Urine Levels of Neopterin May Help Determine Therapy Efficacy in Trials

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Urine levels of neopterin, a marker of inflammation, are linked to disease progression in people with amyotrophic lateral sclerosis (ALS), a study revealed.

That means, according to researchers, that neopterin could be used as a biomarker to monitor disease status and determine whether certain treatments will be effective.

The study, “Urinary neopterin: A novel biomarker of disease progression in amyotrophic lateral sclerosis,” was published in the European Journal of Neurology.

“In undertaking research to treat [ALS], it’s important we have a way of identifying its progress and to see if the treatment is working,” Mary-Louise Rogers, PhD, the study’s co-principal investigator and an associate professor at Flinders University, in Australia, said in a university press release.

“The lack of biomarkers for [ALS] that can be used to determine if drugs are working poses a major obstacle to therapy development,” Rogers said.

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Neopterin, a molecule released by immune cells and secreted in urine, indicates the presence of inflammation and has been proposed as a candidate biomarker for ALS.

Now, researchers investigated if neopterin levels might indeed predict ALS status or progression.

Led by Rogers and Michael Benatar, MD, PhD, a professor of neurology at the University of Miami, in Florida, the team collected clinical information and urine samples from 46 ALS patients (ages 42 to 85) and 21 healthy volunteers (ages 49 to 71) who were recruited between 2011 and 2021 from Flinders Medical Centre and the ALS Research Program at Miami.

Most observed cases of ALS were sporadic, or without a genetic basis; genetic mutations were identified in two of the 46 people with ALS.

Results showed that baseline, or starting, concentrations of urinary neopterin were elevated in people with ALS — 181.7 micromole per mole of creatinine (micromol/mol creatinine) versus 120.4 micromol/mol creatinine in healthy volunteers. Of note, when measuring compounds in urine, clinicians and researchers take into account how well the kidneys are working. That can be done by determining the levels of creatinine, a substance that is filtered out of the blood and into the urine by the kidneys.

The researchers noted that neopterin levels were found to distinguish between ALS patients and healthy volunteers 74% of the time.

Baseline neopterin also was correlated with disease status, which was measured using the revised ALS functional rating scale (ALSFRS-R), which assesses and tracks changes in a person’s physical function over time.

Among the 46 ALS patients, 44 deaths were reported during follow-up. Individuals with neopterin levels that were above the group median value survived, on average, 10.7 months, whereas those with levels below the median survived longer — an average of 19.8 months.

Despite this difference, neopterin levels were not considered predictive of survival and do not have significant prognostic value, the researchers emphasized.

“Higher neopterin levels at baseline, whilst statistically significant, did not meaningfully predict survival,” the team wrote.

Longitudinal data were available for 29 of the 46 ALS patients. In these people, levels of neopterin increased over time, which was correlated with a consistent decrease in the average ALSFRS-R, meaning worse functional capacity.

“The urinary concentration of neopterin increased from diagnosis by an average of 6.8 [micromol/mol] creatinine each month,” the researchers wrote.

Overall, these results indicate that “urinary neopterin holds promise as marker of disease progression in ALS,” they added.

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Since neopterin is released by immune cells, the researchers hypothesized that it might be a useful biomarker for determining who will do well with anti-inflammatory therapies.

While several clinical trials for immunomodulatory therapies in ALS  have been conducted, the results of these studies, according to the researchers, “have been disappointing.”

Indeed, “their negative results have highlighted the need to better understand the immune response in ALS, and to identify biomarkers that might identify potential responders at trial [enrollment],” the team wrote.

“It will be valuable, in future studies, to determine if high baseline neopterin levels might identify the subset of ALS patients most likely to benefit from anti-inflammatory drugs in trials,” they wrote.

In addition, neopterin could be used to determine how well an anti-inflammatory treatment is working once it has been administered.

“Neopterin might also be used as a pharmacodynamic biomarker in clinical trials that target the immune system, where a decrease in the monthly change in neopterin levels with an experimental treatment might suggest a beneficial reduction in the pro-inflammatory response,” the researchers added.

This is not the first biomarker to be discovered by this research team. Previously, they identified that p75ECD, part of the neurotrophin receptor, is another urinary biomarker of ALS. Now, in this new study, the researchers showed that urinary neopterin and p75ECD correlated with each other, and that p75ECD levels also predicted disease progression over time.

Such urinary biomarkers might be advantageous because urine is less complex than blood and easier to collect, the researchers noted.

“Both biomarkers have the potential to be used in future Phase 2 and 3 clinical trials as a way of determining if a drug treatment is working,” Rogers said.

The researchers noted, however, a need to validate these findings in more patients and also to refine precise methods for measuring neopterin levels.