The future of dual α-/γ-peroxisome proliferator-activated receptor agonists may be in question now that development has been halted on two such agents after the completion of phase III trials.
In early May, AstraZeneca announced the discontinuation of tesaglitazar (Galida), its dual α-/γ-peroxisome proliferator-activated receptor (PPAR) agonist. Phase III data suggested elevations in serum creatinine and a decrease in glomerular filtration rate, effects previously associated with the PPAR-α agonist (fibrate) portion of the molecule. Two weeks later, Bristol-Myers Squibb said it was halting development of muraglitazar (Pargluva).
The action followed the Food and Drug Administration's request for additional long-term data to clarify the agent's cardiovascular risk profile.
The specific reasons for the decisions differed, but both reflect the difficulty associated with developing agents that maximize the glucose-lowering effect without increasing the risk for side effects, according to Dr. John B. Buse, the American Diabetes Association's vice president for medicine and science and director of the Diabetes Care Center at the University of North Carolina, Chapel Hill.
“I think the FDA got it right. What the world needs is not a stronger diabetes drug, but a safer one,” he said.
Indeed, for lowering glucose levels, tesaglitazar and muraglitazar were at least as good as the currently marketed agents pioglitazone (Takeda's Actos) and rosiglitazone (GlaxoSmithKline's Avandia).
However, increased doses of pioglitazone and rosiglitazone are often associated with significant weight gain and edema without much further improvement in lowering glucose, compared with the more moderate doses, Dr. Buse pointed out.
Given that pioglitazone, which also has a lipid-lowering effect, may become generic in 2011, Dr. Buse commented that new PPAR-agonist drugs face substantial challenges for successful development unless their efficacy rivals that of the current glitazones and their safety and tolerance are superior.
Such a drug could particularly benefit the 25% of insulin-requiring type 2 diabetic patients with contraindications or inability to tolerate rosiglitazone or pioglitazone.
“We have good drugs. What we need are better tolerated drugs,” he said.
Dr. Buse has no current financial ties to AstraZeneca, Bristol-Myers Squibb, Glaxo-SmithKline, or Takeda.