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In Parkinson's Project, C4X Discovery's Patient Stratification Platform Shows Drug Rescue Capability

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NEW YORK – PatientSeek, a platform developed by C4X Discovery, has homed in on a gene signature that may identify best responders to a previously failed Parkinson's disease drug. 

While Manchester, UK-based C4XD is presently focused on identifying drug targets for immuno-inflammatory diseases and doesn't intend to pursue development of this undisclosed Parkinson's drug, the company is hoping that the research it has conducted with the Garvan Institute of Medical Research, an institute in Australia that aims to improve disease prevention and treatment with genomics, will showcase the ability of the PatientSeek platform to aid in precision drug development and even rescue failed drugs by pinpointing genetic subgroups of patients most likely to respond to them.

C4XD launched the PatientSeek platform earlier this year on the back of a research collaboration and validation project with the Garvan Institute. PatientSeek operates on the Taxonomy3 technology that C4XD created to identify novel drug targets from genetic and clinical datasets; Taxonomy3 is now the engine that analyzes genetic data and powers PatientSeek's ability to identify patient subgroups.

In recent decades, the biopharmaceutical industry has made strides in developing treatments that target the molecular pathways that go awry in monogenic disorders, observed Clare Murray, senior VP of drug discovery at C4XD. But drugmakers haven't had the same level of success when it comes to developing precision therapeutics for more complex diseases caused by heterogeneous factors. "There is an urgent need to develop patient stratification approaches for complex, chronic diseases, such as in neurodegeneration and inflammation," she said.

As part of C4XD's collaboration with the Garvan Institute, in which researchers assessed the Parkinson's disease drug, the firm used PatientSeek to identify a genetic signature to stratify patients into subgroups. Investigators from the Garvan Institute retrospectively reanalyzed patients' outcomes from a Phase III trial of a failed Parkinson's drug according to those subgroups.

Murray declined to share details of that reanalysis since investigators are hoping to publish their findings in a peer-reviewed journal, but she noted that the retrospective analysis was of data from a Phase III trial that was not sponsored by C4XD. Moreover, the investigators at the Garvan Institute designed the experiment, including selecting the failed drug they wanted to reassess with the help of PatientSeek-identified genetic signatures, because they were interested in identifying potential biomarkers that could carve out responders.

Parkinson's disease is presently diagnosed based on a set of heterogeneous clinical symptoms, said Antony Cooper, an investigator on the study and research director at Australian Parkinson's Mission, the Garvan Institute's program focused on genomics-informed clinical trials. At present, there aren't clear biomarkers on which to hinge a diagnosis, he said.

While Cooper said there is likely no one mechanism that causes Parkinson's, "there might be multiple different biological and molecular mechanisms that cause dysfunction and present with the symptoms of Parkinson's." That there are varying contributors to Parkinson's could be one reason why there aren't drugs on the market that slow or stop disease progression, he said, noting that each of those root causes might require a different disease-modifying treatment.

Cooper has been studying how the underlying genetic factors at play in Parkinson's can be harnessed and targeted in drug development. While variants in some genes, like GBA and LRRK2, have a well-established link to the disease, for at least 85 percent of Parkinson's patients, the disease isn't associated with a monogenic mutation.

In the study with C4XD, researchers at the Garvan Institute found that PatientSeek successfully homed in on a genetically defined subgroup of participants that responded to this previously failed drug. To Cooper, this affirmed that genetics plays a role in Parkinson's, but he cautioned this drug shouldn't be used to treat patients yet since his group's findings need to be validated.

It's "a very strong first step to say that these [subgroups] do have clinical relevance," Cooper said. Next, his team will delve further into the underlying disease biology of responding patients identified by this genetic signature and try to better understand the mechanisms driving their disease.

While in other medical specialties, such as oncology, psychiatry, and cardiology, genomics is being used to inform treatment decisions, the same isn't true in Parkinson's.

Joseph Quinn, director of the Parkinson's Center and Movement Disorders Program and a neurology professor at the Oregon Health & Science University School of Medicine, called the approach being taken by the Garvan Institute and C4XD a "viable idea." 

"Whether it'll work in Parkinson's disease remains to be seen," said Quinn, who wasn't involved in the Phase III data reanalysis. He noted that the researchers must test the genetic signature in an independent population before they know if it is truly predictive of treatment response.

Researchers previously have identified dozens of genes that could potentially be linked with Parkinson's based on genome-wide association studies, said David Standaert, chair of the neurology department at the University of Alabama at Birmingham, who also wasn't involved in the study. "Each one of these individual genes only creates a very small amount of risk, so trying to understand how the overall picture adds up to Parkinson's disease is a real challenge," Standaert said, noting that seeking out patterns of variants across multiple genes may be an interesting approach to tackling this problem.

He added that identifying such genomic underpinnings could also be useful for reviving previously failed disease-modifying therapeutic candidates. Although there aren't any disease-modifying treatments for Parkinson's at present — there are ones that address the disease's symptoms — "that's not for lack of trying," Standaert said. "There have been a lot of clinical trials that have failed … things that worked in mouse models and didn't translate into humans."

Murray emphasized that while C4XD's initial work with PatientSeek has been in Parkinson's, the platform is disease agnostic and can be applied to probe the genetic basis for many diseases. The 15-year-old company is looking to study drugs based on patient subgroups identified by PatientSeek for immuno-inflammatory diseases, including ulcerative colitis and Crohn's disease.

C4XD was originally founded to identify small molecule drug candidates that it could hand off to pharmaceutical and life sciences companies to advance clinically. Murray said PatientSeek could aid in its drug discovery work and help drugmakers interested in identifying biomarkers of response or using companion diagnostics to home in on best-responder populations in their drug trials.

In this way, just as the Garvan Institute researchers explored in their reanalysis, a company might be able to "rescue" drugs that previously failed clinical trials by identifying a specific patient subgroup in which the drug is effective, Murray said. But since C4XD's main focus is on developing treatments for immuno-inflammatory disease, she said the company will not develop or validate the Parkinson's drug studied in the analysis with the Garvan Institute. 

She hopes the findings will inspire other drugmakers, however. "By publishing these results, we hope to enable other companies in the space to progress this exciting potential treatment for patients," she said. The Parkinson's findings, she added, "pave the way for investigation of the subgroups identified by PatientSeek more widely across ongoing and failed clinical trials."