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Canada's PROOF Center to Develop Risk Stratification Test to Personalize COPD Treatment

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Canada's Prevention of Organ Failure Centre of Excellence in Vancouver is using C$1.5 million (US$1.5 million) in funding from Genome British Columbia and other groups to develop a molecular test intended to personalize treatment for chronic obstructive pulmonary disease.

The protein and mRNA biomarker-based test will determine COPD patients' risk of acute exacerbations, which the PROOF researchers hope can be used to guide treatment for the disease and reduce the incidence and cost of hospitalizations.

The team is currently focused on validating a small group of biomarkers identified in earlier discovery work that could accurately stratify patients at greater and lesser risk of exacerbation.

As a side effect of its marker validation work, the team is hopeful the project may also spur a renaissance of drug discovery for COPD by making data available to pharmaceutical company partners, which include GlaxoSmithKline among others, to enable more accurate patient identification and stratification as well as the potential identification of molecular targets for new therapies, Bruce McManus, one of the project co-leaders, told PGx Reporter this week.

"In the purest of way of thinking, in the short term, if you had a discoverable and validatable marker set that could distinguish these subgroups, you don’t [really] care what … those markers are," McManus said. "But there is a whole range of molecules in different sub-networks [in our set,] so on the fly, while doing this practical work, we're also looking at the biology … [and] some [of these markers] could become new focuses for drug targeting."

McManus said the group, co-led by Don Sin, has so far narrowed its initial discovery group, which included thousands of potentially predictive markers, to fewer than a dozen proteins and 20 genes.

These markers represent molecule groups relating to immune cell products and proteins associated with chronic lung injury and altered repair, as well as genes that reflect immune cell activation or relate to biological functions like cell migration and adherence, he explained.

But as far as the group's primary short-term goal is concerned, the biology behind these markers is less important than their ability to identify patients with a greater risk of COPD exacerbation — a condition that involves more frequent severe breathing problems than milder COPD phenotypes.

"The burden of COPD continues to grow in the developed and developing world," and COPD exacerbations "are the leading cause of hospital admissions among chronic disease sufferers through the emergency room in many jurisdictions, including across Canada," McManus said.

According to a release from Genome BC, these COPD attacks account for more than C$5.7 billion in direct healthcare costs and C$6.7 billion in indirect healthcare costs every year.

"The issue is that some patients will be going along just fine and will have maybe none or one exacerbation a year. Then they will change their phenotype, and start having these lung attacks on a frequent basis — two or three times per year," he explained.

"The significance of this is that a patient goes to the hospital emergency room, and is likely to be admitted to the hospital, incurring significant healthcare cost. We don't know [right now,] of those patients going along at the low level, who is going to stay there versus who is going to change that trajectory."

The PROOF team believes its biomarker signature will be able to improve outcomes and save money by giving physicians a way of identifying which patients with a milder presentation of the disease may progress to a state of exacerbation in the future. This would allow doctors to change the way they treat these at-risk patients.

McManus explained that the ability to risk-stratify COPD patients could spur a range of changes in the treatment paradigm for the disease. First, doctors could give more aggressive doses of current therapies like physiotherapy, bronchodilators, and other corticosteroids.

"In the short term, while [these] are imperfect therapeutic interventions, they could be intensified in those patients with a high probability of moving to more exacerbations," he said.

"It also might mean that certain patients who are predicted never to transition to more exacerbations … might be able to have reduced intervention," he added.

The real impact of this personalized strategy is not yet known. Evaluating clinical outcomes as physicians use the group's biomarker signature to guide treatment — aggressive interventions for those in the higher-risk group, and less therapy for those in the lower-risk group — will be part of the team's study under the Genome BC grant, McManus said.

"Our purpose is to develop tools that can improve the ability to manage patients in a more personalized way and improve outcomes [and] lives. So there's a great deal of work that goes on in parallel into socioeconomic analyses, health economics modeling, and the like. That's all part and parcel of this kind of work and part of the plans under this grant," he said.

According to Genome BC, the group expects to be able to start proof-of-concept studies in the clinic "within two to three years."

McManus explained further in an e-mail that experts on the team "are using a range of tools to assess the potential for cost savings in various healthcare systems, the impact on quality-adjusted life years for patients, and the potential of wealth creation through the implementation of clinically useful tests based on the discriminative biomarker panels."

In the longer term, the team is also hoping the project may spur the development of better therapies that can be integrated into the personalized paradigm they hope their biomarker test will enable for COPD.

"Companies like GSK that provide access to data or direct investment [in the project], will have non-exclusive access to the biomarker sets that predict exacerbators [as well as] others we are developing that can distinguish different COPD phenotypes, so they can use those in their drug discovery process to do two things," McManus said.

"First, they can evaluate the effectiveness of new therapeutics in a COPD pipeline that has been mostly dry, because there hasn't been a good biomarker to distinguish even the presence or absence of COPD, to say nothing of exacerbation."

"Secondly, on the front end of clinical trials, this could help pharmaceutical companies do a better job of stratifying patients into clinical trials," he said.

Though the researchers have not yet focused much on the biology behind their predictive risk markers, McManus said the group hopes some of them could become molecular targets for new therapies.

The grant from Genome BC will support the project through two years, as the team completes its work to validate the biomarker signature and begins investigating whether the markers can be used to personalize care toward better outcomes and lowered healthcare cost.

McManus said the team is also applying for additional Genome Canada funding in the next few weeks to support another two to three years of research, which the researchers hope will offer "further granularity around the clinically relevant questions we need to interrogate to see if we can improve patient lives using this kind of approach."

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