Esperion Therapeutics’ investors are today lamenting that bempedoic acid has trailed Praluent and Repatha to the market. Shares plunged 36% to $10.32 in early trading this morning after the disclosure that the US FDA might not authorise heart disease drugs on their cholesterol-lowering effectiveness alone.
The FDA feedback could delay the approval of Esperion’s pill to 2022, pending data from a long-term cardiovascular outcomes trial that the Michigan-based group plans to begin by the end of the year. Without the cash to fund this study to conclusion, bempedoic acid will need to perform flawlessly in a shorter pivotal test measuring its efficacy at reducing low-density lipoprotein (LDL) to attract a partner big and brave enough to back its clinical programme.
Does it save lives?
As statins have proven their worth in reducing the occurrence of cardiovascular death and hospitalisations along with lowering LDL, regulators now demand that newer heart disease drugs do the same – LDL decreases are no longer seen as a surrogate for positive outcomes.
The new injectable drugs blocking the protein PCSK9, Repatha and Praluent, have only received a label for patients with hereditary LDL elevation and those with cardiovascular disease who are unable to achieve cholesterol control with statins. They are now awaiting the results of outcomes trials to determine whether they can be used more broadly.
Likewise, Esperion has struggled to persuade the FDA that its pill, which blocks ATP citrate lyase, ought to be approved on the strength of the LDL-reduction surrogate endpoint (Esperion’s U-turn on the LDL fast track, September 29, 2015).
The trouble for Esperion is that, should Praluent’s Odyssey Outcomes study or Repatha’s Fourier trial fail to show a survival or hospitalisation benefit, Esperion will have much more to prove. Bempedoic acid, the active ingredient in ETC-1002, has proven in phase II only that in combination with Lipitor it outperforms Lipitor alone in lowering LDL. To replicate this in pivotal trials will no longer do at the FDA.
In any case, should Odyssey Outcomes or Fourier show a benefit, bempedoic acid's commercial outlook will worsen as Praluent and Repatha become the new standards of care as statin add-ons.
In a conference call with analysts, Esperion took pains to say that the FDA “did not provide clarity” on whether LDL lowering would suffice for initial approval, and that “it remains a possibility”.
“We believe in the LDL lowering hypothesis, and we believe the LDL-lowering hypothesis will be validated by the ongoing cardiovascular outcomes trials,” said the group's chief executive, Tim Mayleben.
So now Esperion is in the difficult position of having an unpartnered cardiovascular project that must begin a nearly 15,000-patient phase III programme.
With cash of $283m at March 31, the group says it has enough to fund itself through early 2019 and completion of the $100m, 2,000-patient efficacy trial in patients on an optimal statin backbone; this will compare bempedoic acid as an add-on versus placebo.
The 12,600-patient outcomes trial is a different matter. It will cost $250m, $125m of which would be spent before a potential regulatory submission on the basis of the smaller efficacy trial. Esperion's market cap this morning sits at $242m.
Completing that trial, as the group would be ethically bound to do, would require a cash call should a partner not emerge on the basis of the efficacy trial.
Mr Maylebean describes the efficacy trial as Esperion’s “most important value inflection point”. He is not kidding. To avoid a painful dilution, Esperion might need to show not only that bempedoic acid can outperform statins alone, but also that it can differentiate itself from Repatha and Praluent.
By then, those two agents might just have shown that they save lives.