Pfizer and Roche may have failed with CETP inhibitors, but Dutch start-up Dezima believes it can succeed.
Over the last 12 months the venture capital-backed company has built itself around a phase I compound licensed in from Mitsubishi Tanabe Pharma, TA8995. Dezima’s founders not only believe the drug will avoid the problems of the previous failures, they reckon it has substantial advantages over the two CETP inhibitors that remain in development, by Merck & Co and Eli Lilly. This is quite an ambition for a class of drug that has so far only produced disappointment – and late-stage, very expensive disappointment at that.
CETP inhibitors were initially developed for their capacity to boost HDL or good cholesterol, a particle that at high levels is widely believed to have cardioprotective properties. The cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesterol between lipoproteins like HDL and LDL, and blocking its action results in higher levels of HDL, and lower bad cholesterol, or LDL.
However despite producing a substantial rise in HDL, both Pfizer’s torcetrapib and more recently Roche’s dalcetrapib failed to show any cardiac benefit in large pivotal studies. This was for very specific reasons – torcetrapib also raised blood pressure and actually worsened cardiac outcomes, while it seems dalcetrapib was probably just not a potent enough molecule.
As a result, many believe that CETP inhibition still holds potential.
“These failures were not class effects, they were compound effects,” says Rob de Ree, Dezima’s chief executive. “HDL continues to be a promising treatment target, particularly in combination with lowering LDL.”
Despite CETP inhibitors’ original label as HDL boosting agents, it now seems that their impact on other aspects of a patient’s lipid profile might actually be the key to their promise.
The Merck and Lilly compounds, anacetrapib and evacetrapib, have been shown to not only more than double a patient’s HDL level, they also prompt a significant drop in LDL, even in patients also taking statins. Mr de Ree says DEZ-001, as the Mitsubishi compound is now called, has an impact on HDL and LDL in a similar range to these two compounds.
“We put a lot more money on the LDL effect than on the HDL,” says Sander van Deventer, a member of Dezima’s scientific advisory board. “We expect a large additional effect on LDL, on top of statins.”
Mr van Deventer believes DEZ-001 has other just as important attributes: it has shown a big effect on LP(a), another lipid particle that has a strong association with cardiac mortality but that is not improved by statin therapy. And there is also the potential for CETP inhibition to improve glucose tolerance, an effect that emerged from the torcetrapib data, he says.
This is important because high dose statin use over many years is now linked to an increase in type II diabetes. So if a CETP inhibitor can be used to lower the statin dose, these agents also hold the potential to mitigate the side effects of these otherwise hugely effective heart pills.
Of course, if DEZ-001 can do all this, the possibility remains that anacetrapib and evacetrapib will be able to as well. And huge pivotal studies are already well under way with these agents.
DEZ-001 has an important differentiator, however: greater potency that equates to a much lower dosage. While the Merck and Lilly drugs are dosed at 100mg or more, DEZ-001 should be effective at 5mg to 10mg, Mr de Ree says.
“We are more potent, and there are a couple of goodies associated with this compound that have to do with pharmacokinetics, potency, and less potential for off-target effects, that make us think we are better [than anacetrapib and evacetrapib],” says Mr van Deventer. “We think there is room for two if not three of these inhibitors. The battle will be for the better profile.”
He points out that although all three drugs inhibit CETP, they are all completely different compounds with nothing in common in terms of structure.
With €14.2m ($18.6m) raised from its VC backers – Forbion, BioGeneration Ventures and New Science Ventures – and a loan from the Dutch government, Dezima has set out to prove DEZ-001’s attributes in a phase IIb study. Called Tulip, the double blind, placebo controlled trial will recruit 380 patients with mild dyslipidaemia, testing the drug at various doses with and without statins. Results are expected around the middle of next year.
An interim look at Merck’s huge 30,000 patient Reveal trial being conducted with anacetrapib is thought to be due at around the same time. Which means next year should shed more light on the future for CETP inhibitors.
The data will also shape the future for Dezima, which plans to look for a partner if they are positive. Given past setbacks, DEZ-001’s third place position and the substantial investment required to get the drug to market, that will not be an easy task. But the CETP inhibitor story is not over, and Dezima could be writing the next chapter.