In recent months, there have been quite a few articles on the need to fix the clinical trial system. Among the most recent articles is the one by Boston-based Nature writer Heidi Ledford, Ph.D. published as a News Feature in the 29 September issue of Nature. In my humble opinion, this is the best article on the subject among those that have been published recently.

The pharmaceutical/biotechnology industry is frustrated with the increasing expense and the low output of the clinical trial system. This low productivity is economically unsustainable. The current clinical trial paradigm is over 50 years old. Back in the 1960s, the norm was to conduct single trials at single sites, each designed to answer a single question.

Nowadays, the norm is the large, multicenter clinical trial, especially for Phase 3 trials. “Multicenter” means that a trial is conducted at multiple sites, often in different countries, and could involve thousands of investigators and staff members. As pointed out in Dr.Ledford’s article, the large trials are mandated by the need in our more risk-adverse world to detect safety issues that occur in only a small percentage of patients, and to obtain good statistics for drugs that confer only a small benefit over the standard of care. However, certain major diseases require large trials of long duration even for drugs that may confer large benefits. For example, because the percentage of patients per year in cardiovascular disease (CVD) trials who experience cardiovascular events is small, these trials must be large and multiyear, in order to see any benefit even for a breakthrough drug.

The advent of personalized medicine–developing drugs and combinations of drugs that are specific for the molecular mechanism behind a patient’s disease–has put additional burdens on the clinical trial system. A disease may be found to be a collection of rare diseases in terms of mechanistic subtypes, each of which affects only a small number of people. This makes patient recruitment difficult.

As stated by Dr.Ledford, “Solving the problem may require fundamental changes to the clinical-trial system to make it faster, cheaper, more adaptable and more in tune with modern molecular medicine.”

Don’t use an “e-commerce” approach to determining drug efficacy!

Other commentators have recently noted the need to make clinical trials “faster, cheaper, and more adaptable.” Several of them have suggested bringing in strategies from other industries, especially e-commerce and social media.

For example, in an editorial published in the 23 September issue of Science, Andrew Grove, the former Chief Executive Officer of Intel, proposes moving towards an “e-trial” system, based on such large-scale e-commerce platforms as that of Under the proposed e-trial system, the FDA would ensure safety only, not efficacy, and would continue to regulate Phase 1 trials. Once Phase 1 trials have been successfully completed, patients would be able to obtain a new drug through qualified physicians.

Patients’ responses to a drug would be stored in a database, along with their medical histories. There would be measures to protect a patient’s identity, and the database would be accessible to qualified medical researchers as a “commons.” The response of any patient or group of patients to a drug or treatment could then be tracked and compared to those of others in the database who were treated in a different manner or were untreated. These comparisons would provide insights into a drug’s efficacy, and how individuals or subgroups (perhaps defined in part via biomarkers) respond to the drug. This would liberate clinical trials from the “tyranny of the average” that characterize most trials today. As the database grows over time, analysis of the data would also provide information needed for postmarketing studies and comparative effectiveness studies.

Dr. Grove’s proposal is one of several in which the mandate of the FDA (and regulatory agencies in Europe, Japan, etc.) is to regulate safety only (via Phase 1 clinical trials) not efficacy. Efficacy is then determined via some sort of open system, with information gathered and provided to patients and physicians electronically, via systems reminiscent of e-commerce or social media.

We are opposed to removing efficacy from the oversight of the FDA and other regulatory agencies. There are two reasons for this, both of which are illustrated graphically in Box 1 of Dr. Ledford’s article, entitled “the clinical trial cliff”. Approximately half of Phase 2 clinical trials between 2008 and 2010 failed due to inability to demonstrate efficacy. (Around one-third of Phase 2 failures were due to safety, and the remaining failures were mainly due to strategic decisions to terminate a drug.) Among Phase 3 failures between 2007 and 2010, around two-thirds were due to efficacy, and around one-quarter were due to safety. These results indicate that the majority of drugs entered into clinical trials lack efficacy.

The second reason is that many safety problems–especially the rarer safety issues that occur in only a small percentage of patients–are typically not detected in Phase 1, but in Phase 3 and even the postmarking period.

