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Autism Dx Firms Exploring Role of Metabolic Imbalances in Diagnosing, Treating Condition

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NEW YORK (360Dx) – Metabolic dysregulation has emerged as a major focus for research into autism spectrum disorder (ASD) with a number of academic groups and commercial outfits looking to such abnormalities to diagnose and treat the condition.

Last year, Madison, Wisconsin-based Stemina Biomarker Discovery launched its first metabolomic test for diagnosing ASD through its NeuropointDx division.

And in December, researchers associated with San Francisco-based BioRosa Technologies published a study in Frontiers in Cellular Neuroscience looking at whether metabolomic measurements could gauge the effectiveness of several different ASD treatments.

BioRosa is now planning prospective clinical trials to further test the approach described in the Frontiers in Cellular Neuroscience paper, while NeuropointDx plans this year to release an additional metabolomic test that will cover more subtypes of the disease.

NeuropointDx launched its initial test, called the NPDX ASD test, in November. Based on data from the Children's Autism Metabolome Project (CAMP), a 1,102-patient trial the company sponsored with the goal of identifying metabolomic profiles linked to autism, the test is intended to help doctors make earlier diagnoses of autism and to guide treatment in certain subsets of patients.

While NeuropointDx envisioned early diagnosis as the primary use of the test, it has actually seen more uptake for guiding therapy, said CEO Elizabeth Donley, who noted that the test is still only available at limited sites as part of an early access program.

In a paper published in September in Biological Psychiatry based on the CAMP data, the company and its collaborators identified a set of three amino acids — glutamine, glycine, and ornithine — that when measured as a ratio against the levels of three branched chain amino acids (leucine, isoleucine, and valine) distinguished a subset of subjects with autism from typically developing controls.

Donley said that thus far, the NPDX ASD test has primarily been used by doctors exploring whether treatment with branched chain amino acids could help children who have not responded to behavioral therapies.

"They are trying to figure out whether or not there's an imbalance in the amino acids, and then trying to pair that with some kind of supplement that might help to remedy it," she said.

In part this use has predominated due to the fact that the test has thus far been used primarily by neurodevelopmental specialists who have already diagnosed their patients based on more traditional measures, Donley said.

Driving adoption of the test for diagnostic purposes will likely require "getting in front of pediatricians who are the ones who would typically look to it in an early diagnosis scenario to help decide whether or not to refer [a child] to a neurodevelopmental specialist," she said. "And we don't have a sales force to do that right now."

Donley added that early feedback has also suggested the company will need to broaden its panel to capture a larger segment of the ASD population to achieve diagnostic uptake. Currently, the test has been validated in 12 subtypes accounting for roughly 30 percent of children with ASD. Donley said that doctors have indicated that they would be more likely to use the test diagnostically were it able to cover at least 50 percent of the ASD population.

"It all comes down to the health economics," she said. "People say, 'Well, what do I get for the amount that I am paying? How much certainty does it bring me in what I tell my patients?'"

"So we're going to continue to offer what we have available on our early access program, but I think adding to the offering and being able to describe more children with a high degree of specificity will resonate, particularly with those frontline physicians," she said.

NeuropointDx is also working on a study with Denise Ney, professor of nutritional sciences at the University of Wisconsin-Madison to look at whether patients identified in the CAMP study as having amino acid imbalances would benefit from treatment with a branched-chain amino acid supplement.

"If it proves out that these children respond well [to the supplement], that will be a really important component [of the firm's strategy]. Because it will be the first time we are actually able to use a very precise approach to look at [patient] metabolism imbalances and pair that with a supplement meant to deal with those imbalances," Donley said.

BioRosa is similarly developing metabolomic-based tests for diagnosing ASD and guiding therapy, though the company is taking a more targeted approach to its discovery effort than NeuropointDx. It is focusing on metabolic pathways related to DNA methylation and oxidative stress that were linked to ASD by research led by Jill James, director of Arkansas Children's Hospital Research Institute Autism Metabolic Genomics Laboratory, a cofounder of BioRosa, and author on the Frontiers in Cellular Neuroscience study.

In addition to the biomarkers identified by James and her colleagues, the company has licensed machine learning technology from Juergen Hahn, head of the department of biomedical engineering at Rensselaer Polytechnic Institute, senior author on the Frontiers in Cellular Neuroscience paper, and a member of BioRosa's scientific advisory board.

The Frontiers in Cellular Neuroscience work was completed before the launch of BioRosa but serves as a proof of concept for the company's plans, said John Slattery, its cofounder and CEO and a coauthor on the study. In the study, the researchers first built a model using metabolomic markers linked to the folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) pathways that distinguished between individuals with ASD and typically developing (TD) controls and then used that model to assess whether ASD patients from three clinical trials showed movement toward TD metabolite profiles in response to treatment.

Slattery said that in addition to developing the markers for early diagnosis of ASD, BioRosa is partnering with companies working on treatments for the condition with the aim of developing tests to help select patients for clinical trials and to help assess the effectiveness of those treatments within the trials.

"The near-term goal is to partner with groups that are developing treatments in order to use [BioRosa's technology] for predictive diagnostic purposes within clinical trials," he said, noting that the company was currently doing contract work for several pharma firms conducting studies of treatments for ASD.

Longer term, BioRosa is working to develop a biomarker model that can aid in early diagnoses for children with ASD. Slattery said the company is currently raising capital to fund a prospective double-blind trial that it hopes will demonstrate the ability of its approach to distinguish patients with ASD from those with non-autism developmental concerns. He said BioRosa hopes to raise around $3 million in funding for this work.

The company launched in May of 2018 and was accepted into San Francisco-based biotech incubator Indie Bio, from which it graduated in November.

NeuropointDx is likewise in fundraising mode. The company is looking to raise a minimum of $10 million, which Donley said it will use to continue development of its tests as well as to build a sales and commercialization force that it will use to drive adoption, particularly among non-specialist pediatricians.

Donley said NeuropointDx is also looking to partner with companies with experience distributing products to this physician population and is negotiating agreements for distribution of the test outside the US, including in South America, Asia, and the Middle East.