Toronto, ON - That rumble toward the end of 2006, with reverberations felt throughout the cardiology research community, was the sound of one of the most heavily hyped drugs in the pharmaceutical pipeline coming crashing to the ground. In early December, data from a major morbidity and mortality trial ended all hopes for Pfizer's torcetrapib, when early reports showed the drug increased the risk of death and cardiovascular events.
As a result, Pfizer halted its entire torcetrapib development program, a tremendous blow to the company as well as a disappointment to clinicians who hoped the HDL-raising drug might be used with other drugs, particularly statins, to provide a one-two punch in the fight against cardiovascular disease.
"It is a big shock, in general, and I was surprised," Dr Michael Davidson (Radiant Research, Chicago, IL) told heartwire . "I'm also disappointed. I had been optimistic that the mechanism would turn out to be an effective way to raise HDL cholesterol, but now that's in doubt as well."
That mechanism was an inhibition of the cholesteryl-ester-transfer protein (CETP), which promotes the transfer of cholesteryl esters from antiatherogenic HDL to apolipoprotein B (apoB)-containing lipoproteins, including very low-density lipoproteins (vLDL), vLDL remnants, and LDL. A deficiency in CETP, something torcetrapib was designed to bring about, has been shown to be associated with increased HDL-cholesterol and decreased LDL-cholesterol levels, a typically antiatherogenic profile.
Still, despite the surprise, most experts, like Davidson, always knew the success of torcetrapib was never a done deal. Just as there are many ways to skin a fish, there are a number of ways to raise HDL cholesterol, and experts were never sure if raising HDL cholesterol with a CETP inhibitor would be the correct way to go.
"There was always a little cloud hanging around CETP inhibition, for a variety of reasons, although we were hoping against hope that those reasons would be dispelled," Dr Prediman Shah (Cedars-Sinai Medical Center, Los Angeles, CA) told heartwire . "But I think those worst fears came true. The whole concept of raising HDL through CETP inhibition has had pros and cons, based on both experimental observations as well as the human genetic studies. There has been no consistency, so there has always been this problem about whether or not it would work. You could argue that raising HDL levels through CETP inhibition might actually reflect a stunted reverse cholesterol transport rather than an enhanced cholesterol transport."
Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) told heartwire that despite the setback it still makes sense to search for ways to raise HDL-cholesterol levels. Torcetrapib, however, highlights the danger of some of these new treatment strategies in such a complex metabolism.
"Even back when we had agents that weren't very good at lowering LDL cholesterol, the genetics for disorders that lead to high LDL cholesterol or apoB-containing lipoproteins are very straightforward," he said. "For HDL cholesterol, it is vastly more complicated. We're not yet sure of the right way to raise HDL cholesterol. The other issue is, What is the actual mechanism of HDL protection? If it's reverse cholesterol transport, there are other approaches to improving reverse cholesterol transport that don't actually raise HDL- cholesterol levels at all. Still, this is an area where the epidemiology of HDL cholesterol is at least as strong as LDL cholesterol, and there are strong reasons to pursue this from a research perspective."
Early warning signs not good with torcetrapib
In addition to concerns that raising HDL with a CETP inhibitor might not be effective in general, Pfizer's torcetrapib came under fire specifically. Early data from phase 2 and 3 trials showed that the drug raised systolic blood pressure by as much as 3 to 4 mm Hg. While some experts weren't concerned with this increase, noting that it could be treated and that the cardiovascular benefits of raising HDL cholesterol might likely offset the increase in blood pressure, others argued that such an increase would translate, in the general population, into a 20% higher stroke mortality and a 12% higher mortality from ischemic heart disease.
"We knew that torcetrapib increased blood pressure, so at least one possible explanation is that the increase in mortality is all blood-pressure related, and that it's not the mechanism of HDL raising," Dr Steven Nissen (Cleveland Clinic, OH) previously told heartwire . "However, I also think there is a distinct possibility that the type of HDL that is produced when you inhibit CETP is actually proatherogenic rather than antiatherosclerotic."
One aspect of the torcetrapib story that made last month's news so surprising was that Pfizer was so optimistic about the drug the company said it would seek early Food and Drug Administration approval based on the results of intravascular ultrasound (IVUS) and carotid intima-media thickness (IMT) studies being presented in early 2007. While Pfizer's drug is now officially finished, these trials remain critical to understanding what went wrong with torcetrapib and could help shed light on this particular CETP- inhibition mechanism.
However, the studies, according to some experts, could throw the entire lipid field for a loop.
