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GenieUs Genomics Aims to Stratify ALS Patients Using Bioinformatics Platform, Long-Read Sequencing


NEW YORK – Australian bioinformatics firm GenieUs Genomics aims to improve clinical trials for neurological disease, starting with amyotrophic lateral sclerosis (ALS), through personalized genetic analyses to better discern those most and least likely to respond to specific therapies.

The Sydney-based company has designed a research-use-only bioinformatics platform called Deep integrated Genomic Analysis Platform (DiGAP) that uses a supervised classification model alongside proprietary methods to determine the likely pathogenic causes of an individual's disease. The company plans to use this platform to analyze long-read sequencing data from ALS patients in the hopes of better understanding how to classify them for more targeted and effective therapies.

As part of this effort, GenieUs aims to validate DiGAP in a new open-label Phase II clinical study of ALS in collaboration with Duke University and Temple University, and sponsored in part by long-read sequencing specialist Pacific Biosciences.

ALS is a rare and fatal neurodegenerative illness, also known as Lou Gehrig's disease. Motor neurons deteriorate over the course of the disease, resulting in the progressive loss of muscle control. Respiratory failure caused by the loss of control over the muscles responsible for breathing is the leading cause of death in ALS and few treatments specific to the disorder exist.

The US Food and Drug Administration, for instance, has approved only six therapies for ALS to date and the agency often finds itself caught between balancing the need for strong clinical evidence against the huge unmet needs of the ALS community.

Earlier this year, for example, Amylyx Pharmaceuticals paused promoting Relyvrio (sodium phenylbutyrate and taurursodiol) as a treatment to slow progression of ALS after the therapy failed to meet its endpoints in a Phase III clinical trial. The FDA had approved Relyvrio in 2022 on the back of a single Phase II study and in spite of questions concerning the drug's efficacy.

Similarly, the FDA granted Biogen's Qalsody (tofersen) accelerated approval last year, based on the drug's ability to reduce the biomarker neurofilament light chain, even though it failed to meet a primary endpoint of improving patients' physical functions.

"There's such a high degree of heterogeneity in this disease," said GenieUs CEO Sherie Ma. "And that's really what plagues drug discovery, especially in those pivotal Phase III trials."

GenieUs and its academic collaborators think that they may be able to improve patient selection, and ultimately the diagnosis and treatment of ALS by identifying and treating the biological pathways driving patients' disease progression.

"We use the genomics of individuals to address this heterogeneity," Ma said. "We believe that a lot of the missing genetics for this disease lies in the reliance to date on short-read sequencing."

The study that the company launched along with Duke and Temple, called ROAR-DiGAP: A Widely Inclusive, Largely Virtual Pilot Trial Utilizing DiGAP, is in the process of enrolling 50 participants with ALS, which GenieUs and its collaborators intend to categorize into four separate subtypes based on each participant's genomic profile and the associated biological pathway thought to drive their symptoms.

Each group will receive a subtype-specific experimental therapy. Researchers will then measure a panel of each patient's biomarkers, including the established ALS marker neurofilament light chain, and progression on the Revised ALS Functional Rating scale (ALSFRS-R).

GenieUs and its collaborators will apply DiGAP's analytic capabilities to DNA samples processed using HiFi long-read sequencing on Pacific Biosciences' Revio system to identify mutations such as insertions, deletions, structural variants, and differential methylation patterns, as well as phasing, or the identification of which chromosome a mutation occurs on.

"Using that information, we're going to target people with supplements directed at that pathway, where there's some evidence that it can mitigate disease [via] that pathway," said Terry Heiman-Patterson, one of the study's investigators and director of the MDA/ALS Center of Hope at Temple University's Lewis Katz School of Medicine.

The four pathways under study are neuroinflammation, oxidative stress, impaired autophagy and axonal transport, and mitochondrial dysfunction. Patients will receive astaxanthin, a type of carotenoid found in certain algae, for neuroinflammation; protandim, an herbal dietary supplement, for oxidative stress; melatonin for impaired autophagy; and the antioxidant MitoQ for mitochondrial dysfunction.

Stan Crooke, founder, CEO, and chairman of personalized medicine nonprofit N-Lorem, which develops targeted therapies for ALS and other rare disorders, applauded the trial for its general approach to categorizing and seeking to treat ALS, but expressed skepticism toward the categories themselves.

"Anything that actually categorizes patients into something actionable is a step forward," he said. He worried that the pathways chosen as categories in the ROAR-DiGAP trial, however, are "very crude subdivisions," that might not be sufficiently precise to have meaningful clinical value, nor is it clear that the supplements will have their desired effects.

"But the idea of thinking of ALS not as a single disease but as multiple genetic diseases makes total sense," he said.

Ma said that starting with broad measures such as pathways and shifting toward more focused targets as data is acquired is the strategy of GenieUs and its academic collaborators.

"If we see positive results in one or some of the participant categorizations, based on the mechanistic biomarker assays and/or targeted drug treatment, we'll explore a focused follow-up study," she said.

Ma said that with the current version of DiGAP, the company is only analyzing DNA, rather than any treatment-related differential gene expression, which she said might be the focus of follow-up studies. For the current study, Ma said that PacBio's long-read sequencing capabilities will play a key role in helping to better understand ALS genetics.

Crooke largely agreed that long-read sequencing –– which is typically applied more to whole-genome sequencing than to short-read sequencing, which is used more often to analyze exomes –– will benefit our understanding of ALS.

"Exome sequencing is rarely sufficient for us to know what we need to know," he said. "Whole-genome sequencing is far better, [and] the more information we have, including both short and long reads, the more sophisticated your approach can be."

In addition to collecting blood samples for biomarker analysis throughout the study, Ma said that GenieUs will also harvest patients' peripheral blood mononuclear cells (PBMC), which the company plans to reprogram into induced pluripotent stem cells (iPSCs) and then motor neurons as part of an effort to find transcriptomic patterns that correlate to the genomic subtyping done in the current study, particularly with respect to any responders.

"That will provide clinical evidence for the pathway mutation burden approach," she said.

All this effort, Ma said, will contribute to the company's plans to include other omics analyses in the overall pathway burden model. The company is currently working to expand beyond single nucleotide variants to include larger structural variants and epigenetics, for which she said the Revio platform will be instrumental.

"The long-read sequencing, in addition to detection of larger variants than 50 base pairs, also provides methylation," Ma said. "That's just an added bonus of the sequencing, which is fantastic because we know that epigenetics plays such an incredible part of this disease."

In addition, she noted, "the clinical evidence that we're collecting as part of this study will go towards our long-term goal of having DiGAP accredited as a software for medical devices."

Ma said that the company is initially focused on gaining commercial clearance in the US and then Australia.

GenieUs is still working out its precise marketing strategy for when it acquires regulatory clearance. Ma said that the company is evaluating both offering DiGAP as a service and as a software package that can be integrated into other platforms, as well as licensing it to customers.

At the moment, GenieUs is focused solely on ALS. Ma mentioned, however, that because DiGAP captures genetics relevant to the other motor neuron diseases, the company is open to applying its technology to other disease contexts in the future.