7:03 PM
Feb 14, 2019
 |  BC Innovations  |  Tools & Techniques

Heartening predictors in diabetes

How the diabetes and CV fields should organize to gain new biomarkers

New biomarkers of cardiovascular risk could relieve a decade-old bottleneck for diabetes drug development, but validating them will require companies to invest in strategic trial designs, and public and private stakeholders to pool thinking.

As diabetes companies await new FDA guidelines that might do away with the blanked requirement for costly post-market cardiovascular outcomes trials (CVOT) that have hampered progress over the last ten years, they also anticipate increased pre-market CV requirements that could negate some of the savings, making it unclear how much new development the change will spur (see “Cashing Out CVOT”).

Better biomarkers for predicting major adverse cardiac events (MACE) could trim development costs for both pre- and postmarket diabetes trials. Translational research is starting to identify candidates that, if validated, could enable smaller, shorter trials through improved enrichment for high-risk patients.

A common refrain among experts interviewed by BioCentury is that the CV field needs to take a page from the cancer playbook in its approach to biomarkers.

“There are examples in oncology, for example in breast cancer treatment, where biomarkers are not only used for diagnosis, but also for establishing prognosis and selection of specific therapies,” said James Januzzi, professor of medicine at Harvard Medical School and cardiologist at Massachusetts General Hospital. “In cardiovascular disease, there’s no reason why we could not do the same.”

“What we’ve seen repeatedly is these machine learning-leveraged, multiple-marker panels out-perform traditional single biomarkers every single time.”

James Januzzi, Harvard Medical School

According to Januzzi, the key to predictive power will be measuring multiple signals at once.

“What we’ve seen repeatedly is these machine learning-leveraged, multiple-marker panels out-perform traditional single biomarkers every single time,” he said.

His retrospective CASABLANCA study of 1,251 patients referred for catheterization laid the groundwork for CV proteomics panels being developed by Prevencio Inc.

The challenge, said Januzzi, is moving from retrospective analyses of previously collected samples to prospectively defined validation studies of biomarker signatures.

That could involve incorporating biomarker validation into Phase II trial designs. But the need for extensive validation data suggests companies might do best to work together in data-sharing consortia.

“In order to not reinvent the wheel, you need to invest in collaborative efforts,” said Klaus Romero, director of clinical pharmacology and quantitative medicine at the Critical Path Institute.

There’s also an opportunity for closer collaboration between consortia in the CV and diabetes fields, given the large overlap and co-morbidity between the two diseases.

Marking hearts

In the decade since a spate of diabetes studies raised safety concerns that prompted FDA to require CVOTs for all non-insulin diabetes therapies, the number of clinical candidates entering Phase II and Phase III trials has been slashed by about two thirds (see “CVOT Damage in Diabetes”).

Yet none of the 15 CVOT studies completed since 2009 found substantial safety hazards, according to a review published last month in Diabetologia, while studies of SGLT2 and GLP-1R agonists showed CV benefit. Estimates of the trials’ costs come in at $200-$500 million apiece.

Last October, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) argued CVOTs should be obligatory only when...

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