Reduce clinical attrition with new trial designs and improved animal models

Dr. Ledford’s proposals for fixing clinical trials leave regulatory agencies in charge of overseeing both safety and efficacy. They mainly focus on improving clinical trials by reducing “attrition”–i.e., failure of drugs in the clinic, especially in Phase 2 and Phase 3, and on improving patient recruitment. Haberman Associates has produced publications–as well as articles on this blog–during the 2009-2011 period that provide a more in-depth discussion of strategies for reducing attrition than is possible in a 3-page article such as Dr. Ledford’s.

Two of Dr. Ledford’s strategies involve modifications of clinical trial design. Both of these are discussed in Chapter 6 of our book-length Cambridge Healthtech Institute (CHI) Insight Pharma Report, Approaches to Reducing Phase II Attrition. The first is the “Phase 0” trial. This is a type of pre-Phase 1 clinical trial, which uses microdoses of a drug to assess such parameters as pharmacokinetics and target occupancy. As Dr. Ledford suggests, in some cases Phase 0 trials can reduce or eliminate pharmacological testing in animals, and allow researchers to get human data more quickly.

The other trial design strategy mentioned in Dr, Ledford’s article is the use of adaptive clinical trials. This type of trial allows researchers to change the course of a trial in response to trial results. For example, this may mean assigning new patients to specific doses, changing the numbers of patients assigned to each arm of a trial, and changes in hypotheses or endpoints. Monitoring and changing the trial is typically done by an independent data monitoring committee [DMC] so that ideally, double-blind conditions are maintained.

As Dr. Ledford states, adaptive clinical trials may result in shortening the time and cost of the clinical trial process. But, as with Phase 0 microdosing trials, there are many controversies surrounding adaptive clinical trials. Both of these strategies are works in progress.

The other strategy for reducing attrition discussed in Dr. Ledford’s article is to use improved animal models (i.e., animal models designed to more faithfully model human disease) in preclinical studies. We discussed this strategy in Approaches to Reducing Phase II Attrition, and in greater detail in another book-length report, Animal Models for Therapeutic Strategies. I also recently led the workshop “Developing Improved Animal Models in Oncology and CNS Diseases to Increase Drug Discovery and Development Capabilities” at Hanson Wade’s 2011 World Drug Targets Summit.

Several articles on our Biopharmconsortium Blog also focus on improved animal models for predicting efficacy of drug candidates in discovery research and in preclinical studies. Our April 15, 2010 blog post, based on an article in The Scientist, focused on “co-clinical mouse/human trials”. This type of clinical trial was developed by Pier Paolo Pandolfi, MD, PhD (Director, Cancer and Genetics Program, Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center) and his colleagues.

These trials utilize genetically engineered transgenic mouse strains that have genetic changes that mimic those found in specific human cancers. These mouse models spontaneous develop cancers that resemble the corresponding human cancers. In the co-clinical mouse/human trials, researchers simultaneous treat a genetically engineered mouse model and patients with tumors that exhibit the same set of genetic changes with the same experimental targeted drugs. The goal is to determine to what extent the mouse models are predictive of patient response to therapeutic agents, and of tumor progression and survival. The studies may thus result in validated mouse models that are more predictive of drug efficacy than the currently standard xenograft models.

The new Ledford Nature article discusses co-clinical trials as a means to develop more predictive animal model studies–not only using improved, potentially more predictive animal models, but also treating these animals in similar way (in terms of doses, formulations, schedules of medication, etc.) to the humans in the parallel human clinical trial.

The Ledford article mentions the animal-model portion of a co-clinical trial, which was published in January 2011. This trial utilized two genetically-engineered PDGF (platelet-derived growth factor)-driven mouse models of the brain tumor glioblastoma multiforme (GBM), one of which has an intact PTEN gene and the other of which is PTEN deficient.

Unlike the “standard” mouse xenograft models, these models more closely mimicked the human disease, including growth of tumors within the brain, not subcutaneously. Thus any drug administered to these mice systemically (e.g., intraperitoneally, as was done in this study) had to cross the blood-brain barrier (BBB), as in the case of human clinical trials. This would not be the case with a standard xenograft model, which is one deficiency of these models for brain tumors such as GBM.

