The statistics are just plain scary. New estimates released by the International Diabetes Federation (IDF) to mark World Diabetes Day 2012 last week say that 371 million people have diabetes and 187 million diabetes cases remain undiagnosed. The IDF data mean that millions of people are at risk of costly and debilitating diabetes complications, including nerve and kidney disease.

The 2011 IDF Diabetes Atlas put the number of people afflicted with diabetes at 366 million and the number of deaths due to the disease at 4 million. The latest figures, representing a 1.4 percent increase, indicate that the disturbing upward trend in diabetes incidence is likely to continue, IDF says. By the end of the year, 4.8 million people will have died from diabetes related complications. Half of these deaths will be in people under the age of 60.

In the U.S. diabetes affects nearly 8.3 percent of the U.S. population and, according to the U.S. Centers for Disease Control and Prevention (CDC), the number of Americans diagnosed with diabetes has more than tripled since 1980.

Growing Market

It is small wonder that the global diabetes market is predicted to reach $65 billion by 2020, according to a Jeffries & Co. report. The company estimates that the market will grow by a 10 percent CAGR during this period driven by "socio-demographic changes, the increasing prevalence of obesity and diabetes in emerging markets due to adoption of Western diets and lifestyles, product innovation, long patent lives for key oral brands, limited value erosion from biosimilars and the increased use of combination treatments."

While insulins still remain the major standard of care and will continue to dominate the market, new products are beginning to emerge. A recently released report from the Pharmaceutical Research and Manufacturers of America (PhRMA) says there are about 221 products currently in development targeting diabetes and its related conditions. These potential therapies are either in clinical trials or under review by the FDA. They include 32 compounds indicated for Type I diabetes, 130 for Type II diabetes and 64 for diabetes-related conditions.

Among these are compounds aimed at promising new targets. For example, Apofore Corp., a Cambridge, Mass.-based start-up founded in 2011, is developing therapeutics for Type II diabetes based on the naturally occurring protein, Apolipoprotein A-IV (apo A-IV), which appears to possess the ability to reduce blood sugar and increase insulin production.

The protein apoA-IV previously had been identified as playing a role in inflammatory processes and food intake regulation, but its role in insulin secretion wasn't clear until the creation of apoA-IV knockout mice demonstrated reduced insulin secretion and impaired glucose tolerance. (See BioWorld Today, Sept. 4, 2012.)

Unlike glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors, apoA-IV is found in a later phase of insulin secretion. Another advantage is that the protein only works when blood glucose is high; it's ineffective when blood glucose is low, meaning it won't cause hypoglycemia, a common side effect of drugs designed to control insulin levels.

Apofore licensed rights to the technology from the University of Cincinnati to develop a recombinant form of apoA-IV for Type II diabetes. The firm was seeded with a $10 million investment from Cambridge, Mass.-based HealthCare Ventures LLC.

Poxel SA's lead oral diabetes drug, imeglimin, appears to act by restoring the energy balance, by modulating the functioning of the electron transport chain in the mitochondria of cells in the muscle, liver and pancreas. It activates AMP kinase, a master switch in energy metabolism and also modulates reactive oxygen species, leading to a decrease in glucose production by the liver and an increase in glucose utilization by muscle tissue. It also appears to have positive effects on insulin secretion. (See BioWorld Today, Nov. 8, 2012.)

The compound reached the primary endpoint in a Phase II trial in Type II diabetes patients, demonstrating statistically significant decreases in plasma glucose and fasting plasma glucose levels when administered in combination with sitagliptin vs. treatment with sitagliptin alone.

The company is planning to conduct a six-month, Phase IIb dose-ranging monotherapy trial in 400 patients early next year.

Artificial Pancreas

In the area of Type II diabetes (T1D) promising research is ongoing towards the development of an artificial pancreas. This involves an external system of devices and software that people afflicted with the disease could use to replace their body's lost ability to automatically control their blood sugar level.

The Artificial Pancreas Project is a key research initiative of the Juvenile Diabetes Research Foundation (JDRF), which coordinates global research efforts in this area. A basic artificial pancreas system, the JDRF says, would work by connecting a continuous glucose monitor with an insulin pump using sophisticated computer software to automatically deliver the right amount of insulin at the right time.

JDRF-funded studies have already shown the significant value of prototype artificial pancreas systems in better managing a person's T1D.

They are funding a prototype artificial pancreas system developed by artificial intelligence expert Nigel Greenwood, an honorary senior fellow at the University of Queensland. He has teamed up with diabetes specialist Jenny Gunton from the Garvan Institute of Medical Research in Sydney, Australia, to work on the project. Greenwood founded NeuroTech Research Pty Ltd, for which he developed machine intelligence software called Neuromathix – the key component in the system.

"We basically collected real-life data from two subjects, which was used to generate many in silico subjects for the trial," Garvin indicated. "The software was specially designed to incorporate most of the uncertainties that operate in all people with Type I diabetes, in order to operate with 'real-world' problems. These include uncertainty over carb counting, timing of meals, and the imprecision of continuous glucose monitors."

Intelligent Software

The patient information was "interrogated" by the software. To help itself understand what it was observing, the machine-intelligent software generated a further 2,599 possible diabetic profiles to study and control. The software calculated suggested insulin dosages, which were given to the simulated patients. Blood glucose readings were analyzed after insulin delivery, over 55 simulated days.

"The outcomes were very impressive, and we're keen to take it into trials," Garvin noted. "If all goes well, and we obtain funding early in 2013, the system could be ready for real-world marketing in 2016."

The FDA is also helping advance the development of an artificial pancreas device system and has just released its final artificial pancreas guidance designed to help provide clarity for manufacturers, investigators and reviewers in the development of this technology.

One biotech company working in this area is Biodel Inc., of Danbury, Conn., a recipient of a National Institutes of Health's Small Business Innovation Research program grant for the development of stable glucagon formulations for use in an artificial pancreas, also known as a closed loop pump system. The two-year, $582,763 grant is intended to fund research to develop a candidate optimized to algorithmically deliver glucagon as part of a bihormonal closed loop system to mitigate hypoglycemic events. (See BioWorld Today, Sept. 25, 2012.)

And in October ViaCyte, Inc., of San Diego, said it received a $10.1 million Strategic Partnership Award from the California Institute for Regenerative Medicine (CIRM). The company's stem cell-based therapy for diabetes has been supported by several previous rounds of funding from CIRM, which has helped in the development of VC-01, a combination product consisting of pancreatic beta cell progenitors encapsulated in a durable macroencapsulation device. When implanted under the skin of a patient with diabetes, VC-01 is expected to produce insulin and other factors, which should control their disease.

ViaCyte said it is on track to initiate clinical evaluation of VC-01 in 2014.