HDL-raising is a damaged surrogate. Or at least that's what FDA's Office of Medical Policy director Bob Temple says. And that should give some pause to any companies in the business of developing drugs to raise high-density lipoproteins or those making investments in those companies.
It's not that this class is dead in the water; FDA would love to see a major advancement in this area. But the burden of proof will be much higher and take longer compared to other classes of drugs.
Pfizer's investigational HDL-raising drug torcetrapib was supposed to be the next Lipitor and then some. But torcetrapib, which acts by inhibiting cholesterylester transfer protein (CETP), wound up getting scrapped because of too many deaths observed in clinical trials. That result cast a pall on the entire class.
Torcetrapib hasn't stopped other companies on betting that HDL-raising will be the next big thing. Merck is working on an HDL drug. Cerenis Therapeutics, founded by ex-Esperion executives, raised 25 million and 41 million Euros in 2005 and 2006, respectively, in its first two venture rounds. Cerenis, however, is investigating HDL drugs outside of CETP inhibition.
Pfizer, Roche and Resverlogix are all keeping their HDL hopes alive, looking at Apo-a-1, a major protein component of HDL in plasma.
So drug development in HDL is still alive and well. But FDA will want to see outcomes and long-term data.
Below is an excerpt from a roundtable discussion with FDA Office of New Drug director John Jenkins, Office of Surveillance and Epidemiology director Gerald Dal Pan and Temple (to see the full interview, click here for Part I and here for Part II).
The RPM Report: So low-density lipoprotein, LDL-lowering, you don’t need an outcomes study but if it were something else, you would ask for outcomes data?
Temple: It depends on what it is. If it were triglycerides, I don’t want to speak for that division—I don’t know what their decision on that is—but everyone is nervous about HDL because of the results of the single drug, torcetrapib.
The RPM Report: You discussed torcetrapib. Was this a drug you all were excited about?
Temple: Well, I was excited, my HDL is 30. I was looking forward to it. I was very disappointed.
Jenkins: I think that’s an example of an area where we might not have been excited about that particular drug but the idea of having drugs that can specifically raise HDL and hoping that would lead to a cardiovascular benefit, I’m sure there was a lot of surprise and disappointment internally and externally when that drug failed.
It’s important to distinguish between a torcetrapib finding and is that true of any drug that raises HDL? We don’t know that yet. But having laid that down as the first case, you’re probably going to want to see some good data before you start accepting that as a surrogate. That would require longer-term data before approval.
Temple: It’s a damaged surrogate.
Jenkins: It went against what everyone would have thought. Although I think the epidemiologic data haven’t been as strong for HDL-raising as they have been for LDL-lowering. Now you’ve got torcetrapib and it’s hard to ignore that finding, but it could be a drug-specific finding that other drugs that raise HDL may actually prove to be beneficial.
Temple: There were reasons to hope. For example, some of the LDL-lowering drugs in relatively normal people only worked in people whose HDL was low. So there were reasons to hope. I think everyone was quite surprised.