GBM is both the most common and the most malignant primary brain tumor in adults. It has a poor prognosis. PDGF-driven GBMs, which results from deregulation of the PDGF receptor (PDGFR) or overexpression of PDGF, account for about 25-30% of human GBMs. These mutations result in the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. These tumors may also exhibit mutation or loss of heterozygosity of the tumor suppressor PTEN, which also upregulates the PI3K/Akt/mTOR pathway.

The researchers tested the Akt inhibitor perifosine (Keryx Biopharmaceuticals, an alkylphospholipid) and the mTOR inhibitor CCI-779 (temsirolimus; Pfizer’s Torisel; originally developed by Wyeth prior to the Pfizer merger and approved for treatment of renal cell carcinoma), both alone and in combination, in vitro and in vivo. Specifically, the drugs and drug combinations were tested in cultured primary glioma cell cultures derived from the PTEN-null and PTEN-intact mouse PDGF-driven GBM models, and in the animal models themselves.

The studies showed that both in vitro and in vivo, the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null cells or animals was achieved by using both inhibitors in combination.  In vivo, the decreased Akt and mTOR signaling seen in mice treated with the combination therapy correlated with decreased tumor cell proliferation and increased cell death; these changes were independent of PTEN status. The co-clinical animal study also suggested new ways of screening GBM patients for inclusion in clinical trials of treatment with perifosine and/or CCI-779.

According to Dr. Ledford’s Nature article, the National Cancer Institute (NCI) invested $4.2 million in Dr. Pandolfi’s co-clinical trials in prostate and lung cancer in 2009. In addition to the co-clinical trials with genetically-engineered mouse models run by Dr. Pandolfi and others, researchers at the Jackson Laboratory are conducting co-clinical trials with mouse xenograft models that receive tumor cells from patients to be treated in human clinical trials.

Use patient registries in recruitment of patients for clinical trials

In Dr, Ledford’s article, she discusses a crucial factor other than clinical attrition that hinders progress in conducting clinical trials–patient recruitment. According to the article, at least 90% of trials are extended by at least six weeks because of failure to enroll patients on schedule. Only about one-third of the sites involved in a typical multicenter trial manage to enroll the expected number of patients. As a result, clinical trials are longer and more expensive, and some of them are never completed.

Personalized medicine, in which researchers use biomarkers or other criteria to determine what fraction of patients with a particular disease are eligible for a trial (e.g., cancer patients with an activating mutation in a kinase that is the target of the drug to be tested), makes recruitment harder. That is because researchers must screen large numbers of patients to identify the fraction of patients that would be eligible for the trial. So they need to recruit (and screen) a much larger number of patients than in conventional clinical trials with no patient stratification.

Therefore, researchers, “disease organizations”, and patient advocates are devising new strategies to facilitate recruitment of eligible volunteers. Dr. Ledford cites the example of the Alpha-1 Foundation (Miami, Florida), a “disease organization” that focuses on the familial disease alpha-1 antitrypsin deficiency. (This disease renders patients susceptible to lung and liver diseases.) This foundation has  created a registry of patients with alpha-1 antitrypsin deficiency who are willing to be contacted about and to participate in clinical trials.

There are also cancer registries. Dr. Ledford mentions the Total Cancer Care program run by the Moffitt Cancer Center (Tampa, Florida). This program, which involves 18 hospitals, compiles medical history, tissue samples (stored for future analysis) and genetic information about each patient’s tumor. Patients can consent to doctors contacting them about trials. There are other similar programs being developed in the Netherlands and elsewhere. Dr.Ledford mentions the difficulty in negotiating agreements between institutions, and the need for adequate, ultra-secure networks to support registries that connect multiple hospitals and research centers.

Patient registries that are designed to proactively support recruitment for clinical trials have some resemblance to a “social media” approach to recruitment. However, there is a big difference–the need to secure the privacy of patient records. The current trend in social media (and in some e-commerce platforms) is anti-privacy. This is yet another important reason why a social media or e-commerce approach to clinical trials or other aspects of biotech/pharma R&D is not a suitable model. (To his credit, Dr. Grove mentions the need to maintain patient privacy and confidentiality. But this is not the norm with e-commerce and social media.)

