Esperion’s U-turn on the LDL fast track

Esperion Therapeutics’ claims about the FDA’s position on its cholesterol lowering agent ETC-1002 have rebounded. Shares fell 34% today after executives backtracked on whether low-density lipoprotein (LDL) lowering would be an acceptable endpoint for approval of ETC-1002.

Acknowledgement that approval in at least one indication might not take place until after completion of long-term cardiovascular studies represents a setback for Esperion. The company was quick to emphasise an opportunity in statin-intolerant patients, but the damage has been done.

Between the lines

In a bad week for biotechnology, Esperion’s falloff has not been the largest, but its decline since a record high of $112.70 in April has been steep – shares were trading at $23 early today (Biotech’s 2015 gains disappear, September 29, 2015). One had to read and listen closely to the wording of Esperion’s official pronouncements after Monday’s market close to work out why investors reacted so severely.

In announcing that Esperion had evaluated the minutes from its end-of-phase II meeting with the FDA, the group said it acknowledged that it might need first to complete a cardiovascular outcomes trial to get approval of ETC-1002 for use in more than 5 million patients not achieving LDL-lowering goals by taking a maximum tolerated dose of statins.

Given the regulator’s stance on new cardiovascular drugs this seems a benign statement – outcomes trials have been required for many new drugs to support the hypothesis that LDL lowering prevents hearts attacks, strokes and cardiovascular death. However, compared with its statement after an August meeting with the FDA, in which it stated that the regulator viewed LDL lowering as a sufficient endpoint for approval, this represents a significant change in position.

It could leave just statin-intolerant patients as a population in which Esperion could get approval without outcomes data, a population the group estimates at 3.5 million. Executives put the best face on this, saying they were pursuing a “dual strategy” that would characterise fully the profile of the pill, which inhibits fatty acid synthesis and promotes their oxidation.

As for the change in the wording about the larger population of patients not reaching LDL goals, Esperion called the science “dynamic” and pointed to upcoming cardiovascular outcomes trials that could alter the FDA’s views of LDL as a surrogate endpoint. These are studies of the PCSK9 inhibitors Praluent from Regeneron and Sanofi and Repatha from Amgen, as well as the CETP inhibitors anacetrapib from Merck & Co and evacetrapib from Lilly.

“What we’re trying to do is balance the history of using LDL as an accepted surrogate versus the future, which we can’t predict,” Esperion's chief executive, Tim Mayleben, said. “There are at least four cardiovascular outcomes trials that will certainly read on whether LDL remains an accepted surrogate.”

The takeout scenario 

With today’s decline, Esperion – which at one time had a valuation of more than $2bn – has shrunk to a half-billion-dollar company. When Amgen passed over Esperion to pick the CETP specialist Dezima it did cause some observers to wonder what was more attractive about the private Dutch group other than its relatively cheap $300m price tag (Amgen doesn’t buy Esperion, September 17, 2015).

At that time, Esperion was worth more than $1bn. Today’s cheaper valuation could make it a more likely takeout target for buyers looking for the next big lipid-lowering class. They may, however, want to wait until the evacetrapib Accelerate trial reads out next year before making a move.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @ByJonGardner on Twitter

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