urate level may further reduce the risk of urolithiasis related to inosine treatment," the investigators say.

Treatment was tolerated by 95% of participants at six months, and no participant withdrew because of an adverse event.

Secondary analyses suggest a disease-modifying benefit of inosine is possible, the researchers say. In a UPDRS-based futility analysis, inosine dosed to mildly and moderately elevate urate demonstrated nonfutility for slowing disability. Total UPDRS scores worsened at an average rate of 1.7 points per year for participants in the moderate elevation treatment group compared with 4.7 points per year for those in the placebo group, the researchers report.

In an email to Reuters Health, Dr. Schwarzschild said the study "exceeded" their expectations "because it provided very clear answers to our primary question for this early stage trial, namely whether inosine could safely produce a well-tolerated elevation of urate levels in blood and brain in this disease."

"Based on these strongly positive answers for safety and 'proof-of-principle' we now have a solid foundation on which to build a next-stage trial for effectiveness of slowing the clinical progression of Parkinson's," he said.

A larger more definitive clinical trial designed to directly test whether urate-elevating treatment with inosine can protect people with Parkinson's from worsening is planned, Dr. Schwarzschild told Reuters Health.

"Just as the Michael J. Fox Foundation stepped up to fund SURE-PD, it will take another major investment to conduct a definitive trial at this next stage. We are currently preparing an application to NIH to this end. Note that because inosine is a natural substance in our bodies and no company is supporting its development for Parkinson's we are seeking philanthropic and public funding to investigate its potential to become the first disease-modifying therapy for the disease," Dr. Schwarzschild said.

SOURCE: http://bit.ly/1cP0o7J

JAMA Neurol 2013.

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