Roche Terminates Diabetes Drug Aleglitazar in Phase 3

by Deborah Toscano 11 Jul 2013
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Roche announced yesterday that they have terminated all trials of aleglitazar, a dual PPAR alpha/gamma agonist in Phase 3 for diabetes management as well as cardiovascular risk reduction in diabetes patients.  All ongoing trials were discontinued due to safety concerns that arose in AleCardio, the trial assessing the potential benefit of the drug in diabetes patients with acute coronary syndrome, a particularly high risk population.  While this development is undoubtedly a tremendous disappointment to Roche, it is also another letdown for the medical community desperately seeking an answer and solution to the problem of residual cardiovascular risk in diabetes patients.  Diabetic patients are at particularly high risk of heart disease and death (equivalent to a previous heart attack), even if glucose levels are managed carefully with every known therapy.  The PPAR agonists were a drug class that could hopefully address the problem, particularly the dual agonists targeting both alpha and gamma.  PPAR gamma agonists, or thiazoladinediones (TZDs) are well known to be effective insulin sensitizing drugs, but fraught with safety issues, well demonstrated by the success and then eventual failure of Avandia and Actos.  PPAR alpha agonists, also known as fibrates (e.g. Tricor), are safe and effective lipid modulators, particularly for mixed dyslipidemia.  It was hoped that by designing drugs that target both PPAR receptors but avoiding the class-associated side effects, the end result would be a safe and effective glucose and lipid lowering agent that would not only normalize glucose in diabetic patients but would also help prevent heart attacks.  Despite late-stage failures of several related drugs such as Bristol-Myers Squibb’s muraglitazar and AstraZeneca’s tesaglitazar and most others scrapping similar programs, Roche admirably pressed on with aleglitazar in the hopes that they had something that would be effective and safe enough in these high risk patients desperately in need of something to reduce the risk of a second heart attack and/or death.  Unfortunately, residual cardiovascular risk, in non-diabetic as well as diabetic patients remains an unsolved mystery.  Drug developers searching for answers are targeting multiple risk factors such as chronic inflammation, dyslipidemia, and endothelial dysfunction in the hopes of at last discovering a life-saving drug that can prevent cardiovascular and cerebrovascular events in the growing high risk patient population.

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