Addressing the unmet need of diabetics with new generation non-insulin antidiabetics

It is estimated that there are more than 38 million people in the seven major markets with diabetes and this figure is set to rise to 50 million in 2012. However, despite this vast potential patient population, low diagnosis rates, the chronic nature of the disease, the need for combination therapy, the lack of an oral antidiabetic agent offering effective long-term therapy and the association of injectable therapies with poor patient compliance mean that a broad spectrum of unmet needs exists. However, the last few years have bore witness to a great surge of activity towards the discovery and development of new agents that could address the unmet needs in diabetes therapy and potentially change the way that this disease is treated. The new classes of drugs that are soon expected to enter the market include GLP-1 agonists; DPPIV inhibitors and; dual PPAR agonists.

The data and conclusions in this feature are discusses in depth in our new feature on non-insulin antidiabetics - click here for further information

Despite the presence of well established treatments of diabetes, such as insulin, metformin and sulfonylureas and the recent introduction of new classes such as thiazolidinediones (TZDs), alpha glucosidase inhibitors (AGIs) and prandial glucose regulators (PGRs), there are still important unmet needs in the treatment of diabetes.

Incomplete control of HbA1c levels is the major drawback to current non-insulin antidiabetics

The two most important unmet needs are the ability of an agent to exhibit prolonged efficacy in reducing hyperglycemia and to be disease-modifying, i.e. to target the underlying causes of the disease rather than its symptoms. Many opinion leaders feel that currently available drugs are not efficient enough in lowering glycated hemoglobin (HbA1c). Most of the commonly used antidiabetics, with the exception of insulin, are only able to reduce HbA1c by approximately 1%. This is frequently not enough for patients who have had diabetes for a long time and whose HbA1c is much greater than the recommended targets.

Additionally, even if good glycemic control is achieved, many agents fail to maintain their antihyperglycemic effect over a prolonged period. This is one of the major contributing factors driving combination therapy and the need for switches between drug classes. The main reason for the lack of prolonged efficacy is the fact that the currently available agents attempt either to sensitize specific tissues to the effects of insulin, or to enhance the insulin producing activity of the pancreas. The true underlying cause of the disease, which is the declining function of pancreatic beta cells, is not sufficiently targeted. An agent that could effectively address this issue would have a huge market potential.

The next two most important unmet needs are safety and side-effect profile of prospective agents. The need for robust safety data has become increasingly important in the recent years, with approved agents such as the TZD Rezulin having to be withdrawn. This followed an increasing numbers of reports that patients who were taking Rezulin developed serious liver toxicity.

Patient compliance ranked much lower among all the unmet needs examined. This reflects the belief that if an agent is proven safe and has a good side-effect profile, compliance is bound to be good.

The need for routine screening following the administration of the drug is a price that physicians are willing to pay in order to achieve good glycemic control. However new therapeutics that do not require such extensive monitoring would carry a considerable advantage, especially in a chronic disease like diabetes. Routine screening may be required in the form of complicated biochemical tests, such as the liver function tests that had to be undertaken every six months following the administration of TZDs, or in the form of self-monitoring, such as the fingertip glucose measurements that patients on insulin need to repeat many times a day in order to reduce the risk of a hypoglycemic incident. As a result, routine screening may become a nuisance for the patient, while at the same time incurring extra costs (glucose meters and strips) and hence affecting patient compliance.

GLP-1 agonists lead the way forward in the search for new non-insulin diabetic agents

Oral antidiabetic drugs have traditionally focussed on metformin and sulphonylurea. Until 1995, the sulfonylurea class of drugs which act by increasing insulin secretion was the only choice in the United States other than insulin for treating type 2 diabetes. The explosion of drugs available for controlling blood glucose began when Glucophage (metformin) became available in 1995, quickly followed by the approval of the insulinotropic agent Repaglinide in 1997 and the thiazolidinedione PPAR gamma agonist insulin sensitizers such as Avandia and Actos, which were both launched in 1999. GLP-1 is a gut hormone released after food consumption to stimulate insulin secretion.

