We have published two articles on high-density lipoprotein (HDL, or “good cholesterol”) raising drugs on this blog:
- Can HDL-raising drugs be a big field after all? (May 19, 2011)
- HDL-raising drugs revisited (June 1, 2011)
The more recent of these article has received quite a few hits lately. This is probably because of recent news of a clinical trial failure in the HDL drug field. It therefore seems appropriate to publish an update on HDL-raising drug clinical trials, in order to bring our blog up to date.
Update on the trials and tribulations of niacin-based HDL-raising drugs
As of the time of our June 1, 2011 article, high-dose niacin was the only drug that was approved by the FDA for raising HDL. However, generic high-dose niacin can cause adverse effects such as skin flushing and itching. Therefore, two companies, Abbott and Merck, were developing high-dose niacin-based products designed to reduce these adverse effects.
In May 2011, as discussed in our June 1, 2011 article, the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) stopped a large clinical trial (known as AIM-HIGH) of Abbott’s Niaspan, an extended-release formulation of high-dose niacin, because the drug failed to prevent heart attacks and strokes. There was also a small increased rate of strokes in patients taking Niaspan, which researchers cautioned may have been due to chance. Niaspan remains an FDA-approved drug, and it is now owned by Abbot spin-off AbbVie. However, Niaspan is scheduled to go off-patent later in 2013.
Merck’s high-dose non-flushing niacin product is known as Tredaptive or Cordaptive in different markets. It 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 remained investigational in the US. However, in 2009 Merck launched Tredaptive in international markets including Mexico, the UK and Germany. The drug has been approved in over 45 countries. Merck had also been 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 intended to file for approval of the drug in the US in 2012, based on the results of this trial if it had been positive.
However, on December 20, 2012, Merck announced that its clinic trial of Tredaptive, known as the HPS2-THRIVE Study (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events), did not achieve its primary endpoint.
As a result of this finding, Merck does not plan to seek regulatory approval for this medicine in the United States. It also–as of January 11, 2013–began a recall of Tredaptive in the 40 countries in which it had been approved. The HPS2-THRIVE Study not only showed that Tredaptive was of no benefit in reducing cardiovascular events in high-risk patients on statins, but it also significantly raised the incidence of such adverse effects as blood, lymph and gastrointestinal problems, as well as respiratory and skin issues.
The results of a new study published online on February 26 2013 showed that around a quarter of all patients taking the niacin/laropiprant combination Tredaptive had dropped out of the trial–compared to fewer than 17% in the placebo arm. This was mostly due to itching, rashes, indigestion and muscle problems. There were also dozens of serious reactions, including 29 cases of myopathy.
Skin-related adverse effects seen in some patients with Tredaptive resemble those seen with high-dose niacin. The addition of laropiprant was supposed to ameliorate these adverse effects, but may not have done so in all patients. As for the serious adverse effects such as myopathy, several medical researchers assert that it is not known whether niacin, laropiprant or drug-drug interactions between these two agents and/or the statin (simvastatin) used in the study was responsible. Simvastatin is known to have adverse interactions with certain other drugs. Moreover, one-third of subjects enrolled in HPS2-THRIVE were Chinese, a patient population that is known to be more sensitive to the effects of statins, especially the 40-milligram dose of simvastatin used in the trial. It was the Chinese patients enrolled in the trial who showed the highest risk of myopathy.
In addition, some of the researchers question whether laropiprant is a “clean drug” that has no effects on atherosclerosis and thrombosis. A recent study has shown aneurysm formation and accelerated atherogenesis in mice with deleted prostaglandin D2 receptors; these receptors are the target of laropiprant. Thus the use of laropiprant may have been a factor in the failure of the trial, as well as in the adverse effects seen in patients treated with the niacin/laropiprant combination.
Full results of the HPS2-THRIVE study will be presented by lead investigator Dr Jane Armitage (Oxford University, UK) on March 9, 2013 at the American College of Cardiology 2013 Scientific Sessions (San Francisco, CA.)
Thus–although generic niacin and Niaspan remain FDA-approved HDL-raising drugs–the results of the AIM-HIGH and the HPS2-THRIVE studies have put niacin-based HDL-raising drugs–and the whole HDL-raising drug field–under a cloud.
