Dalcetrapib goes to new home with focused clinical strategy
Dalcetrapib is not dead yet. Roche has found a good home for the failed heart disease drug in the private Canadian group DalCor Pharma, which intends to investigate a genetic profile that showed a positive response to the cholesterol-modulating pill.
DalCor estimates that it will cost $250m to pursue this hypothesis, a huge sum given the amount of investment Roche and other big pharmas have already sunk into dalcetrapib’s class, with little to show for it. The emergence of purpose-built DalCor is a sign that the future of cardiovascular care might look less like the broad-brush approach of statins and more like the narrowcasted protocols of cancer treatment.
In the genes
The group, founded this year with funding from Sanderling Ventures, will chase a finding from a post hoc analysis of the dal-Outcome study in which patients with a specific polymorphism in the adenylate cyclase type 9 (ADCY9) gene who took dalcetrapib were 39% less likely to experience a cardiovascular event than those taking placebo.
This discovery came from a whole genome study of 5,000 dal-Outcomes patients as well as a targeted genotyping panel of patients in the dal-Plaque 2 imaging trial. Dalcetrapib is a CETP inhibitor, and this class of drugs was once thought to hold great promise because it was believed both to lower low-density lipoprotein (LDL), or “bad” cholesterol, and raise high-density lipoprotein (HDL), or “good” cholesterol.
Investigators have failed to prove this hypothesis, however, as Pfizer ended a trial of torcetrapib with Lipitor early because of an increase in mortality and cardiovascular events compared with Lipitor alone. Dalcetrapib was the second to fail, ending after a second interim analysis (Roche’s dalcetrapib failure not end of the road for CETP, May 8, 2012).
Merck & Co’s anacetrapib is due an interim phase III analysis sometime around the middle of 2015, and Lilly’s evacetrapib is expected to wrap up its phase III trial in mid-2016; all compare performance against statins or other lipid-lowering therapies.
These are all-comers trials in that they only required enrolees to have been diagnosed with cardiovascular disease rather than also having a specific genetic marker. Among the four CETP inhibitors, more than 73,000 patients have already been enrolled in pivotal trials.
DalCor represents an alternative approach in that it has identified a high-responder group and hopes it can show a significant benefit. The group said it plans to screen 30,000 patients with acute coronary syndrome to find 5,000 with right ADCY9 profile for the Dal-GenE trial. Roche is developing a companion diagnostic to assist in the screening.
From broad to narrow
This approach is similar to that followed by oncology with the gradual shift away from systemic chemotherapies and towards targeted drugs and immunotherapeutics. Indeed, this is a recognition that though statins are very potent drugs that ought to be widely prescribed, they are not perfect: many patients cannot control their LDL using statins and others do not find them tolerable.
Part of the debate by FDA expert advisers today and tomorrow with the PCSK9 agents Praluent and Repatha is the appropriate patient population. Statin intolerant or resistant patients and those with genetic hyperlipidaemia are among the groups that will be favoured, although when it comes to clinical practice at least, given the expected price, these decisions could be driven as much by payers as by clinical needs (Event – Amgen and Sanofi face final check before start of PCSK9 chase, May 21, 2015).
From a commercial perspective it does not hurt that, should DalCor’s genetic biomarker hypothesis be proven, as a “precision medicine” it could command a higher price than another pill with broader application. This, of course, could in future also apply to torcetrapib, anacetrapid and evacetrapib.
Statins have proven themselves hard to improve on, which makes the job of cardiovascular drug developers difficult. DalCor’s niche-seeking strategy has shown a way forward.