One of the most exciting classes of agents in development is GLP-1 agonists. The naturally occurring incretin hormone, GLP-1 stimulates the body’s ability to produce insulin in response to elevated levels of blood glucose, inhibits the release of glucagon following meals and slows the rate at which nutrients are absorbed into the bloodstream. In animal studies administration of GLP-1 agonists resulted in preservation and formation of new beta cells which fail as type 2 diabetes progresses. This class aims to address two of the main unmet needs in diabetes treatment, prolonged efficacy and the potential to act on the underlying cause of the disease rather than on its symptoms. Although there have been suggestions that these agents will exhibit efficacy over an extended period of time and that they will possibly offer some effect on beta-cell preservation, these findings need to be conclusively proven through specifically designed trials. It will also be crucial to stress that the administration of GLP-1 analogs will not need to be accompanied by frequent glucose monitoring since the risk of hypoglycemia is small.

Because GLP-1 analogs are injectable, GLP-1 analogs will inevitably be compared with insulin, as well as most probably being reserved for later stages of therapy compared with other developmental and established medications. Since insulin is the most potent agent in reducing HbA1c, it will be difficult for GLP-1 analogs to prove comparable efficacy. As the situation stands today, the ideal population for GLP-1 analogs would be patients who are failing on oral antidiabetic drugs, but who are reluctant to move to insulin therapy out of fear of hypoglycemia, weight gain and/or frequent glucose monitoring. This however will mean that GLP-1 analogues will need to be disease modifying at a late stage of the disease, which is a tall question to ask of this class.

Nethertheless, the GLP-1 analogue Exenatide is expected to be the first new generation non-insulin antidiabetic to reach the market. Exenatide is a synthetic form of exendin-4 which was initially isolated from the venom found in the saliva of a poisonous South American lizard known as the Gila monster. Exenatide was initially developed by Amylin however in September 2002 the company announced a global agreement with Eli Lilly to collaborate on the development and commercialization of exenatide. The combination of potency and the glucose dependent mechanism of action inherent in exenatide make it well suited for the development of a sustained release formulation. In May 2000, Amylin signed an agreement with Alkermes, Inc. for the development, manufacturing and commercialization of an injectable sustained release formulation of exenatide, referred to as exenatide LAR. The launch of exenatide LAR is expected to lag behind that of exenatide by about two years, however the forecast revenue of the former is likely to dwarf that of its predecessor. Exenatide is forecast to peak with sales of $97 million in 2007, at which time exenatide LAR should be launched. Sales are expected to grow steadily reaching $1.5 billion by 2012. Liraglutide, a long-acting derivative of GLP-1, is also expected to be launched in 2007. This candidate, developed by Novo Nordisk will exhibit all of the effects of native GLP-1, but in addition will offer a very simple and convenient dose regime of once a day injection. Still, analysts do not expect sales of Liraglutide to come anywhere near those of exenatide LAR, reaching $200 million in 2012

DDPIV inhibition offers an improved approach to increasing GLP-1 bioactivity

Another class of agents soon expected to enter the market are DPPIV inhibitors. These agents target the same biochemical pathway as GLP-1 agonists, but instead of supplementing the natural pool of GLP-1, they attempt to inhibit the enzyme responsible for its breakdown. This difference is a source of both advantages and disadvantages.

