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Esperion Therapeutics: Why IMPROVE-IT Hasn't Cast A Shadow Over ETC-1002


Failure of IMPROVE-IT doesn't create statistical powering risk for ETC-1002's CVOT.

The bar for a CD risk reduction label wasn't raised with IMPROVE-IT.

The LDL hypothesis still holds true, but is context dependent.

On February 15th, 2016, Merck (NYSE:MRK) received a complete response letter from the FDA for Zetia and Vytorin. The letter denied a proposed label extension for the reduction of cardiovascular risk based on the results of the IMPROVE-IT outcomes study. The reasons for the denial centered on the modest additional benefits shown in patients on Vytorin in comparison to patients on statin monotherpy, along with inconsistencies in the trial's data set. Post rejection, investors began to focus on the reasoning of the EMDAC to find clarity on the decision. IMPROVE-IT was a seven-year, 18,000+ patient population trial that didn't achieve adequate statistical powering, and this might create real doubts about Esperion's (NASDAQ:ESPR) ability to conduct a similar CVOT with only a proposed 12,500 patients. The fear being that if a non-statin drug cannot show clinically and statistically significant results from such a robust trial, then this places an insurmountable mountain for ETC-1002. However, a reasoned examination of the FDA guidance from the EMDAC meetings for IMPROVE-IT, Sanofi (NYSE:SNY) and Regeneron's (NASDAQ:REGN) Praluent and Amgen's (NASDAQ:AMGN) Repatha show that instead of the bar being raised for ETC-1002, the result just means that the FDA won't allow the bar for proving CD risk reduction to be set as low as the standard produced with IMPROVE-IT.

What is the LDL hypothesis?

One of the central developments in the cholesterol-lowering field since the release of IMPROVE-IT and the approval of Praluent and Repatha is that the long-standing LDL hypothesis might no longer be a sufficient basis for approval for non-statin, LDL-C lowering drugs.

The hypothesis is based on the belief that elevated levels of circulating LDL-C in the liver are a major causative factor in the onset of cardiovascular disease (CD). Meta-analysis of nearly 30 trials (equating to approximately 175,000 participants) by the CTT has shown that:

1) Reduction of LDL-C using statin therapy substantially reduces the risk of major vascular events and vascular mortality by about 20% for each 1 mmol/L reduction in LDL-C achieved.

2) Further reductions in LDL-C with more intensive statin therapy produce further reductions in the incidence of adverse events.

As such, LDL-C is recognised as a valid surrogate endpoint marker by the FDA. The concern in the validity of the hypothesis arose from two areas. One was the unfounded confidence placed by the FDA in Zetia/ezetimibe by approving it for LDL-C lowering alone when its first two outcomes studies raised efficacy doubts and a safety concern (ENHANCE and SEAS). The second is that when the non-statin trials are examined together, it proves difficult to make a connection between the relationship of different levels of LDL-lowering...