Cutting red tape for faster and cheaper clinical trials

Dr Ledford also mentions ways to deal with more bureaucratic issues that can slow down or block the progress of clinical trials. The NCI is now initiating a data-management system that will standardize data entry across all 2,000 sites that conduct NCI-sponsored trials. This should help reduce costs and cut down on record-keeping errors and omissions.The FDA is also looking into ways to reduce reporting requirements and paperwork. so that investigators can submit summaries of case reports rather than each individual document.

To adapt to the multicenter nature of clinical trials, the US Office for Human Research Protections (Rockville, Maryland), which oversees NIH-funded human studies, has proposed changes to its guidelines that would require designation of a single review board for each project. This may greatly improve the current situation, in which multicenter trials must get approval from each center’s institutional review board. This can take months or even years. Despite the definite advantages of more centralized review, individual research centers may be reluctant to give up their direct oversight of clinical trials.

Something important was not in Dr. Ledford’s article

The space limitations for Dr. Ledford’s “News Feature” article, plus its strict focus on clinical trials per se, did not permit her to include something of crucial importance to reduce clinical attrition. That is utilizing such strategies as biology-driven drug discovery in the research phase of drug development. These strategies are designed to select the best targets and to discover drugs that are more likely to be efficacious in treating a particular group of patients. These research strategies are then coupled with early development strategies that emphasize designing clinical trials aimed at obtaining rapid proof of concept in humans. Such trials typically involve the use (and often the discovery) of biomarkers.

We discussed these issues extensively in our report, Approaches to Reducing Phase II Attrition, as well as in an article published in Genetic Engineering and Biotechnology News (and available on our website) “Overcoming Phase II Attrition Problem“. We also discussed a specific case of the use of this strategy in our October 25, 2010 article on this blog.


Given the low productivity of pharmaceutical R&D, it is tempting to take an envious look at the success of e-commerce and social media, and to attempt to devise strategies that apply methodologies from these industry sectors to the biotech/pharmaceutical industry. We should remember, however, that not so long ago some pharmaceutical executives attempted to apply methodologies from such industries as aerospace, computer hardware, and the auto industry to pharma R&D. Not only did that not work too well for the pharmaceutical industry, but as we all know, the industries that served as a model for these approaches haven’t done very well in recent years either.

In contrast, pharmaceutical and biotechnology companies that have formulated strategies that embrace the uniqueness of biology, such as Novartis and Genentech (the latter now merged with Roche), have done a lot better.

There are other strategies for making clinical trials faster, cheaper, and better that are now under discussion in the biotech/pharma industry and the FDA.  These strategies are based on clinical experience, not e-commerce. We shall discuss them in further blog posts.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.


Niacin (nicotinic acid)


In our blog post of May 19, 2011, we discussed the late-stage development of two cholesterol ester transfer protein (CETP) inhibitors, designed to raise serum high-density lipoprotein (HDL), or “good cholesterol”. These agents are Merck’s anacetrapib and Roche’s dalcetrapib. The clinical results with these agents have  have reignited enthusiasm for CETP inhibitors in the medical and drug discovery and development community.

Now comes the news that The National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) stopped a large clinical trial of Abbott’s Niaspan, an extended-release formulation of high-dose niacin, because the drug failed to prevent heart attacks and strokes. High-dose niacin is the only drug that is approved for raising HDL. Generic high-dose niacin is usually taken 2-3 times per day, and can cause adverse effects such as skin flushing and itching. Niaspan, as an extended-release formulation of the drug, is taken once a day, and was developed to reduce the extent of these adverse effects. Niaspan is an FDA-approved drug.

Merck has meanwhile been developing its high-dose non-flushing niacin product, Tredaptive/Cordaptive (extended-release niacin/laropiprant). This is a combination product consisting of extended-release high dose niacin plus  laropiprant. Laropiprant is designed to block the ability of prostaglandin D2 to cause skin flushing; niacin-induced skin flushing works via the action of prostaglandin D2 in the skin. In 2008, the FDA rejected Merck’s New Drug Application for Tredaptive/Cordaptive, so the drug remains investigational in the US. However, in 2009 Merck launched Tredaptive in international markets including Mexico, the UK and Germany. The drug is approved in over 45 countries. Merck is also conducting a 25,000-person trial of Tredaptive for reducing the rate of cardiovascular events in patients who are at risk for cardiovascular disease (CVD). Merck intends to file for approval of the drug in the US in 2012, based on the results of this trial if it is positive.

