Diabetes and the pharmaceutical industry

New developments in treatments for type 2 diabetes

In type 2 diabetes, raised blood glucose levels have important effects on many different cellular processes in a wide range of cell types and body organs. While this results in the great variety of changes that may cause clinical symptoms, it also enables many different approaches to be taken towards developing effective treatments.

Different mechanisms underlie the activities of the five existing classes of oral antidiabetic agents, and a increasing understanding of these and other disease mechanisms has suggested new ways of intervening to normalise blood glucose regulation. This section outlines some new compounds presently under development that are aimed at achieving this control without the limitations and disadvantages of existing therapies.

New insulin sensitisers
The insulin-sensitising properties of the glitazones have made them useful agents for treating type 2 diabetes, as insulin resistance is the main feature of the disease, especially in those who are overweight. However, the weight gain and fluid retention seen with pioglitazone and rosiglitazone lessens their appeal. Several new insulin sensitisers are currently under investigation. Some of these belong to the glitazone class, but others have unrelated chemical structures.

Existing insulin sensitisers specifically target the cell nucleus receptors known as PPAR-gamma receptors, and there are other compounds of this type in development. Eli Lilly and Ligand Pharmaceuticals are jointly developing naveglitazar, a non-glitazone medicine currently in Phase 2 research that mainly acts on PPAR-gamma but also has a weak effect on PPAR-alpha. Astellas also has a non-glitazone PPAR-gamma agonist (FK-614) at this stage in the US and Japan.

Sankyo has a PPAR-gamma-specific glitazone type agonist (rivoglitazone) in Phase 2 development, as has Amgen (AMG 131). Roche also has a PPARgamma agonist (R483) in Phase 2 trials.

PPAR-gamma is a transcription factor (protein) that binds to DNA and regulates the expression of a number of genes, including that linked to the glucose transporter protein that causes glucose entry into cells. Stimulating PPAR-gamma leads to increased glucose uptake.

PPAR-gamma, found mainly in fat cells, is only one of three such transcription factors. The first to be discovered, PPAR-alpha, regulates genes that are important for lipid metabolism. As people with diabetes often have adverse changes to their plasma lipid profile, it would be useful to find an agent that could activate PPAR-alpha, and sanofi- aventis has such a compound (AVE8134) in Phase2 trial. An existing class of medicines, the fibrates, also act on PPAR-alpha and may be prescribed to control dyslipidaemia. However, a single agent that could stimulate both PPAR-alpha and PPARgamma would be more valuable, and several companies are researching such dual activators.

Two dual PPAR agonists, both of the non-glitazone type, are muraglitazar (MSD and Bristol-Myers Squibb), in Phase 3 trial, and tesaglitazar (AstraZeneca), also at the Phase 3 stage. Takeda has a non-glitazone dual agonist (TAK-654) at the Phase 2 stage.

AVE0847 (sanofi-aventis) is in Phase 2a trial and there are several other dual agonists at the Phase 1 stage: AZD 6610 (AstraZeneca), E-3030 (Eisai) and R1439 (Roche). Still in pre-clinical development are AVE0897 and AVE5376 (sanofi- aventis).

In 2004, the US authorities requested a worldwide regulatory review of the safety and toxicology of all dual PPAR agonists, because of concerns about the development of tumours in rodents during testing of some earlier discontinued compounds, and development of this class of medicines may be delayed by this decision.

Recent research has shown that a third PPAR receptor, PPAR-delta, plays an important role in stimulating fatty acid oxidation. As excess circulating free fatty acids are thought to contribute importantly to insulin resistance, this too would appear an attractive target in type 2 diabetes. PPAR agonists active against all types (panagonists) are being developed by GSK (677954; Phase 2), Perlegen Sciences (netoglitazone; Phase 2) and Wyeth/Plexxikon (PLX204; Phase 1).

In a different approach, Metabolex is developing a selective PPAR-gamma modulator of the nonglitazone type (metaglidasen), which has reached the Phase 2 stage (with a back-up compound MBX- 2044 at Phase 1). By selectively activating the PPAR-gamma receptor, the company believes that the compound will switch on the genes responsible for increasing insulin sensitivity without at the same time stimulating the weight gain and oedema seen with conventional glitazones. The company has also identified PPAR dual agonists and selective PPAR-delta agonists which are in preclinical research.

Lastly, GSK is developing two fixed-dose combinations of existing medications (extended release rosiglitazone + metformin, now available in Europe, and rosiglitazone + sulphonylureas, awaiting authorisation) that may assist in achieving convenient dosing schedules in type 2 diabetes.