Update on development of CETP inhibitors
As discussed in our earlier articles, the development of cholesteryl ester transfer protein (CETP) inhibitors has been a particular focus of several pharmaceutical companies. 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 clinical failure of Pfizer’s CETP inhibitor torcetrapib in 2006 put a severe damper on development of drugs in this class. However, the toxicity of torcetrapib was found to be due to an off-target effect, and other CETP inhibitors do not display this toxicity. Thus companies have been developing three CETP inhibitors: Roche’s dalcetrapib, Merck’s anacetrapib, and Lilly’s evacetrapib.
However, on May 7, 2012 Roche announced that it had–following the recommendation of an independent group of experts (the Data and Safety Monitoring Board)–halted its Phase 3 trial of dalcetrapib “due to a lack of clinically meaningful efficacy.”
Dalcetrapib’s lack of efficacy might possibly be due to its relatively low potency in raising HDL. Dalcetrapib boosted HDL by 30%, as compared to 138% for anacetrapib and 130% for evacetrapib, depending on the dose. Moreover, anacetrapib and evacetrapib, unlike dalcetrapib, also lower LDL (“bad cholesterol”).
Currently, anacetrapib and evacetrapib are being evaluated in large Phase 3 clinical trials–REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) and ACCELERATE (A Study of Evacetrapib in High-Risk Vascular Disease), respectively.
Is HDL-raising drug development high-stakes gambling or rational clinical research?
Given the lack of success–so far–in developing a safe HDL-raising drug that lowers the frequency of cardiovascular events in high-risk patients, some commentators speculate that attempting to develop HDL-raising drugs such as CETP inhibitors might be a form of high-stakes gambling. Chemist and leading pharmaceutical industry blogger Derek Lowe in particular takes this point of view. As we discussed in our June 1, 2011 article, the biology of HDL is complex. For example, 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.
The unknowns of HDL biology, combined with the need to conduct huge expensive clinical trials and the big payoffs for success in the large dyslipidemia market, convinced Derek Lowe that CETP inhibitor development more resembles gambling (in which only Big Pharmas can play) than rational clinical research. The same, according to Lowe, applies to Alzheimer’s disease drug development. According to Lowe, Big Pharmas may be undertaking these “go-for-the-biggest-markets-and-hope-for-the-best” research undertakings because they think that success in large markets are the only things that can rescue them.
Nevertheless, Steven Nissen, M.D. (chief of cardiovascular medicine at Cleveland Clinic), a veteran HDL researcher who has often been critical of the pharmaceutical industry, persists in running clinical studies of novel HDL-raising drugs. Although he considered dalcetrapib a “long-shot”, he continues to believe that anacetrapib and evacetrapib have a reasonable chance of success. And he has expressed particular enthusiasm for anacetrapib.
Dr. Nissen is involved in clinical trials of Resverlogix’s epigenetic agent RVX-208, a first-in-class small-molecule drug related to resveratrol that induces endogenous production of the protein component of HDL, apolipoprotein A1. On August 28, 2012, Resverlogix reported that RXV-208 significantly increased HDL-C, the primary endpoint of a Phase 2b clinical trial known as SUSTAIN. SUSTAIN also successfully met secondary endpoints–showed increases in levels of Apo-AI and large HDL particles. Both of these are believed to be important factors in enhancing reverse cholesterol transport activity. Safety data from SUSTAIN indicate that increases in the liver enzyme alanine aminotransferase (ALT) reported in previous trials were infrequent and transient, with no new increases observed beyond week 12 of the 24-week trial. Thus the drug appears to be suitable for chronic use.
Thus, despite the features of CETP-inhibitor clinical trials that resemble high-stakes gambling, we must wait for the results of the clinical trials to draw any meaningful conclusions about the prospects for development of these agents. Moreover, other approaches to developing HDL-raising drugs, such as Resverlogix’ epigenetic strategy, may turn out to be superior to older approaches. And as with Alzheimer’s disease, continuing studies on the basic biology of HDL may eventually yield breakthrough strategies to discovery and development of novel antiatherosclerotic drugs.
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 contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.