According to an NIH press release, the NHLBI trial, known as AIM-HIGH, involved combination therapy with Niaspan and a statin (simvastatin). Participants selected for the trial had been taking a statin and had well-controlled LDL, but were still at risk for cardiovascular events since they had a history of CVD, as well as low serum HDL and high serum triglycerides. In the treatment arm of the study, participants received a combination of a stain and Niaspan, while those in the control arm received a statin plus placebo.

During the 32 months of the study, subjects in the treatment arm exhibited increased HDL and lower triglyceride levels, as compared to participants in the control arm.  However, combination Niaspan/statin treatment did not reduce cardiovascular events or strokes as compared to statin treatment plus placebo. The NIH therefore stopped the trial 18 months earlier than planned.

In the AIM-HIGH study, subjects had a lower rate of cardiovascular events and strokes than the trial researchers expected. Of the 1,718 people in the treatment arm, 5.8 people per year had cardiovascular events, as opposed to 5.6 cardiovascular events per year among the 1,696 people in the control arm. There was a small increased rate of strokes in patients taking Niaspan, but researchers cautioned that this may have been due to chance. However, the increased rate of strokes, along with the failure to demonstrate efficacy, contributed to the NHLBI’s decision to end the trial early.

As noted by the AIM-HIGH researchers (and mentioned in the NIH press release), the lack of efficacy of high-dose niacin was unexpected, and in striking contrast to the results of previous trials and of observational studies. For example, a 2010 meta-analysis of clinical trials evaluating niacin, alone or in combination with other lipid-lowering drugs (published between 1966 and mid-2008) found significantly positive effects of niacin in preventing cardiovascular events and in reversing or slowing the progression of atherosclerosis. However, the bulk of the studies analyzed had been performed before statin therapy had become the standard of care. As pointed out in a recent article by clinical outcomes researcher Harlan Krumholz, MD (Yale University School of Medicine), it was important to compare Niasapn with a good treatment–in this case, the standard treatment with a statin–rather than comparing it to a poor treatment or to placebo alone.

The results of the AIM-HIGH study may not apply to other patient populations, including higher-risk groups such as patients with acute heart attack or acute coronary syndromes, or in patients who have poorly-controlled LDL despite statin treatment. As a press release from Abbott pointed out, the relevance of the results of AIM-HIGH to patient populations other than the one studied–patients with stable, non-acute, pre-existing cardiovascular disease and very well controlled LDL on simvastatin–is unknown. However, it is not known whether there are any patient populations that might benefit from treatment with Niaspan plus a statin as compared to a statin alone.

The results of AIM-HIGH also do not apply to other drugs that are designed to raise levels of serum HDL. Each drug must be tested in the clinic before drawing conclusions about its efficacy and safety. Various drugs may have different effects on human disease biology. Thus, for example, one should not use the results of the AIM-HIGH trial of Niaspan to conclude that the CETP inhibitors anacetrapib and dalcetrapib, discussed in our previous blog post, are not likely to be efficacious.

The 19 May issue of Nature contains a special Insight section on cardiovascular biology. An article in this section, by leading cardiovascular researcher Peter Libby (Brigham and Women’s Hospital, Boston MA, where he is the Chief of the Division of Cardiovascular Medicine) and his colleagues, is entitled “Progress and challenges in translating the biology of atherosclerosis”. That article refers to HDL as a “frustrating next frontier” (beyond lowering LDL with statins) in cardiovascular drug treatment. HDL biology is complex, with HDL promoting efflux of cholesterol from macrophages in atherosclerotic plaques and exerting anti-inflammatory and other beneficial effects, as also discussed in our previous blog post. HDL particles in blood serum are heterogeneous, with some HDL particles having a greater degree of positive effects on atherosclerotic plaque biology than others. As a result, treatments (e.g., drugs, diet) that raise HDL, as determined by standard clinical assays for serum HDL, may not necessarily result in clinical benefit, because of qualitative changes in populations of HDL particles.

