RFP: Raise Temple's HDL

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.

Temple and Comparative Effectiveness Standards Revisited

We told you to pay attention to the case of Vanda Pharmaceuticals.

To read our story, click here.

We haven’t changed our minds on the importance of FDA’s decision to reject the company’s atypical antipsychotic iloperidone and some of the regulatory and policy issues it brings to the fore.

We quoted comments from FDA’s Bob Temple at a July 30 Institute of Medicine meeting on evidence-based medicine. Temple heads up the office which regulates psychopharmacologic drugs and also serves as director of FDA’s Office of Medical Policy.

At the meeting, Temple said this:

“We have taken a couple of steps that I think are interesting. We’ve turned down new antipsychotic drugs because they didn’t seem as effective as the available therapy. I can’t remember if that ever happened before or whether we didn’t have the [courage] but we did. We decided that it wasn’t good if you’re an acute schizophrenic in the middle of an episode to be treated poorly.”

Our story has generated a number of comments, but we thought you’d be most interested in this one from Temple himself, who says we didn’t get it exactly right when analyzing his remarks at the meeting.

“Some of what I said is misinterpreted,” Temple said in an email. “At the IOM, I was explaining what I perceive drug companies to be perceiving and doing, not describing an FDA standard. That is what I was referring to when I said that ‘It’s getting harder to develop the third, fourth, fifth, and sixth member of a class of drugs because when there’s a generic available [within a class], people are inclined to use the cheap one.”

Our mistake. We thought we communicated that but after re-reading our story, it was confusing. Here’s the rest of Temple’s comments in their entirety. When Temple speaks, we always pay attention.

Temple: “Your next sentence said that comparative randomized studies ‘are the best, and maybe only, way to get drugs through FDA.’ That interpretation and conclusion are incorrect, and surprising, as your next sentence seems to recognize the commercial aspect of what I was saying: ‘To get anyone interested in the next member, you almost need to have some sort of advantage.’

It seems apparent that in my statement I was referring to my impression of what companies are doing to have a commercially viable product when there is a generic available for the drug class, and was not referring to any FDA requirement. In most settings, especially for symptomatic treatments, we do not get or ask for comparative data and are perfectly willing to approve a drug that is shown effective.

I did then go on to say that for antipsychotics (not naming a particular drug) we have rejected drugs that seemed clearly inferior to standard treatment because leaving someone with schizophrenia inadequately treated (which can take weeks to recognize) represents a risk. This is not so novel a position. We ask that new antibiotics, new anti-cancer drugs, new drugs intended to save lives or prevent bad outcomes (stroke, heart attack) have effects close to standard treatment for the same reason - importantly decreased effectiveness is not safe. We had not seen examples of anti-psychotic drugs that were markedly less effective than standard therapy; so I’m not sure you can really say that there's a new higher threshold.”

When looking at Vanda’s iloperidone, we still think there’s little room for negotiation on whether the company will have to do a head-to-head study against Risperdal. The company will have to decide whether it’s worth the money—and risk.