By Turna Ray
Researchers from 21 European institutions and four major drug companies have launched a large research effort to identify molecular biomarkers associated with type 2 diabetes, develop an algorithm that can predict patient response to existing drugs, and use the markers to advance new personalized treatments for the disease.
With €45 million ($61 million) in funding from the European Union and the European Federation of Pharmaceutical Industries and Associations, researchers involved in the Diabetes Research for Patient Stratification, or DIRECT, project will apply systems biology and pathway analysis approaches to investigate more than 100,000 samples from type 2 diabetes patients. Through these studies, the investigators are hoping to gain deeper insights into which patients get diabetes, what types of patients experience accelerated disease progression, and which patients respond well or poorly to treatments.
Ultimately, DIRECT researchers are aiming to identify biomarkers that can be used as predictive or prognostic diagnostics for patient stratification, or to help pharmas develop new drugs for type 2 diabetes.
"We hope that we will be able to subdivide type 2 diabetes into multiple subtypes defined by genetic, genomic, and physiological biomarkers and/or by the development of a genomic profiling methodology that makes use of hundreds of thousands of data points and that these subtypes will respond differently to diabetes drugs, or progress differently to insulin," Manolis Dermitzakis, a researcher at the University of Geneva and a project participant, told PGx Reporter via e-mail.
There are 285 million people worldwide who have type 2 diabetes — a metabolic disorder in which insulin hormone becomes less effective in lowering blood sugar. If gone unchecked, the disease may affect more than 400 million people by 2030, according to an estimate from DIRECT project researchers.
If changes in diet and exercise fail to control the disease in patients, they are then prescribed insulin or metformin. Other anti-diabetic medications include sulfonylureas, nonsulfonylurea secretagogues, alpha glucosidase inhibitors, and thiazolidinediones.
To date, research has uncovered at least 36 diabetes-associated genes, which explain only about 10 percent of the heritability of type 2 diabetes, according to an article published last year by Christian Herder of the University of Dusseldorf and colleagues in the European Journal of Clinical Investigation. "The genetic susceptibility to type 2 diabetes appears to be determined by many common variants in multiple gene loci with low effect sizes," Herder et al. wrote in the paper.
"Future studies need to target the issue of hidden heritability and to detect the causal gene variants within the identified gene loci," they concluded. "Improved understanding of the genetic contribution to type 2 diabetes may then help address … questions [of] whether genotyping is useful to predict individual diabetes risk, identifies individual responsiveness to preventive and therapeutic interventions or at least allows for breaking down type 2 diabetes into smaller, clinically meaningful subtypes."
According to Ewan Pearson of the University of Dundee, one of the study leads in DIRECT, there are currently no clinically actionable pharmacogenomic markers in polygenic type2 diabetes. Although studies have revealed some predictive associations, such as between CYP2C9 alleles and sulphonylureas or variants at the ATM locus and metformin response, the effect sizes of these markers are too small to be translated into clinical practice.
"There are, however, clear examples of PGx in diabetes. Monogenic forms of diabetes often masquerade as type 1 or type 2 diabetes," Pearson reflected. For example, he noted that heterozygous HNF1A mutations cause so-called maturity-onset diabetes of the young. These patients have shown in clinical trials to be "exquisitely sensitive" to sulphonylureas and the marker has been used to transfer people off insulin.
In DIRECT, the researchers will focus on characterizing glycemic deterioration in patient groups and model how patients progress from developing diabetes to requiring insulin. As part of this work, the researchers will conduct a prospective biomarker analysis of 3,000 high-risk patients and compare their progression against their pre-diabetes states. This high-risk cohort will be "intensively phenotyped" at the start of the study and followed for up to 36 months.
Researchers will also collect samples and phenotype data from 1,000 patients with early diabetes and follow them for 18 months to try to correlate when these patients start on insulin and the rate at which their beta cells decline. One of the observations in the Herder et al. paper was that "most of the discovered gene variants [to date] have been linked to beta-cell dysfunction rather than insulin resistance, which might challenge established thinking of type 2 diabetes as a predominant disorder of insulin action."
DIRECT researchers will conduct further retrospective and prospective analysis to characterize which patients are "extreme responders" and "non-responders" to metformin and sulphonylureas, and patients who have "extreme intolerance" to metformin. The researchers will also conduct prospective analysis of good and poor response to GLP-1 receptor agonists and look at genetic determinants of acute response to IV glucose, GLP-1, arginine, and tolbutamide in normal controls.
According to Dermitzakis, the first three years of DIRECT will be dedicated to biomarker discovery. "Multiple levels of genomic (genetic, transcriptomic, metabolomic, proteomic, metagenomic) and biochemical data will be collected on these patients, and integrated with other data such as expression QTL data from human islets in a systems biology approach," he said, adding that following validation of these discovered biomarkers, DIRECT will study their clinical utility for another three or four years.
The genomic technologies that DIRECT will use to analyze patient samples have yet to be determined. "We will likely employ the full range of methods including sequencing, genome-wide association studies and other custom chips, [such as] exome SNP chips," said Mark McCarthy, one of the research leaders in DIRECT and head of the diabetic medicine research group at the Wellcome Trust Centre for Human Genetics.
DIRECT investigators plan to present their findings at scientific conferences and publish their discoveries in peer-reviewed journals. "We hope we'll have early results by the end of the first year, but most of the results will not be in until two to four years," Pearson said.
The DIRECT project evolved out of Europe's Innovative Medicines Initiative, a public/private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations — a sign that industry is interested in discovering personalized medicine approaches in diabetes treatment.
According to figures from market analysis firm GlobalData, the type 2 diabetes treatment market was worth nearly $24 billion last year and is expected to be worth $45.1 billion by 2020. Since the type 2 diabetes patient population is expected to balloon in coming years, drug developers can hope to capture significant profits within this space if they are able to differentiate their products with diagnostics that predict which patients will respond well to their treatments and those who might experiences poor response or adverse reactions.
The pharma companies involved in DIRECT — Novo Nordisk, Servier, Sanofi-Aventis, and Eli Lilly — are all major players in the diabetes treatment space with profitable products in the market. Novo Nordisk and Servier are study participants, while Sanofi-Aventis and Lilly are heading up the DIRECT coordination team alongside the University of Dundee.
Sanofi-Aventis markets Lantus, a long-acting insulin for type 2 diabetes that led the market last year with $3.6 billion in sales. Novo Nordisk, the company to first market insulin in 1923, sells Novolog and Levemir insulin injections for diabetes mellitus; Glucagen injections for severe hypoglycemia; Victoza injection to improve glucose levels in type 2 diabetes patients; and Prandin tablets to control blood sugar levels for type 2 diabetics. In Lilly's portfolio are Glucagon for severe hypoglycemia, several types of insulin injections under the brand name Humalog, and Tradjenta tablets to control blood sugar for those with type 2 diabetes.
Diamicron MR, a modified-release version of the sulfonylurea drug gliclazide for the treatment of adults with type 2 diabetes, is one of the best-selling products in Servier's portfolio. The French pharmaceutical firm also previously sold the diabetes drug Mediator (benfluorex), which health regulators pulled from the market following reports that it caused heart valve damage and pulmonary hypertension in patients.
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