In this connection, the 2010 study by Alan Tall and his colleagues, which we discussed in our May 19, 2011 blog article, provides hope for the efficacy of anacetrapib. These researchers showed that although niacin treatment in humans resulted in a moderate increase in the ability of HDL to promote net cholesterol efflux (measured in in vitro assays), anacetrapib treatment caused a more dramatic increase. This was due not only to a higher level of HDL in anacetrapib-treated subjects, but also to enhanced ability of anacetrapib-induced HDL particles to promote cholesterol efflux, especially at high HDL concentrations. Although this study suggests that anacetrapib treatment induces increases in HDL particles that promote beneficial effects on atherosclerotic plaque biology, we must wait for the results of the REVEAL trial (expected in 2014-2016) to determine the efficacy of this drug. Meanwhile, the clinical trial of Roche’s CETP inhibitor dalcetrapib, known as dal-OUTCOMES, is ongoing, with efficacy results expected in 2012-2013.

Steven Nissen, M.D. (chief of cardiovascular medicine at Cleveland Clinic), a veteran HDL researcher who has often been critical of the pharmaceutical industry, was recently interviewed on public television about the AIM-HIGH trial. He said that ever since the introduction of statins in 1987, we have not had a successful new drug class that provides significant clinical benefits by modulating serum lipids. Even when new types of lipid-modulating drugs have given apparently better biochemical results (e.g., LDL lowering or HDL raising), they have not provided clinical benefit in terms of preventing cardiovascular events.

Nevertheless, despite past disappointments with HDL-raising therapies, and despite the results of AIM-HIGH, Dr. Nissen persists in running clinical studies of novel HDL-raising drugs. He is now working on testing Resverlogix’ (Calgary Alberta, Canada) RVX-208, a small-molecule drug related to resveratrol that induces endogenous production of the protein component of HDL, apolipoprotein A1. And, as discussed in our last blog post, Dr. Nissen is enthusiastic about the prospects of Merck’s anacetrapib, although he states that the FDA will require hard clinical evidence of this drug’s efficacy before approving it.

Statins, despite their leading role in cardiovascular therapy, only reduce the risk of heart attack and stroke by 25% to 35%. Thus there is the need for new classes of drugs, and HDL is–frustrating though it be–the next frontier. Thus researchers persist in discovery and development of HDL-raising drugs, and there are promising new candidates on the horizon.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.


Atherosclerosis. From Nephron.


In the April 29, 2011 issue of Cell, there is a Leading Edge review entitled “Macrophages in the Pathogenesis of Atherosclerosis”, by Kathryn J. Moore (New York University Medical Center, New York, NY ) and Ira Tabas (Columbia University, New York, NY). This 15-page  review (including 4 pages of references) covers a big subject–the central role of the macrophage in the pathogenesis of atherosclerosis, and of the resulting acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. The review will be helpful to those who wish to update their knowledge of the mechanistic basis of atherothrombotic disease, or to those who want an introduction to the subject.

Included in the review is a discussion of the role of high-density lipoprotein (HDL), or “good cholesterol” in promoting regression of atherosclerotic plaques. HDL, as well as the protein component of HDL, apolipoprotein A1, are key players in the process of cholesterol efflux, or removal of cholesterol from macrophages in atherosclerotic plaques. HDL may also have other beneficial roles, including prevention of subendothelial apolipoprotein B-lipoprotein (apoB-LP) retention (which starts the atherosclerotic process in the first place), decreasing activation of endothelial cells, and reducing LDL oxidation. (ApoB is the protein component of low-density lipoprotein [LDL], or “bad cholesterol”.) In human populations, low HDL is generally recognized as a major cardiovascular risk factor, and high HDL is recognized as being protective.

In its discussion of therapeutic strategies based on our current picture of the mechanistic basis of atherosclerosis, the authors of the review state that the most effective way to treat the condition would be to decrease subendothelial apoB-LP retention by lowering apoB-LPs in the blood via lifestyle changes and drugs. In order to completely prevent atherosclerosis, serum apoB-LPs (i.e., mainly LDL and VLDL [very low-density lipoprotein]) would need to be lowered below the threshold level required for subendothelial apoB-LP retention in the arteries. However, in Western societies (and in other societies that have been rapidly adopting Western lifestyles), initiation of atherosclerotic lesions occurs in the early teens; thus this preventive approach is not currently feasible.