"One of the next most fascinating aspects of this story is what the atherosclerosis imaging studies—the IVUS and carotid IMT studies—are going to show," Dr Daniel Rader (University of Pennsylvania, PA) told heartwire . "One can imagine interesting scenarios across the board. One of the most consistent would be if the clinical outcomes from the IVUS and IMT studies showed increased progression of atherosclerosis. Well, that would be fairly dramatic, but it would be consistent with the clinical outcome. If this is the case, I think it would pose a major problem for CETP inhibition. It might still be due to the molecule, but if that's the case, it starts to feel like it might be related to the mechanism."
Two other dramatic scenarios could occur, too. The imaging studies might be neutral, which would downplay the value of the imaging, said Rader, but it's also possible the imaging studies might show improvement, either reduced progression or regression. With the adverse clinical outcomes from Pfizer's major morbidity and mortality trial, "it would pretty much strike the death knell for using either of these two imaging modalities for assessing new drugs, and not just HDL raising, but for other mechanisms as well," said Rader. "If there were such a discrepancy between the surrogate end points and the clinical outcomes, it would be hard to have confidence in these surrogate measures."
Dr Michael Miller (University of Maryland, MD) said the best news for the lipid community would be if the increased risk of cardiovascular events were caused by the increase in blood pressure, only because it would mean a shakeout of this agent rather than the demise of the entire class of drugs. Roche Pharmaceuticals, licensing from Japan Tobacco, for example, still has a CETP inhibitor in development that has been shown to raise HDL cholesterol without any significant effects on blood pressure.
"This is the critical issue," he said. "If we can establish that the increase in blood-pressure elevations led to increases in stroke rates, pulmonary edema, or other findings that were attributable to blood pressure, and the imaging studies come back positive, then I think the drug class is still safe. It's a case of not throwing the baby out with the bathwater just yet. Let's wait to see just what these important pieces of the puzzle show us."
CETP inhibitors in development
|JTT-705||Roche and Japan Tobacco|
|CETP inhibitor vaccine||Avant Immunotherapeutics|
Shah, on the other hand, told heartwire that he does not believe the increase in blood pressure is responsible for the adverse cardiovascular outcomes. "My own suspicion is that the blood-pressure effect is probably not what killed it, or certainly not the whole story. I think there may very well be something to the concept of this dysfunctional HDL cholesterol that, depending on how you raise HDL cholesterol, might have different consequences. CETP inhibition might raise HDL-cholesterol levels, but the HDL produced is actually defective."
Rader told heartwire that the increase in blood pressure with torcetrapib, by all accounts thus far, does not appear to be mechanism based, which provides some clues that the deleterious effects of torcetrapib are related to the molecule through direct vascular effects, including direct thrombotic effects. Direct thrombotic effects might be the easiest way to explain the increased cardiovascular events in a relatively short time period, he said.
"It is hard for me to imagine that the harm is due to impaired reverse cholesterol transport over that relatively short period of time, but, of course, anything is possible," said Rader.
Development slow, but the drugs will come, say experts
While there are many questions that remain after the torcetrapib collapse, nearly all experts agree that it will be much more difficult in the future to get any HDL-raising drug—or any other novel drug in the lipid field—approved without hard clinical-outcome trials. While most were skeptical that Pfizer could obtain approval from the FDA based on imaging studies alone, the adverse clinical outcomes now mean that any new drug is still five to 10 years away from the market if hard clinical end points are required.
"The field is complicated, and people are questioning not just this compound but other drugs as well," said Davidson. "Now, what do we need to do? We have statins and other cholesterol-lowering drugs, so the question is, why risk harm to patients unless you can prove you have an outcome benefit? I hope this isn't the way it goes, but a lot of people are talking that way right now. There is a feeling that we are going to have to be more conscientious about these therapies."
Despite the setbacks, the research community still believes future development is necessary. As Ballantyne told heartwire , "Primarily the focus is on lowering LDL cholesterol first, but we can do that very well now. We have very effective statins, we have combination therapy, but we're left with this issue of HDL and triglyceride levels. We can push diet and exercise, as well as use nicotinic acid, the most effective agent we have at the moment for raising HDL cholesterol and lowering triglyceride levels, but there is still a need for other drugs."
While niacin can raise HDL cholesterol by 30%, it has been given a bad rap, mainly because as many as 20% to 30% of those who take it have side effects, such as itching and flushing. Still, niacin is making a comeback, especially since recent research has helped shed light on the cause of flushing, with selective agonists in development to alleviate these symptoms. In the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), for example, a new combination tablet containing extended-release niacin and a specific blocker of prostaglandin D2 to prevent flushing is being tested in 20 000 patients, with the hope of reducing MI, stroke, or revascularization procedures in patients with existing vascular disease. The 3300-patient US National Institutes of Health (NIH) Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study will compare the incidence of major cardiovascular events in patients randomized to extended-release niacin plus simvastatin or simvastatin alone.
