One such published study, actually two studies in one report, from Steve Nissen et al (he’s one busy dude this week) describes Phase 2 experience with Lilly’s (LLY) investigational PPAR-alpha agonist, LY518674.
As you probably know, PPARs have been an extremely active target for the drug industry for decades. Despite the fervent interest in PPARs, the only PPAR modulators marketed in the U.S. are the relatively PPAR-gamma-selective agonists, rosiglitazone and pioglitazone for treatment of hyperglycemia in type 2 diabetes, and the relatively PPAR-alpha-selective agonist fibrates (e.g. fenofibrate, gemfibrozil), which are used to lower triglycerides and raise HDL-C in dyslipidemia to reduce risk of cardiovascular events. The demise of the PPAR-gamma agonist, troglitazone, has been well documented.
According to CDER, over 50 INDs have been filed for drugs designed as agonists of the PPAR receptors, including dual and pan agonists. But successful development to market has thus far eluded all comers, due to disappointing efficacy and a variety of clinical safety and preclinical toxicity issues, including rodent neoplasia seen with the PPAR gamma/alpha dual agonists.
Based on their promise in animal lipid-disorder studies, highly potent and selective PPAR-alpha agonists have been developed to improve upon fibrates. Lilly has managed to advance its highly potent and selective PPAR-alpha agonist through Phase 2 studies, the first pharma to do so, which is the subject of the Nissen et al. report in JAMA.
I’ll dispense with a review of most of the data in the report. The bottom-line implications for those still hoping that PPAR-alpha is a good target for treating atherosclerotic combined dyslipidemia is that it’s probably time to give up hope and move on to more promising targets. LY518674 is plenty potent and selective for PPAR-alpha, so LY518674 tests the PPAR-alpha agonist hypothesis adequately. It looks like the relatively low potency fibrates have maxed out improvements in apo A1/HDL-C levels that can be effected by alpha agonist treatment.
Although effects on CV outcomes with fibrate treatment have been generally favorable (see this for review and meta analysis), it’s unlikely that LY or other potent PPAR-alpha agonists will be tested in CV outcome studies. I say this because of the worrisome dose-related increase in LDL-C with LY that appeared to be correlated with baseline triglycerides in the dyslipidemia study. This surprising finding, more than anything else in the LY studies, will contribute to an understanding of PPAR-alpha’s role in human metabolism of lipoprotein metabolism, even as it signals what should be the end of the road for potent PPAR-alpha agonists.
LLY 1-yr chart