DefinedHealth

Michael C. Rice, MS, MBA

Wall Street’s punishment of Pfizer upon its discontinuation of torcetrapib after $800 million of development expense was swift and merciless as $22 billion in market capitalization was shed. The event has cast a pall over CETP inhibitors, which are in development by nearly every major pharmaceutical company and many biotechs. Although an increase in blood pressure was observed in some patients, it remains unclear exactly what caused the increased mortality in the torcetrapib + atorvastatin arm vs. the atorvastatin arm alone. The question also looms as to whether this agent’s toxicities will prove to be present in others in its class (as was the case for the oral GpIIb/IIIa antagonists and dual-acting PPARs), or specific to torcetrapib.

HDLs are complicated particles comprised of a myriad of proteins and lipids that interplay to alter cholesterol metabolism, and HDL activity is not nearly as well understood as that of LDL. For example, data from the Framingham Heart Study Offspring suggest that patients with a specific mutation that results in a 20-30% reduction in CETP activity have higher levels of HDL, and a reduced risk of heart disease. By contrast, some studies of Japanese patients with no CETP activity have shown large, dysfunctional HDL molecules which result in decreased ability to remove cholesterol and an increased risk of heart disease. Indeed, the very concept of inhibiting CETP may be called into question, since it is needed to “off-load” cholesterol at the liver to avoid accumulation of dangerous levels of HDL.

Researchers remain optimistic that some means of adjusting the composition of HDL will add benefit to the dyslipidemia regimen alongside the statins. There are a variety of approaches being explored in addition to CETP inhibition, such as Apo A-1 Milano and synthetic mimetics, D-4F, PPAR agonism and endocannabinoid receptor inhibition, among others. What is the impact to the cardiovascular market in the wake of torcetrapib? In this installment of our 7th annual Insight Series, Defined Health will characterize the changing cardiovascular marketplace, and discuss opportunities and barriers to the creation of future value from today’s development pipelines.