Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression

Abstract

IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.OBJECTIVE To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.DESIGN, PARTICIPANTS, AND SETTING Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.INTERVENTIONS Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. MAIN OUTCOMES AND MEASURESThe primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. RESULTSBased on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine 11.1 [95% CI,] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, −0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).CONCLUSIONS AND RELEVANCE Among patients recently diagnosed as having PD, 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 PD.

Serum Uric Acid Levels in Parkinson’s Disease: A Cross-Sectional Electronic Medical Record Database Study from a Tertiary Referral Centre in Romania

“…A randomized, double-blinded, placebo-controlled safety, tolerability, and dose-ranging trial of oral inosine in PD (i.e., Safety of Urate Elevation in PD, SURE-PD) found that oral inosine titrated to mildly or moderately elevate the serum U levels is safe and well tolerated for up to 2 years (except for the development of kidney stones in 6% of those receiving inosine), leads to an increase in the cerebrospinal fluid concentration of U, and may show a trend towards a modest reduction in PD progression, especially in women [64]. Despite its good safety profile, a subsequent inosine trial, Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression (SURE-PD3), showed no significant differences between the active and the placebo arms concerning the progression of PD [65].…”

Redefining the hypotheses driving Parkinson’s diseases research

“…This is reflected in a lack of PD intervention trials that target specific mechanistic changes in groups of individual patients defined according to the mechanism(s) that contribute to disease development/progression. The SURE-PD3 trial is an exception that targeted only individuals with low serum urate concentrations 9 . However, beyond the SURE-PD3 trial, there is typically no specific measurable biological signal for the success of a disease-modifying intervention for each disease within the PD umbrella 10 .…”

The Disease Modification Conundrum in Parkinson’s Disease: Failures and Hopes

“…Nevertheless, some recent efforts indicate that the field may be moving forward from clinical diagnostic criteria-based enrollment. One example is the SURE-PD3 trial, where the study design purposely used an enrichment strategy (serum urate below the population median concentration), based on the expected mechanism of action of inosine, the study intervention ( Parkinson Study Group et al, 2021 ). Although, this particular study failed to meet its primary endpoint, we believe it to be an important example of how a biomarker-defined specific sub-population of PD, beyond just meeting clinical diagnostic criteria, can be feasibly employed in a large multicenter clinical trial.…”