As the name suggests, insulin sensitisers are a relatively new treatment, which primarily improves the body's response to the hormone. Insulin sensitisers currently on the market can effectively control blood glucose levels. However, they do have significant side effects in terms of oedema and weight gain.
Insulin sensitisers, with worldwide sales of nearly $4 billion (€3 million), represent an attractive treatment option for type 2 diabetes because they target insulin resistance, the underlying cause of the disease. Both MBX-2044 and Metabolex's lead compound, metaglidasen (formerly MBX-102), are insulin sensitisers that have chemical structures and methods-of-action that are different than current insulin sensitisers on the market.
PPARs (peroxisome proliferator-activated receptors) control the expression of genes involved in glucose metabolism, lipid metabolism and inflammation. Metaglidasen and MBX-2044 are Selective PPAR Modulators (SPPARMs) that modulate the genes needed for insulin sensitisation, but not those responsible for oedema and weight gain.
"The marketed insulin sensitisers cause weight gain which can lead many patients to stop taking them. Moreover, many patients should not even start therapy with these drugs because they can induce oedema, or fluid retention, which can lead to the serious side-effect of congestive heart failure," said David Karpf, chief medical officer of Metabolex.
In the Phase 1 clinical trial for MBX-2044, healthy volunteers were given a single dose ranging from 1.5 mg to 120 mg. There were seven dosing cohorts and each cohort consisted of six non-diabetic men and women who were either overweight or normal weight. MBX-2044 was well tolerated at all doses and showed a reduction in uric acid levels, a property also shared by metaglidasen, after a single dose.
"MBX-2044 is an excellent complement to our portfolio of second-generation product candidates, and the results of this trial enable us to move it forward to proof-of-efficacy studies," he said.
The rapid growth of oral antidiabetics seen from 1997 onwards was led by the first thiazolidinedione insulin sensitiser, or glitazone, Glaxo Wellcome's Rezulin (troglitazone), followed by SmithKline Beecham's (now GlaxoSmithKline) Avandia (rosiglitazone) and Actos (pioglitazone) from Takeda, co-promoted by Eli Lilly.
Novo Nordisk has an oral antidiabetic drug (OAD) called Prandin (repaglinide) (NovoNorm outside the US) has been around for around seven years and is considered one of the most effective treatments for type II diabetes. Prandin is an 'insulin secretagogue' as it stimulates insulin secretion, was previously approved for use as monotherapy or in combination with metformin, another type of insulin sensitiser.
An insulin sensitiser that did not have similar luck is troglitazone (rezulin). The manufacturers voluntarily withdraw the drug on March 21, 2000 in the US, Japan, the Philippines, and Australia. It was also suspended in the United Kingdom in December, 1997 pending review of safety data and later withdrawn from the UK market following reports of serious adverse effects on the liver.