A drug in development at Bristol-Myers Squibb and Merck & Co could be the first treatment that tackles both insulin resistance and high blood lipids in type 2 diabetes, according to new data released at the American Diabetes Association’s annual meeting in San Diego this week.
Pargluva (muraglitazar) is a key drug for both B-MS and Merck, which are suffering from the impact of generic competition to leading brands and, in Merck’s case, the aftershock of its withdrawal of arthritis drug Vioxx (rofecoxib) from the market [[01/10/04a]]. And the new data suggest that the drug’s profile – reducing blood glucose while also addressing the lipid imbalances that increase the risk of cardiovascular diseases in diabetics – could drive it to blockbuster status.
Muraglitazar filed for approval in the USA last December, is currently leading the field in a new drug class, the dual PPAR agonists or glitazars. These target a market segment currently occupied by another class, the glitazones, which while enormously successful in commercial terms are clinically far from perfect.
The glitazone class is represented at present by two drugs, GlaxoSmithKline’s Avandia (rosiglitazone) and Takeda and Eli Lilly’s Actos (pioglitazone), which together have revenues in excess of $3 billion dollars. The two products counteract insulin resistance and improve blood glucose control, but have mixed effects on blood lipids. Labelling for both drugs includes a warning of the risk of cardiac failure and other cardiac effects due to edema, and both are known to cause weight gain.
But the glitazars have also had their fair share of development difficulties. B-MS and Merck’s nearest competitor in this class, AstraZeneca, was forced to delay the submission of its dossier for Galida (tesaglitazar) until 2007 after the US Food and Drug Administration (FDA) asked for extended safety studies, as part of a worldwide regulatory authority review of the safety and toxicology of all the drugs in the PPAR agonist class [[06/10/04a]].
Last July, the FDA announced in July that it would not allow any human tests of dual PPARs of more than six months’ duration, until two-year rodent toxicity tests had been completed and submitted to the agency. This request for testing has also delayed the start of Phase II trials of another dual PPAR agonist, Eli Lilly and Ligand Pharmaceuticals’ naveglitazar [[12/07/04e]].
Meanwhile, several promising candidates in the dual PPAR agonist class have already fallen by the wayside because of toxicity, including side effects such as oedema, raised levels of hepatic enzymes and tumours in rodents. Casualties include Takeda’s TAK-559 [[21/12/04c]], Novo Nordisk/Dr Reddy's Laboratories’ ragaglitazar [[22/07/02d]], Japan Tobacco’s reglitazar and Merck & Co’s MK-767.
Muraglitazar seems to remain on track, however, and the two Phase III trials reported at the ADA meeting back up the value of the drug in patients with type 2 diabetes.
In the first, 985 people were given different daily doses of muraglitazar, allowing the researchers to establish that the most effective dose was 5mg a day. The second trial included 1,159 type 2 diabetics - already on the widely used diabetes drug metformin - who were randomly assigned to take either muraglitazar or pioglitazone. After 24 weeks, blood glucose levels were 1.14% lower in the muraglitazar group, compared to 0.85% lower in the people taking pioglitazone.
Meanwhile, muraglitazar-treated patients showed an average 5.9 percent reduction in LDL-cholesterol, compared to a 1.2% decline in those taking pioglitazone, and levels of protective HDL-cholesterol were markedly higher in those taking B-MS’ drug.
With regards to safety data, muraglitazar was associated with oedema at all doses tested, but this occurred in less than 10% of patients on the 5mg dose. There was also a dose-related increase in weight with the B-MS/Merck drug.