The leading drugs for lowering serum LDL are the statins, such as atorvastatin (Pfizer’s LIpitor, which is the largest-selling statin; Lipitor will go off-patent in November 2011), pravastatin (Bristol-Myers Squibb’s Pravachol, generics), simvastatin (Merck’s Zocor, generics), and rosuvastatin (AstraZeneca’s Crestor). Statins are generally accepted as being effective in decreasing mortality in patients with cardiovascular disease (CVD). These drugs are also widely prescribed for patients with a high risk of developing CVD; i.e., patients with high LDL, type 2 diabetes, and/or other risk factors. However, some researchers question the value of statins in primary prevention in patients without preexisting CVD but at high risk of developing the disease. For example, a 2010 meta-analysis published in the Archives of Internal Medicine did not find evidence that statin therapy was beneficial in primary prevention of all-cause mortality in patients at high risk of developing CVD. Moreover, although statins are highly effective in decreasing cardiovascular events (up to 60%) and cardiovascular deaths in patients with pre-existing CVD, a large percentage of patients with or at high risk of developing CVD, despite statin treatment, still experience cardiovascular events and cardiovascular death. Therefore, researchers and companies would like to develop other, complementary drugs that work via different mechanisms from the statins.

HDL raising has long been a key target for pharmaceutical and biotechnology companies in their quest to develop CVD drugs that would be complementary to the statins. In the early-to-mid 2000’s, companies had several candidate drugs, of different types, in development. In an article published by Pharmaceutical Executive in 2006, I was quoted as saying that raising HDL was a big field. However, most of the drugs being developed at that time fell by the wayside, mainly due to failure in the clinic.

A particular focus of pharmaceutical companies has been the development of cholesteryl ester transfer protein (CETP) inhibitors. CETP catalyzes the transfer of cholesteryl esters and triglycerides between LDL/VLDL and HDL, and vice versa. In vivo (in animals and in humans), CETP inhibitor drugs raise HDL and lower LDL.

The leading CETP inhibitor in the early to mid-2000s was Pfizer’s torcetrapib. Pfizer had placed high hopes on torcetrapib, as a potential blockbuster to replace anticipated lost revenues from Lipitor when it went off-patent in 2011. However, in late 2006 Pfizer pulled the drug from Phase 3 trials, after finding that combination therapy with torcetrapib  and atorvastatin gave a 50 percent greater mortality rate that atrovastatin alone. This was not only a huge disappointment for Pfizer and its shareholders, but also cast a pall of gloom over the entire HDL-raising drug field, and especially over CETP inhibitors. Researchers speculated that inhibition of CETP might result in producing a form of HDL that is not cardioprotective, and might even be harmful. There were even calls for pushing the HDL field back to the basic research level, with the need to find just how (and what form of) HDL exerted its cardioprotective effects, in people with elevated HDL due to genetics, lifestyle, or treatment with high-dose niacin (the only drug approved to raise HDL).

However, later studies of torceptrapib found that the toxicity of the compound was not due to an untoward effect of CETP inhibition or HDL raising, but was due to off-target effects of the drug. In animals and in humans, torceptrapib raised serum levels of aldosterone, via release of aldosterone from the adrenals. Aldosterone was responsible for the increase of blood pressure seen in animals and in humans treated with torceptrapib, and aldosterone has proatherogenic effects that go beyond its effects on blood pressure. The hypertensive and aldosterone-raising effects of torceptrapib were independent of its CETP inhibitor activity, and other CETP inhibitors (discussed below) do not raise aldosterone levels or blood pressure.

A March 2011 News and Analysis article in Nature Reviews Drug Discovery reviewed the history of the CETP inhibitor field after the demise of torcetrapib. Although the torcetrapib debacle caused several other companies to exit the CETP inhibitor field, Roche and Merck persisted. Roche has been developing the CETP inhibitor  dalcetrapib, and Merck’s CETP inhibitor is known as anacetrapib.

