Improving Treatment for Diabetes

Dr. James Shannon of Novartis tells NGP about the advantages its new diabetes treatments will bring to patients.

NGP. Could you please give us some background on type 2 diabetes and islet dysfunction?
JS. People with diabetes have difficulty converting food to the energy the body needs to function. Following a meal, food is broken down into a sugar, sometimes called blood glucose, which is carried by the blood to cells throughout the body. Blood sugar is the fuel the body requires, but too much sugar circulating in the blood will cause deterioration of tissues and organs, and is a major contributor to type 2 diabetes.

Type 2 diabetes (also known as adult-onset or non-insulin dependent) is a progressive disease where control of blood sugar deteriorates over time. Islet dysfunction and insulin resistance both contribute to diabetes. Specifically, islet dysfunction can lead to excess sugar production (via glucagon from the alpha cells) and reduced insulin production (from the beta cells).

An imbalance that causes – and worsens – type 2 diabetes occurs deep within the body in the islet cells of the pancreas. Islets contain two specialized cells, alpha and beta cells, that produce the hormones glucagon and insulin, which regulate blood sugar.

NGP. Galvus, Novartis’ new oral treatment for type 2 diabetes, works through a novel mechanism of action. Could you please explain how this mechanism works and why it is innovative?
JS. Galvus is a member of a new therapeutic class developed by Novartis, called DPP-4 inhibitors. Galvus works through a novel mechanism of action targeting pancreatic islet dysfunction, which causes high blood sugar levels in people with type 2 diabetes. It targets both pancreatic alpha and beta cells, improving their ability to appropriately sense and respond to sugar in the blood.

Galvus improves the function of islet cells by blocking the effect of an enzyme called DPP-4 and increasing the levels of a naturally occurring incretin hormone called GLP-1. Increased levels of incretins signal the liver to stop producing excess sugar and stimulate glucose-dependent insulin secretion in the pancreas to make more insulin, resulting in improved blood sugar levels in people with type 2 diabetes.

NGP. What does Galvus’ recent European approval mean for type 2 diabetes patients?
JS. With the European approval of Galvus, and equally importantly Eucreas (a combination of Galvus and metformin), physicians now have access to these novel and targeted ways to more specifically address patients who usually require additional treatment when metformin is inadequate. Less than 40 percent of patients with type 2 diabetes achieve the current treatment targets, and patients usually require at least two medicines, making the choice of what to add next to metformin a key opportunity for a new and better-targeted therapy, such as Galvus.

DPP4-inhibition addresses a basic pathological defect in type 2 diabetes and acts physiologically to restore an important balance between the key hormones involved in hyperglycemia, while avoiding weight gain, hypoglycemia, and having neutral to beneficial effects on lipids and blood pressure. This represents a considerable advance in the treatment of this debilitating disease.

NGP. Galvus lost the so-called ‘Diabetes Duel’ to Merck’s Januvia last year, when the FDA requested more data before Galvus could be approved in the US. How do you now see this competition playing out?
JS. Patients and physicians will benefit from having two companies out there educating the healthcare professionals on the use of this new and important advance in the management of diabetes.

Most diabetics in Europe are already given metformin as the first line agent – it is both effective and generic, and has a proven track record in outcome studies – but the most important treatment choice physicians make is what to do next, given how poor glucose control rates are in diabetics. By having both Galvus and Eucreas available, physicians will have the choice of whether to move patients directly to Eucreas so that there is no loss of convenience for the patient when they fail metformin, or, if they prefer, to use Galvus on top of the current agents, which include metformin, sulphonylurea (SU) or thiazolidinedione (TZD).

The most difficult choice physicians face today in treating diabetes is what effective treatment to use in patients who are on metformin, but who are inadequately controlled. We believe Eucreas will be a very attractive option to physicians who would have otherwise used a TZD or SU. Having a franchise of DPP-4 agents as single and fixed dose combinations provides a competitive advantage for Novartis.

NGP. What challenges and opportunities do you foresee in marketing Galvus on a global basis?
JS. The main challenge we currently face is the impact of the delay with making Galvus available in the US, and the perception that surrounds this. However, this is also an opportunity. As we roll out global registrations and launches for Galvus and Eucreas, we will accumulate confidence and clinical experience worldwide.

A key opportunity for Novartis, and something we are excited about, is also being able to bring both Galvus and Eucreas to regions other than Europe, given the epidemic incidence of diabetes in many of Asian and South American countries.

NGP. How do you see research in type 2 diabetes treatment developing over the next few years?
JS. We have a very active research group creating a pipeline of drugs with novel mechanisms targeted at preventing and managing type 2 diabetes, largely through a series of targets that control how the human body manages energy expenditure and fat metabolism. These targets, if successful, will have the likely additional benefit of reducing weight, and reducing the co-existing and related cardiovascular risks, including blood pressure, lipid abnormalities and inflammatory disease.

We are also actively looking into opportunities to acquire products fitting into this broad metabolic/diabetes strategy for possible licensing, if the strategic fit is good. With the latest and forward-looking draft guidance from the FDA on developing treatments for diabetes, there are some new possibilities for developing drugs for prevention of diabetes. There may even be opportunities to develop new treatments for metabolic syndrome – an important area of medical controversy over the last few years – which may open up the possibility to study new targets in this area.

Dr. James S. Shannon is Chief Medical Officer and Head of Global Line Functions at Novartis Pharma AG, and a member of the Pharma Executive Committee. He joined Sandoz in 1994 as Head of Drug Registration and Regulatory Affairs, Basel. During the merger that created Novartis, he was made Head of the R&D Integration Office, and he has also been Head of Global Project Management, Head of Clinical R&D, Head of Clinical Development and Medical Affairs, and Head of Pharma Development.