LONDON – "Superdrugs" – single peptides containing several hormonal activities – could be available to treat diabetes and obesity within a few years, scientists suggest. One of those composite molecules has already shown promising results in rodent models of diabetes and obesity and could provide a medical alternative to gastric bypass surgery, the researchers said.

A version of the drug containing three metabolically active hormone components successfully reduced blood glucose, appetite and body fat in animal tests, but scientists are already working on versions containing additional hormone components. The relative strength of each component could be tailored to individual patients' needs.

Matthias Tschöp, research director at the Helmholtz Diabetes Center at Helmholtz Zentrum München, in Neuherberg, Germany, told BioWorld Today: "We have shown that it is possible to design these superdrugs containing several metabolically active hormonal ingredients, which produce exceptional results in preclinical models of diabetes and obesity. This is a major step forward toward next-generation precision medicines, which control metabolism by mimicking the entire patterns of natural signals."

He said he envisages that the treatment could be given by injection, perhaps once a day or even once a week.

An important next step, however, will be to validate the "impressive efficacy and safety" of the molecules in clinical studies, he added.

Tschöp and his collaborators, who include Richard DiMarchi, professor of chemistry and chair in biomolecular sciences at Indiana University in Bloomington, Ind., reported their most recent findings in a paper in the Dec. 8, 2014, issue of Nature Medicine. Its title is "A rationally designed monomeric peptide triagonist correct obesity and diabetes in rodents."

Informed by studies that aimed to discover the impact of weight-loss surgery on metabolism, Tschöp, DiMarchi and their teams have worked on ways of combining several different hormone activities in a single molecule. They have already shown that such molecules combining two hormones have beneficial effects in animal models of diabetes and obesity, but the study reported in Nature Medicine goes one step further and combines three hormones.

Those are glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon, which DiMarchi and his team have engineered into a single peptide. Experiments have shown that peptide specifically and equally targets the three receptors of GLP-1, GIP and glucagon.

GLP-1 and GIP predominantly contribute to improving insulin release and reducing blood glucose levels. GLP-1 additionally curbs appetite, while glucagon primarily increases the long-term rate at which calories are burned and lowers lipid content in the liver.

Brian Finan, first author of the paper and a chemist and pharmacologist at the Helmholtz Diabetes Center, said: "This triple hormone effect in a single molecule shows results never achieved before. A number of metabolic control centers are influenced simultaneously, namely in the pancreas, liver, fat depots and the brain."

"We included glucagon," Tschöp said, "which you might initially think would be counterintuitive for a diabetes medication since it drives glucose up; nonetheless, its long-term action helps with promoting burning of calories and melting away the fat. Its adverse glucose effects are safely overridden by the inclusion of two incretin hormones, GLP-1 and GIP. Thus, each compound delivers a unique contribution to the package."

In rodent models of diabetes and obesity, the triple peptide caused blood glucose levels, appetite and body fat to decrease to baseline levels. "We also showed that it cleared liver fat and helped to burn calories, as well as addressing many of the concerns of the metabolic syndrome including, for example, normalizing cholesterol levels," Tschöp added.

The triple peptide reduced the body weight of the animals by around 30 percent, roughly twice as much as the previous dual-action molecules that the team had tested. The rodents' insulin sensitivity also showed a "massive improvement," DiMarchi said.

Future plans include "dozens of other options," Tschöp said. "We are looking at potential combinations of four or five hormonal components. But our long-term goal is to provide a portfolio of personalized medicines, to allow us to deliver custom-built agents like the one we are reporting on now, to the right patient populations. This will also mean we have to find the right biomarkers to allow us to identify those patients and to monitor their therapy."

Most importantly, he concluded, it will be vital to progress the new peptide through clinical studies, in order to demonstrate that the drug can deliver the same results in human patients. "This is the ultimate challenge," DiMarch cautioned.