"If AIM-HIGH comes out negative, I'm throwing in the towel. I'm giving up. I'm retiring," joked Miller.
Gene therapy to increase apoA-1
While there are a lot of unknowns, many believe that the best way to raise HDL- cholesterol levels is to produce more apoA-1, which is the precursor of new HDL cholesterol. ApoA-1 constitutes 70% of the HDL protein and is present on nearly all HDL particles. For this reason, said Rader, the upregulation of endogenous apoA-1 expression is considered one of the most promising approaches to the development of new therapies targeted to HDL cholesterol.
"In terms of pathways, I would say that the holy grail is promotion of apoA-1 gene transcription or apoA-1 production by liver, intestine, or both," Rader said. "If, somehow, a small molecule could be found that turned on the transcription of the apoA-1 gene, I really do think that would be very good, based on everything we know from preclinical models. There is no reason to think that would cause harm, unless there was some off-target effect, but we have every reason to think it would be a good thing."
Shah and his group at Cedars-Sinai Medical Center have performed proof-of-concept gene-therapy studies in mouse models with apoA-1 Milano, a variant of apoA-1, and have shown that it is possible to exploit the benefits of HDL cholesterol in this way. The method, however, is not yet being tested in human clinical trials, although Shah is optimistic that as gene therapy improves and more effective and safe vectors are available, this concept will be brought closer to human testing.
Studies of HDL/apoA-1 infusion*
|Recombinant apoA-1 Milano||ApoE-null mice||Inhibited progression and regression at high doses, reduction in plaque macrophage and lipid content|
|Purified rabbit apoA-1||Cholesterol-fed rabbits||Reduced progression|
|Recombinant apoA-1 Milano||ApoE-null mice, single high-dose infusion||Rapid plaque lipid and macrophage depletion within 48 hours|
|Recombinant apoA-1 Milano||ApoE-null mice and rabbits||Improvement in endothelial function|
|Recombinant apoA-1 Milano||Humans||Stimulation of fecal cholesterol excretion|
|Plasma-derived human HDL||Humans||Stimulation of reverse cholesterol transport|
|Plasma-derived human HDL||Hyperlipidemic humans||Improved endothelial function|
|Recombinant apoA-1 Milano (ETC-216)||Acute coronary syndrome patients||Coronary atheroma regression in 5 weeks|
Probably the most straightforward method, at least theoretically, to increase HDL cholesterol is to simply give the patient more or to give its main constituent, apoA-1. Shah and his colleagues at Cedars Sinai pioneered this approach, where they established the marked atheroprotective benefits of intravenous infusion of a genetically engineered version of apoA-1 Milano protein, a synthetic HDL, in various animal models. This paved the way for a human study done in 2003, with researchers at the Cleveland Clinic, led by Nissen, showing that just five weekly infusions of apoA-1 Milano produced a modest but significant 4% regression of coronary atherosclerosis in 36 ACS patients. While the study generated much enthusiasm for the HDL field, infusions of apoA-1 Milano or another synthetic form of HDL are limited by cost and frequent administration. According to Shah, however, infusions could be used in the initial phase of treatment, followed by an oral agent.
"It could be a one-two punch," he said. "Start with an intravenous infusion, and follow this up with HDL-based therapeutics."
|Esperion and HDL-based therapeutics|
Esperion , a company recently purchased by Pfizer for $1.3 billion, has four candidate drugs that target reverse cholesterol transport. One of those agents is ETC- 216, the recombinant version of apoA-1 Milano that gained attention with the presentation of Nissen and colleagues' 2003
ACS study. Larger studies are now planned. Other agents include:
Other agents available
Raising plasma HDL-cholesterol levels is not the only way researchers are attempting to fight heart disease. Testing has begun on agents that target specific hormone receptors for the purpose of promoting macrophage cholesterol efflux and reverse cholesterol transport. One of the most studied pathways for macrophage cholesterol efflux is the pathway by which the ABCA1 transporter promotes cholesterol efflux to lipid-poor apoA-1.