The main advantage of DPPIV inhibitors is their mode of administration. They will be available as pills or capsules, in contrast to the GLP-1 agonists that will have to be injected. This makes them far more attractive in the eyes of patients and physicians and is likely to help their faster uptake and increased patient compliance. As a result, DPPIV inhibitors will be able to avoid comparison with insulin and will be most likely compared to other oral medications such as TZDs. Although the two classes of agents are distinct in terms of mechanism of action, the fact that they are likely to be close price-wise will facilitate their comparison. Despite the fact that DPPIV inhibitors are lagging behind GLP-1 agonists in the developmental race, this may be a fact that could work in their favor. The earlier introduction of GLP-1 agonists, may prime the market and aid the introduction of the concept of incretin mimetics to physicians. In this way DPPIV inhibitors may not be considered as a totally new class but as a different approach to an already familiar concept.

The greatest disadvantage of DPPIV inhibitors has always been the doubts over their safety due to lack of specificity. However, as the first compounds in this class enter Phase III trials without any reports for significant adverse effects, these doubts appear to be subsiding.

Novartis' LAF-237 is leading the DPPIV inhibitor market with launch expected in 2007. Sales are expected to parallel those of exenatide LAR reaching $1.9 billion by 2012. Merck's MK-431 is lagging behind LAF-237 however launch is expected in 2009 and sales are forecast to exceed $1 billion by 2012.

Liver toxicity and oncogenicity slow the progress of dual PPAR agonists

The peroxisome proliferator-activated nuclear receptor (PPAR) family has received particular scrutiny in the field of diabetes and as a result the thiazolidinediones have emerged as a therapeutic class. First generation thiazolidinediones were agonists of the PPAR gamma receptor and were able to reduce insulin resistance. One adverse effect associated with PPAR gamma receptor agonists is however weight gain. Given the comorbidity of type II diabetes and obesity this can limit the usefulness of such molecules. More recently molecules have been developed that activate PPAR alpha. This class is able to reduce triglyceride levels and is also able to improve insulin sensitivity and as a result dual PPAR alpha/PPAR gamma agonists have been developed with proposed beneficial effects over existing PPAR gamma- and alpha-preferential drugs in treatment of type 2 diabetes.

Although dual PPAR agonists were once hailed as the next big development in the treatment of diabetes, the recent withdrawal of many leading agents following safety concerns has prompted the FDA to request additional safety data before considering the approval of any such compounds. Most recently Takeda have placed their candidate, TAK-559 on clinical hold because of findings of abnormalities in liver enzyme tests in a small number of patients during the course of the phase III studies. In addition many late stage compounds have been withdrawn after they were shown to cause tumors in rodents. As a result, the FDA requested a minimum of two years of animal safety data before allowing any human trials to take place. This will have a profound effect on the agents currently in development, delaying their proposed filing dates by at least 18 to 24 months. Most recently AstraZeneca has delayed the regulatory approval filing target for its dual PPAR agonist, Galida, from 2006 to 2007; likewise Ligand have announced a 2 year delay in the development of Naveglitazar.

Furthermore, many physicians and opinion leaders appear to be losing faith to the concept and question the true benefits that such an approach could offer. In particular some field leaders feel that although PPAR alpha agonism may lower triglycerides more than gamma agonists the combination of a statin with a PPAR gamma agonist would achieve similar results. In the presence of statin therapy, PPAR alpha inhibition has never been shown to have any major effect on outcomes. In fact, there is very little data on PPAR alpha effects for primary prevention of heart disease (the underlying reason for reducing triglycerides) anyway. Furthermore the data that is emerging on the vascular effects of TZDs appear to suggest that PPAR agonists have beneficial cardiovascular effects due to the anti-inflammatory activity of gamma agonism rather than the lipid lowering effects of PPAR alpha activation.

Despite the lukewarm reception destined to meet the dual PPAR agonists a number of candidates are approaching the market. Muraglitazar, discovered by Bristol-Myers Squibb, is likely to be the first approved for marketing in the US. The company submitted a New Drug Application to the FDA in December, 2004. Launch is expected in 2008 however sales are forecast to peak at only$0.4 billion.

Source: LeadDiscovery (January, 2005)

The data and conclusions in this feature are discusses in depth in our new feature on non-insulin antidiabetics - click here for further information