With PSCK9 inhibitors bathing in renewed glory courtesy of data presented at the ESC congress, it is understandable if mid-stage results from a related approach released last week by the small private Dutch group Dezima Pharma have been overlooked.
The company is undeterred, and its chief executive, Rob de Ree, insists that its CETP inhibitor DEZ-001 has now been shown to be at least as potent as the PCSK9s. But a daunting task awaits: Dezima must secure a development partner willing to fund the cost of a massive cardiovascular outcome trial.
Development of DEZ-001 was already a big gamble, and for any partner to put up the necessary funds will take nerves of steel. CETP inhibitors, which boost HDL, were once seen as the future of hyperlipidaemia treatment, but the high-profile failures of Pfizer’s torcetrapib and Roche’s dalcetrapib prompted many analysts to write them off.
Similar, but different
But Dezima insists that DEZ-001 is different, and the limited data from the phase II Tulip trial toplined last week provide support (EP Vantage interview – Dezima dares to go where big pharma has fallen, August 30, 2013).
“We don’t think the HDL-raising story is what drives development,” says Mr de Ree. “DEZ-001 is the most potent LDL-lowering agent.” In Tulip the project had “dramatic effects” on the primary endpoint, a composite of lowering LDL and raising HDL, with no safety or tolerability issues.
Of course, whether lowering LDL, or bad cholesterol, or raising HDL, good cholesterol, improves cardiovascular outcomes is a question that neither CETP nor PCSK9 inhibitors have been able to answer in prospective trials. But the huge promise shown by the latter is clear (ESC – Alirocumab gives hints of great promise for PCSK9s, August 31, 2014).
The bull case is that DEZ-001 could go a stage further. “Where the story comes together is price and delivery,” says Mr de Ree; as an oral small molecule, a CETP inhibitor would be more convenient and cheaper than an injectable antibody.
But just how good are the Tulip data? We will not know for sure until they are published in a peer-reviewed journal in a few months, though the company is bullish, stating that in Tulip DEZ-001 showed a “much stronger effect” in combination with a statin than as monotherapy or a statin alone, and a “nice dose response”.
This is despite Tulip being a relatively small trial, in just 364 dislipidaemia patients given either placebo, or four DEZ-001 doses, or four combinations of DEZ-001 plus Lipitor or Crestor. And the promise of a pill that includes a statin at a lowered dose – a key factor given statins’ links to diabetes, for instance – is obvious.
Big pharma commitment
Still, scepticism around CETP inhibition is undeniable, as the analysts who assume zero sales from Lilly’s evacetrapib and Merck & Co’s anacetrapib will attest. Mr de Ree takes the opposite view, saying that massive studies being undertaken by Lilly and Merck demonstrate the big pharma commitment.
And yes, he confirms that a pivotal DEZ-001 trial would count on enrolling something akin to the 12,000 patients in Lilly’s Accelerate trial of evacetrapib. “We’ll be fully phase III-ready by the end of the year,” says the chief executive. “We’re in discussions with strategic partners.”
This is not to say that Dezima is resting on its laurels in the meantime; it is starting a study looking specifically at elevated lipoprotein(a), a risk factor for atherosclerotic disease, and considering an imaging trial.
And if no partner emerges there is a plan B. Developers of PCSK9 inhibitors spotted the potential of a small initial market in patients with familial hypercholesterolaemia, a genetic condition that causes abnormally high LDL levels; DEZ-001’s LDL-lowering effect shows that this too could provide it an obvious initial population, as long as the compound is as potent as it seems to be.
In Mr de Ree’s eyes, of course, there is little doubt. “The effect is so large that we expect it to add up to a reduction of cardiovascular events.” Actually showing this remains the holy grail, for CETP and PCSK9 inhibitors alike.