Inosine Treatment Found Safe with Potential Benefits for ALS Patients in Pilot Trial

Treatment with a compound called inosine over 12 weeks increased the levels of the antioxidant urate, a neuroprotective agent, in patients with amyotrophic lateral sclerosis (ALS), according to a pilot trial.

The investigational therapy also showed a positive safety and tolerability profile, indicating it might have potential as an ALS treatment.

Having established these positive results, researchers have now begun a multicenter Phase 2 trial (NCT03168711), called SURE-ALS2, to further evaluate treatment with inosine over a 20-week period. Patient enrollment is ongoing. More information can be found here.

Findings from the pilot trial were published in the study, “Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis,” in the journal Annals of Clinical and Translational Neurology.

Oxidative stress has been implicated in ALS, a finding supported by the ability of antioxidant Radicava (edarvarone, by MT Pharma America) to slow disease progression. Levels of urate, a naturally occurring compound with proposed neuroprotective effects, may be increased upon treatment with Radicava.

Studies have shown that high urate levels are associated with increased survival in ALS patients, as well as favorable outcomes in other neurodegenerative disorders.

These findings warrant clinical trials testing urate, according to the authors, which can be conducted through the administration of urate’s precursor compound, inosine. This has already been done in Parkinson’s disease patients, with a Phase 2 trial (NCT00833690) showing that inosine raised urate levels in the serum and the cerebrospinal fluid (the liquid surrounding the brain and spinal cord) with a good safety profile. A Phase 3 study (NCT02642393) is ongoing.

Aimed at studying the ability of inosine to elevate urate levels in ALS patients, the open-label, 12-week pilot study (NCT02288091) enrolled 25 ALS patients at Massachusetts General Hospital. The mean age of the patients was 61.2 years, 72% were woman, and they were at 27.2 months since their first ALS symptom and 15.1 months since diagnosis. Riluzole — marketed as Rilutek and Tiglutik — was being taken by 72% of participants.

For the first two weeks, patients took two daily 500 mg capsules of inosine — orally or through a feeding tube. The dose was then adjusted up to two capsules three times daily to achieve a urate level of 7-8 mg/dL.

Treatment started within three weeks of screening. Follow-up assessments occurred over the phone at weeks two, four, six, and nine, and in-person at week 12. A final phone call was done four weeks after the end of the treatment.

The study’s primary outcomes were safety — occurrence of adverse advents — and tolerability. Treatment effects on plasma biomarkers of oxidative stress and damage were also determined. These markers were 3-nitrotyrosine, previously reported at elevated levels in ALS patients and a mouse model of the disease, naturally occurring glutathione, and the FRAP assay of total plasma antioxidant capacity. Levels of glutathione were also measured in the brain’s motor cortex by a technique called magnetic resonance spectroscopic imaging.

The scientists also used an algorithm to predict clinical progression — ALSFRS-R total score — and compared predictions with observed results.

Results showed an increase in mean serum (blood) urate level from 4.1 — below the overall population median of 5.5 — to the target 7-8 mg/dL at week six. The study met its tolerability goal, with 24 patients (96%) completing treatment. No dose reduction was needed, and no serious adverse events were observed. Adverse events occurred in at least 5% of patients, the most common being falls in 32%, followed by weight loss in 16% and worsened weakness in 12%.

Biomarker data showed a significant increase in FRAP, a measure of antioxidant capacity, and decreased 3-nitrotyrosine levels at 12 weeks. Glutathione levels did not change significantly. A change in plasma FRAP was the only parameter associated with a change in serum urate.

ALSFRS-R total scores declined throughout the study, with little difference from baseline predictions assuming no treatment. Although this suggests no relevant benefit in slowing disease progression, the investigators said this should not be over-interpreted, because the trial was not designed to capture smaller progression benefits over larger periods.

“Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS,” the scientists wrote. “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.”

The Phase 2 SURE-ALS2 trial, now ongoing, “will serve as a helpful stepping stone in preparation for a future multicenter pivotal trial testing the effects of inosine on clinical outcomes,” the investigators said.

One of the limitations, according to the researchers, was the low number of participants. They also cautioned ALS patients against taking inosine, available as an over-the-counter supplement, until its benefit-to-risk ratio is better established.