PPAR co-agonist will progress to phase III trials

June 9, 2009

Aleglitazar, a peroxisome proliferator-activated receptor (PPAR) co-agonist will enter phase III clinical trials after a phase II trial demonstrated efficacy and safety at a range of dosages.

Aleglitazar, a peroxisome proliferator-activated receptor (PPAR) co-agonist willenter phase III clinical trials after a phase II trial demonstrated efficacy andsafety at a range of dosages.

Results of the effect of the dual peroxisome proliferator-activatedreceptor-α/γ agonist aleglitazar on risk of cardiovascular disease inpatients with type 2 diabetes (SYNCHRONY) study were presented by Robert R. Henry,MD, University of California, San Diego. "It will be particularly interesting to seewhether the combined beneficial glucose and lipid effects will translate into abenefit on cardiovascular outcomes," he says.

The sample size of this study was too small to make definitive conclusions, butthat no heart attack or stroke events occurred is reassuring. By contrast, excesscardiovascular events have been noted for patients given muraglitazar androsiglitazone after a fairly short exposure to treatment," says Dr. Henry.

Aleglitazar has similarities to rosiglitazone and pioglitazone, which are botheffective glucose-lowering agents for patients with type 2 diabetes; however, adoubling of heart failure and distal fracture risk associated with rosiglitazone has been reported this week.

"The balance of safety and efficacy in today’s paper is encouraging, but it isimpossible to draw definitive clinical conclusion from such a phase II study,"comments Bernard Charbonnel, MD, Institut du Thorax, University of Nantes, France,in an editorial accompanying the SYNCHRONY study results. Both are published onlineahead of print in the Lancet.

"Experience with muraglitazar has shown that a good lipid and blood glucoseprofile is not sufficient to predict clinical outcomes. It is a strength thatcardiovascular events, including heart failure, were adjudicated in SYNCHRONY, butthe sample size and short duration of the study do not allow firm conclusions," Dr.Charbonnel continues.

Phase II results

SYNCHRONY included 332 patients randomized to receive once-daily aleglitazar atdoses of 50 µg, 150 µg, 300 µg, or 600 µg or placebo or open-label pioglitazone 45mg once daily for 16 weeks. There were 55 patients in each aleglitazar treatmentgroup and the placebo group, and 57 patients were randomized to pioglitazone.Patients were either treatment naive or had been previously treated with no morethan two antidiabetic drugs, none at the maximum dose. Baseline hemoglobinA1c (HbA1c) was between 7.0% and 10.0%.

The primary endpoint of the study was change in HbA1c from baseline.Researchers report that aleglitazar significantly reduced HbA1c frombaseline in a dose-dependent manner, and there was a similar dose-dependentreduction in fasting blood glucose levels.

Aleglitazar treatment reduced HbA1c by 0.36% in the lowest-dose groupand by 1.35% in the highest-dose group. All reductions were significant when compared to placebo (range, p=0.048 to p<0.001).The 150-µg, 300-µg, and 600-µg dosages of aleglitazar were associated with largerHbA1c reductions than placebo.

Researchers say that data analyses indicate that the full efficacy of aleglitazarhad not been reached by the end of the 16-week study period.

Edema, hemodilution, and weight gain were adverse events occurring in adose-dependent manner. Frequency of edema was lower among aleglitazar patients thanamong those randomized to placebo or pioglitazone. There were no incidents ofcongestive heart failure, and weight gain with the 150-µg dose was less than halfthat seen with pioglitazone (0.52 kg vs 1.06 kg).

"The favorable balance in the safety and efficacy profile of aleglitazarrepresents encouraging short-term clinical data for this agent and provides goodevidence to enter phase III investigation," Dr. Henry says.