Receptors known as the nuclear receptor liver X receptor α and β (LXRα and LXRβ) are capable of detecting excess cholesterol within the cell. Treatment of macrophages with LXR agonists has been shown to upregulate various genes of lipid metabolism, including ABCA1, which is involved in the initial steps of reverse cholesterol transport, and increases cholesterol efflux to lipid-poor apoA-1 and mature HDL. Synthetic LXR agonists have been shown to promote cholesterol efflux and reverse cholesterol transport in vivo, as well as inhibit the progression of atherosclerosis in mice models, all without having a significant effect on plasma HDL-cholesterol levels.
"I think we should be keeping a close eye on these drugs," said Shah. "Past history of these [peroxisome-proliferator-activated receptor] PPAR agonists and nuclear-hormone agonists has not been particularly great, but there is more enthusiasm about some of the newer LXR agonists, which might potentially have a clinical role."
The PPARs are another class of drugs in development to promote reverse cholesterol transport. Like LXR agonists, PPARs are nuclear receptors that activate ABCA1, which in turn stimulates the first step of reverse cholesterol transport, the efflux of cholesterol out of cells onto HDL particles. There are three types of PPARs—alpha, gamma, and delta—and all are targets for agonists as drugs. Fibrates, for example, work by binding to PPAR-α , causing both an increase in HDL and a decrease in triglycerides. PPAR-γ agonists, including the glitazones, drugs used primarily in diabetes, raise HDL only modestly, and its major effect seems to be a reduction in insulin resistance. PPAR-δ seems to have all three effects.
Another way to raise HDL cholesterol might be through inhibiting the catabolism of apoA-1, thus increasing plasma apoA-1 and HDL-cholesterol levels. Rader told heartwire that the inhibition of endothelial lipase (EL) might be one attractive therapeutic approach to prevent such a breakdown of apoA-1. Plasma EL levels in humans have been shown to be inversely associated with HDL-cholesterol levels and positively associated with a variety of measures of the metabolic syndrome. Plasma EL levels in humans were also shown to be significantly associated with coronary atherosclerosis.
"Endothelial lipase is involved in HDL remodeling, which results in less generation of the free apoA-1 that gets catabolized by the kidneys," said Rader. "In addition, if there is some way of blocking the liver uptake of apoA-1 in a way that didn't constipate reverse cholesterol transport, this might be an interesting target, and again has less to do with raising HDL-cholesterol levels but more to do with preventing the catabolism of apoA-1."
Shah told heartwire that he is optimistic about smaller synthetic peptides such as D4F, made byBruin Pharmaceuticals, in Los Angeles, California, a small company started by University of Alabama scientist Dr Gattadahalli Anantharamaiah in collaboration with University of California, Los Angeles researchers Drs Mohamad Navab and Alan Fogelman. So far, D4F has been shown to be capable of being absorbed by the intestine, an approach that is preferable to the larger molecules like apoA-1 Milano. Shah said the data with these peptides are still in the animal stages, although human trials with D4F have been conducted, and so far no red flags have been raised regarding safety, he said. Efficacy, however, is still unknown.
In addition, one company, Lipid Sciences, based in Pleasanton, California, is developing a lipid-removal process for a patient's plasma, which is designed to enhance the effectiveness of HDL when returned to the blood. This lipid-poor HDL, when returned to the patient, would then act as an efficient scavenger of cholesterol in the tissue. This process of delipidation would work almost like dialysis, but there are obvious problems, such as inconvenience as well as cost, not to mention that it has not yet been shown to be effective, noted Shah.
Prospects and the perfect storm
Despite such research, most experts believe doctors will be looking at more of the same for the time being, that being the use of niacin, with flushing inhibitors in conjunction with niacin, to raise HDL-cholesterol levels. Many believe that a drug to raise HDL cholesterol is at least five to 10 years away from being on the market, particularly since hard end-point trials are going to be needed.
"Getting an agent approved on the basis of HDL raising, I think, is out," said Rader. "It was never really a viable way to get approved anyway. Getting approved based on imaging was always a big question mark. I do think that in the foreseeable future, to get an HDL-raising drug approved, unless it also happens to have the ability to lower LDL-cholesterol levels or another surrogate, will require an outcome trial to prove that it works and that it doesn't cause harm."
"The pharmaceutical industry is in a very difficult position right now," added Davidson. "It's a perfect storm. There are all sorts of patent expirations, increasing regulatory hurdles, pipelines are thin, and there are pressures on pricing. It's not a very good time to be an executive. However, I think there are still many unmet needs, including drugs to raise HDL cholesterol, and if companies want to continue to grow and prosper, they are going to have to spend the money to develop them."
Heartwire from Medscape © 2007
Cite this: Torcetrapib tanks, but there is still a future in HDL cholesterol-raising therapies - Medscape - Jan 22, 2007.