As mentioned in the Nature Reviews Drug Discovery mini-review, Dr. Alan Tall (Columbia University), working in collaboration with Merck researchers, showed in 2010 that niacin treatment in humans resulted in a 30% increase in HDL, while anacetrapib treatment resulted in a 100% increase in HDL. Niacin treatment in humans resulted in a moderate increase in the ability of HDL to promote net cholesterol efflux (measured in in vitro assays) while anacetrapib treatment caused a more dramatic increase. This was due not only to a higher level of HDL in anacetrapib-treated subjects, but also to enhanced ability of anacetrapib-induced HDL particles to promote cholesterol efflux, especially at high HDL concentrations. HDL from both niacin-treated and anacetrapib-treated subjects also exhibited anti-inflammatory activity. This study should help lay to rest the idea that pharmacological inhibition of CETP might result in abnormal pro-atherogenic HDL, as theorized by some researchers after the clinical failure of torceptrapib.

Currently, Roche’s dalcetrapib is in a 15,600-patient Phase 3 clinical trial known as dal-OUTCOMES; this trial was initiated in 2008, and efficacy results are expected in 2012-2013. As of the time of the Nature Reviews Drug Discovery article, Merck planned to initiate its 30,000-patient REVEAL trial of anacetrapib in April 2011. Efficacy results of REVEAL are anticipated in 2014-2016.

In December 2010, the results of Merck’s moderate-sized (1623 patients with or at high risk for CVD, who were already being treated with a statin) Phase 3 DEFINE trial of anacetrapib were published in the New England Journal of Medicine. The DEFINE trial was designed as a safety study. In this 76-week study, anacetrapib showed no significant differences from placebo in terms of safety, as measured by a pre-specified cardiovascular endpoint (defined as cardiovascular death, myocardial infarction, unstable angina or stroke). These cardiovascular events occurred in 16 anacetrapib-treated patients (2.0 percent) compared with 21 placebo-treated patients (2.6 percent). There were also no significant differences in blood pressure, serum electrolytes, or aldosterone levels between anacetrapib-treated and placebo-treated patients.

Anacetrapib treatment also decreased LDL by 40 percent (from 81 to 45 mg/dl vs. 82 to 77 mg/dl for placebo) and increased HDL by 138 percent (from 40 to 101 mg/dl vs. 40 to 46 mg/dl for placebo). Anacetrapib also had other favorable effects on lipid levels (e.g., 36.4% reduction in lipoprotein(a), and 6.8% reduction in triglycerides, beyond the changes seen with placebo treatment).

Although the DEFINE study was too small to provide definitive results regarding the safety of anacetrapib, it gave a 94% predictive probability that treatment with anacetrapib is not associated with the rate of cardiovascular events seen with torcetrapib. The trial also indicated that anacetrapib treatment does not result in the effects (especially raising of serum aldosterone levels) thought to be responsible for torcetrapib’s toxicity. Moreover, anacetrapib treatment resulted in a dramatic increase in HDL levels (beyond that seen with torcetrapib) in the DEFINE study, and the 2010 study by Dr. Tall and his colleagues indicates that anacetrapib-induced HDL is highly effective in promoting cholesterol efflux.

The results with anacetrapib have reignited enthusiasm for CETP inhibitors in the medical community. Even the often-critical Dr. Steven Nissen (Cleveland Clinic) expressed enthusiasm for anacetrapib. However, despite these promising results, the efficacy of CETP inhibitors, in terms of significantly reducing the rate of cardiovascular events, has not yet been demonstrated. Only large, adequately-powered Phase 3 clinical trials, such as dal-OUTCOMES for Roche’s dalcetrapib and REVEAL for Merck’s anacetrapib, can definitively establish both the efficacy and the safety of these drugs.

The development of CETP inhibitors represents a situation in which the leading drug in the class failed because of off-target effects. However, these off-target effects were not class effects, and targeting CETP in order to raise HDL now seems like a good idea after all. Pfizer ignored warning signs (especially the modest elevation in blood pressure induced by torcetrapib, which did not appear to be very significant) in pursuit of its commercial goals, while Roche and especially Merck pursued a more moderate and science-based approach to development of CETP inhibitors. Other companies stopped development of their CETP inhibitors, thus losing their opportunities in this field. Meanwhile, various companies and academic group have been developing other approaches to HDL raising, such as apolipoprotein A1 mimetics, which are in early stages of development.

Despite its early setbacks, HDL-raising drugs may turn out to be a big field after all.


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