Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

Abstract

ObjectiveTo test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS).MethodsThis was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores.ResultsTwenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions.InterpretationInosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS.

Motion correction methods for MRS: experts' consensus recommendations

“…Real‐time motion correction with shim update has been used in clinical MRSI studies with adult subjects, including clinical studies of patients with brain tumors, 91 amyotrophic lateral sclerosis (ClinicalTrials.gov/NCT02288091), 92 multiple sclerosis, and neurodegenerative disorders (eg Parkinson's disease and mild cognitive impairment) 93 . Cancer IDH mutations (IDH 1&2) have high de novo production of the oncometabolite 2HG, and in vivo imaging of 2HG is a key application of MRSI in neuro‐oncology.…”

“…Robust 3D MRSI of 2HG with real‐time ReShMoCo MEGA editing was used in mutant IDH glioma patients to assess tumor burden, 94 response to standard radiochemotherapy, 91 and targeted therapy with novel mutant‐IDH inhibitors. 91,95 The same methodology was used to image GSH in the brains of patients with amyotrophic lateral sclerosis (ClinicalTrials.gov/NCT02288091), 92 including the motor cortex and corticospinal tracts, or in patients with mutant IDH glioma tumors 95 . GABA was imaged using the same methods in patients with Parkinson's disease 93 .…”

Inosine in Biology and Disease

“…Oral administration of inosine has been explored in clinical trials to treat neurological conditions such as Parkinson’s disease (PD). Inosine administration elevates the urate levels in serum and cerebrospinal fluid (CSF), thus affording neuroprotection through radical scavenging [ 53 , 54 , 55 ]. In PD patients, inosine administration may slow the progression of mental disability, but a phase 3 trial was prematurely terminated as the anticipated efficacy was not met [ 56 ].…”

Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases

“…This was highlighted in different experimental studies in vitro but positive outcomes have also emerged in PD mouse models, encouraging scientists to consider preclinical studies also on ALS models [172,173]. Nowadays, there are some clinical trials that have confirmed safety and efficacy of inosine in increasing urate levels in both pathologies (NCT00833690; [174]; NCT02288091; [175]).…”