The glucagon/GLP-1 approach
Most of the medicines for the treatment of type 2 diabetes discussed so far affect either the release or action of insulin. This is partly a reflection of the historical importance of insulin. However, there is another pancreatic hormone called glucagon that plays a major role in blood glucose regulation. This hormone was first described soon after insulin itself, but it was not until the late 1970s that its role became clear.

Glucagon is released from the alpha cells of the pancreas, which make up about 15-20 per cent of the cells in the islets. Like insulin, it passes via the portal vein into the liver. In the liver, it stimulates the breakdown of stored glycogen and the formation of glucose, releasing it into the circulation. Insulin has the opposite effect on these two processes. Glucagon can thus be thought of as a sort of “anti-insulin”. It is the balance between these two hormones that maintains normal glucose levels.

Injection of glucagon leads to a rapid rise in blood glucose. For this reason, glucagon is given to treat severe hypoglycaemia when oral or intravenous glucose is not effective.

Efforts to intervene directly in this process, by finding inhibitors of glucagon action, have not proved successful. However, an alternative approach builds on the ability of another peptide hormone (GLP-1) to modulate the insulin/glucagon balance and is currently the subject of lively research.

GLP-1 (Glucagon-Like Peptide 1) is a peptide that is released from cells in the lining of the small intestine in response to food intake.

GLP-1 has several actions that are of considerable interest for the treatment of type 2 diabetes:

• It acts on a specific receptor on pancreatic beta cells, stimulating insulin formation and release
• This action is glucosedependent, occurring when blood glucose levels are high and decreasing as they drop
• It inhibits the release of glucagon from alpha cells, reducing glucose output from the liver
• It improves insulin sensitivity
• It improves the functioning of beta cells, slowing cell death and encouraging the development of new beta cells
• It slows the emptying of the stomach
• It produces a feeling of fullness, reducing the desire to eat.

GLP-1 itself is not suitable as a therapeutic agent, as it is very quickly destroyed by the enzyme dipeptidyl peptidase IV (DPP-IV) in the body. It also causes nausea and vomiting. Instead, research centres on compounds which work in a similar way to GLP-1 - GLP-1 analogues - and on finding inhibitors of the DPP-IV enzyme that breaks it down.

GLP-1 analogues
GLP-1 analogues (incretin mimetics) seek to extend the duration of action as compared with natural GLP-1 and to avoid unpleasant gastrointestinal side-effects, while retaining the regulatory activity of the natural hormone.

Exenatide (Lilly/Amylin) is the furthest advanced compound of this type and has been approved by the FDA. It is currently being evaluated by the authorities in Europe. This is a synthetic version of a naturally occurring hormone found in the venom of the Gila monster - a poisonous lizard found in the southwestern United States and Mexico.

Exenatide is taken by subcutaneous injection during the hour before the morning and evening meals. In the United States, it is authorised for use in those whose hyperglycaemia is inadequately controlled by metformin and/or sulphonylureas, but an eventual authorisation in Europe may differ from this. When used together with metformin, it did not increase the risk of hypoglycaemia, but thisrisk was increased when used together with a sulphonylurea. Sustained use has been shown to result in additional reduction in blood glucose (about 1.2 per cent in HbA1C) beyond that achieved with metformin or sulphonylureas, and a progressive reduction in weight. A long-acting version of this compound is now in Phase 2 development.

Another GLP-1 analogue in development is liraglutide (NN2211, Novo Nordisk). This is a modified form of GLP-1 which binds strongly to the plasma protein serum albumin, protecting it from breakdown and extending its effect on blood glucose. It is hoped that once-a-day injection will be sufficient in normal use. Liraglutide is expected to enter Phase 3 trials towards the end of 2005.

A similar approach is being taken by ConjuChem, which has produced a chemically modified GLP-1 analogue (CJC 1131) which is at the Phase 2 stage.

Human Genome Sciences, in collaboration with GSK, have taken the alternative step of linking the GLP-1 to albumin as a recombinant gene product prior to injection. This compound (GSK716155) is at the late preclinical development stage.

Beaufour Ipsen is also working on a GLP-1 analogue. This compound (BIM 51077) has reached Phase 2 clinical trial, as has another GLP-1 analogue under development by sanofi- aventis (AVE0010). Sankyo has a nasal spray form of recombinant human GLP-1 (CS-872) which is in Phase 2 development in Japan.

DPP-IV inhibitors
While there have been encouraging results with the GLP-1 analogues, they mostly have the disadvantage that they must be given by subcutaneous injection. Much effort is being devoted to trying to find orally active compounds that affect the GLP-1 system, and this work has centred on finding inhibitors of the DPP-IV enzyme that rapidly inactivates GLP-1.

