Tredaptive fails to thrive in huge outcome study

The winter solstice has brought dark days for advocates of raising “good cholesterol” to prevent cardiovascular events. Merck & Co reported its buffered niacin pill Tredaptive showed no benefit in an outcome trial of 25,000 patients. The New Jersey group announced it will not pursue approval in the US; in Europe, where it has been on the market since 2008, regulators announced they had put Tredaptive under review.

Whilst no analysts gave the HPS2-Thrive trial high odds of success, the failure still put a dent in Merck’s market valuation, with shares falling 3% to $42.16 yesterday on the news. The trial miss also casts a long shadow on hopes for success for the main survivors of the good cholesterol hypothesis, notably Eli Lilly’s evacetrapib and Merck’s own anacetrapib.

High and low

Increased levels of good cholesterol, or high density lipoprotein (HDL), have been linked to prevention of cardiovascular events; the belief is that the HDL “scours” the blood vessels of the low-density lipoproteins (LDL) that cause atherosclerotic plaques (Event – Tredaptive tests HDL-raising hypothesis and generic headwinds, November 2, 2012).

What has been harder to establish is whether a pharmacological intervention to raise HDL has any bearing on cardiovascular events or survival. A series of major phase III trials of HDL-raising compounds – the cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and torcetrapib and Abbott Laboratories’ niacin pill Niaspan – has failed to do this.

This has quashed the hopes of finding a new prevention mechanism beyond the LDL-lowering power of statins and non-statin drugs like Zetia and Tricor.

Niaspan has been shown to significantly raise HDL and lower LDL, but it comes with the common side-effect of flushing, which caused discontinuations in 6% of cases in its pivotal trials. Tredaptive aimed to achieve the HDL and LDL modulation of Niaspan whilst buffering the flushing with a second compound called laropiprant.

The FDA passed on approval in 2008, asking for the results of the HPS2-Thrive trial, which had then just begun enrolling, first (Failure to launch for last year's big hopes, February 6, 2009). The European Union, however, said yes.

HPS2-Thrive found no difference in the rate of coronary deaths, non-fatal heart attacks, strokes or revascularisations between a group taking Tredaptive on a background statin therapy and a group on statins alone. What Merck did note was a significantly higher rate of non-fatal serious adverse events amongst those patients taking Tredaptive and statins.

The results of the Tredaptive study were presaged by the results of the US National Institutes of Health’s Aim-High trial of Niaspan last year, which was terminated early because of a lack of clinical benefit (Aim-High adds fuel to the HDL debate, May 27, 2011). Whilst doubtful of success, analysts had pencilled in modest sales for the drug – EvaluatePharma’s consensus was for $931m in 2018 – a number restrained in part by Niaspan’s patent expiry next year.

In the coming months, the question will be what regulators do with the niacin pills already on the market. The European Medicines Agency said its human drugs panel will decide its action on Tredaptive in January; so far, no agency has mentioned Niaspan, but with generic entry looming regulators must be taking a closer look at its status.

Slip-sliding away

The epitaph on the HDL-raising hypothesis cannot be completed just yet. Results of the next major trial, that of Lilly’s evacetrapib, are more than two years away, and anacetrapib data will follow two years after that.

In the meantime, development is speeding along for a new generation of cholesterol-modulating drugs, the PCSK9 inhibitors, which have shown to be much more potent at LDL lowering even than statins (AHA – PCSK9 inhibitors continue to impress, November 7, 2012). As the HDL-raising hypothesis weakens, these agents promise to take the spotlight – though, as antibodies, price and administration will limit their appeal.

Given the FDA’s demands for rigorous outcomes trials for the HDL drugs, there is certainly some question about the risk of failure for the PCSK9 class. Their developers' decisions so far to target them for statin-resistant patients and other challenging populations has reduced that risk. But the FDA has signalled that it wants to see clear evidence that new cardiovascular drugs show long-term benefit, and the PCSK9 class will have a hard time escaping those demands.

Success for Tredaptive was always seen as a long shot, and now longer odds are probably being placed on the remaining CETP inhibitors. HDL raising interventions will continue to have their advocates, but with scant evidence to support it, the hypothesis is crumbling away.

Trial ID NCT00461630

To contact the writer of this story email Jonathan Gardner at [email protected] or follow @JonEPVantage on Twitter.

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