AstraZeneca delays diabetes drug

Galida is now unlikely to be filed before 2007, adding to AstraZeneca's problems with two other recently launched products, the cholesterol-lowering drug Crestor (rosuvastatin) and Exanta (ximelegatran).

In the summer, European regulators tightened up the labelling for Crestor on concerns about muscular side effects, leading to fears that sales growth of the drug may be held back. Crestor achieved sales of around €175 million in the first half of this year. Meanwhile, Exanta was rejected for sale by US regulators last week, also on safety grounds.

Galida has been delayed by a request by the US Food and Drug Administration for another year of safety studies, as part of a worldwide regulatory authority review of the safety and toxicology of all the drugs in its class, the dual peroxisome proliferator activated receptor (PPAR) agonists.

Galida, a dual peroxisome proliferator activated receptor (PPAR) agonist, targets mechanisms in the cell that control the absorption of fat and sugar in the bloodstream. The compound entered Phase III trials in October 2003 with seven studies currently underway.

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. The first of these agents, Warner Lambert's Rezulin (troglitazone) was withdrawn because of rare but fatal hepatotoxicity, after two other drugs - GlaxoSmithKline's Avandia (rosiglitazone) and Takeda/Eli Lilly's Actos (pioglitazone) became available.

Other casualties include Novo Nordisk/Dr Reddy's Laboratories' ragaglitazar, Japan Tobacco's reglitazar and Merck & Co's MK-767.

In 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.

The efficacy of the current generation of PPAR agonists remains less than ideal and side effects, including fluid retention and anaemia limit their use. This has prompted the development of a variety of other PPAR agonists, in the hope that the newer dual PPARs will have a role not just in treating diabetes but also potentially in preventing the disease and treating heart disease.

With Galida, AstraZeneca is hoping to provide a new PPAR agonist that offers improvements over existing drugs, although at present there is not enough data to back up this claim. And diabetes researchers suggest that many of the new PPAR agonists fall into the 'me too' category, offering little advance over the current generation.

In the early stages of research, attention is now shifting to a subset of PPAR - PPAR delta - and away from the current focus on alpha and/or gamma agonists, Both Avandia and Actos fall into the latter category.

GlaxoSmithKline has at least one PPAR delta agonist in development, and others that have gone public with the news include Fujisawa, and Esperion/Nippon Chemiphar.

For AstraZeneca, the news of the delay of the regulatory filing for Galida gains further significance if one considers the rest of the company's late-stage pipeline. The company suggests that the earliest regulatory filings would come as late as the second half of 2006, leaving a period of at least two years without any significant pipeline development for AstraZeneca.

Meanwhile, while Exanta is already approved in some European markets for treatment of patients after surgery, it has yet to win a green light for long-term use in preventing strokes among people with atrial fibrillation, a far larger and more lucrative market.

Datamonitor notes that although Galida, if approved, will be targeted towards the ever-growing diabetic population, negative perceptions for dual PPAR agonists may limit its appeal. The safety concerns associated with this class of compounds have led to most physicians being wary of them, and generally unwilling to incorporate them in their everyday clinical practice.