Of the many DPP-IV inhibitors being tested, Vildagliptin (LAF 237, Novartis) has advanced furthest in the clinic. Currently being tested in a variety of Phase 3 trials, this compound has shown improved HbA1C and fasting glucose levels in Phase 2 studies, both as a single therapy and in combination with metformin. In a one-year study, there was also evidence that it improved beta cell function, but, in contrast to treatment with GLP-1 analogues, giving vildagliptin did not result in weight loss

Sitagliptin (MK-0431, MSD) is another DPP-IV inhibitor to have reached Phase 3. It has earlier demonstrated a significant reduction in HbA1C in short-term Phase 2 trials in patients with moderate hyperglycaemia who are being treated for the first time.

Several other compounds have reached Phase 2 trials. Bristol-Myers Squibb is progressing saxagliptin (BMS 477188), GSK has denagliptan, Roche has R1438, Prosidion is studying PSN9301 and Takeda has SYR-322. At Phase 1, Roche has R1499, Lilly is developing TS-021 and Tanabe has TA-6666.

Other approaches to glucose regulation
The PPAR-activators, GLP-1 analogues and DPP-IV inhibitors make up the main classes of medicines under investigation for controlling blood glucose in type 2 diabetes, but the number of cellular processes affected by the disease is so great that these approaches are far from exhausting all possibilities. Some other approaches in earlier stages of clinical research are briefly described here.

• Inhibition of gluconeogenesis, the formation of glucose in the liver, is one potential way to reduce blood glucose. Sankyo and Metabasis Therapeutics are conducting Phase 2 trials with the fructose 1,6 bisphosphatase CS-917 (also known as MB06322). This enzyme controls the rate of gluconeogenesis and CS-917 has been shown in early Phase 2 trials to cause a clinically significant reduction in blood glucose levels in patients with type 2 diabetes.
• Inhibition of glycogenolysis (breakdown of stored glycogen) in the liver and muscles is another glucose-reducing strategy. The enzyme The Gila monster has provided a potential lead to a new medicine for diabetes 48477_ABPI_Target_Diabetes.qxd 30/11/05 11:08 am Page 30 31 glycogen phosphorylase controls this process. Prosidion has an inhibitor (PSN357) in Phase 1 trial, as has sanofi-aventis (AVE5688), which also has a second such compound (AVE2865) in preclinical development.
• Glucokinase activators reduce blood glucose by a dual mechanism. The enzyme glucokinase (a “glucose sensor”) transforms glucose in pancreatic beta cells, stimulating insulin secretion, and increasing glycogen formation in liver and muscle cells. Both actions reduce glucose levels in the circulation. The attractiveness of these compounds is that, unlike sulphonylureas, their insulin-secretion stimulating action is glucose-dependent, and they would thus be expected to be less likely to cause hypoglycaemia. Roche has a compound in this class in Phase 1 trial (R1440) and Prosidion has PSN010 in preclinical development. Another compound that increases insulin secretion in a glucose-dependent manner, but whose mechanism of action has yet to be defined, is ID 1101 (Innodia), which was originally identified in fenugreek. This compound has completed Phase 1 trials.

Two further research directions are being actively explored that do not intervene in glucose metabolism in these ways:

• GSK and sanofi-aventis are exploring inhibitors of the sodium-glucose co-transporter SGLT2. Found in the intestines and in the kidney, it is responsible for re-uptake of glucose. If inhibited, excess glucose would be expected to be excreted in the urine, reducing hyperglycaemia. GSK has a compound (869682) in Phase 2 trial and another (189075) at the Phase 1 stage, while sanofi- aventis has AVE2268, also in Phase 1.
• Amylin Pharmaceuticals has developed an amylin analogue, pramlintide, which has recently been approved in the USA. Amylin is a hormone that is secreted together with insulin from beta cells. It inhibits glucagon secretion, delays gastric emptying and produces a feeling of fullness. Pramlintide is used together with insulin at mealtimes in both type 1 and type 2 diabetes, but not as a single therapy. It has been associated with a risk of severe hypoglycaemia. It is in preparation for submission to the European authorities.

Many other interventions in the cellular and biochemical processes involved in glucose regulation are possible, and those discussed here are not exhaustive. Additional targets for development are constantly being identified and explored as more is learnt about the mechanisms behind type 2 diabetes. It should, however, not be forgotten that medications are a partner in treatment and not a replacement for essential changes to lifestyle, such as diet and exercise.