Cardiovascular Pipeline Merely a Drip
By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today
Published: November 13, 2010|
CHICAGO -- After nearly a quarter century of major breakthroughs in the treatment and prevention of heart disease, the field of cardiovascular research is at a crossroads.
With a few exceptions, the pace of blockbuster drugs hitting the market has slowed, especially those that can treat the millions of Americans who don't have known heart disease, but still are at risk.
That is the clinical reality that forms the background for the American Heart Association meeting here.
The 1990s and early 2000s brought cholesterol-lowering statins, new blood pressure medicines and anti-clotting drugs.
More recently, anticoagulant drugs that may replace the need for the troubling old standby, warfarin, have shown great promise.
But the field has been stung by promising drugs that turned out to be dangerous and some of the best drugs now have been on the market for more than a decade.
As a result, heart disease remains America's number one killer and doctors say it is unclear when and from where the next blockbusters will come.
"Cardiology is no longer low-hanging fruit," said James Stein, MD, a cardiologist at the University of Wisconsin School of Medicine and Public Health. "I don't see anything in the next five years that is going to dramatically change how we treat, other than the new blood thinners."
Stein, director of preventive cardiology at UW Hospital, and others say that over the last five years there has been a paucity of drugs that have had a major effect on preventing heart attacks and strokes.
Gone are the days when drug companies were assured of FDA approval based on improvement of surrogate endpoints, replaced now by the hard clinical endpoints of myocardial infarction, stroke, hospitalization, and death.
And often that proof must come in an expensive head-to-head clinical trial against a proven product rather than a placebo.
Showing those kinds of meaningful clinical benefits requires many thousands of patients over several years as opposed to one thousand or fewer people over a year or less, said Robert Harrington, MD, a cardiologist at Duke University Medical Center.
"That's probably taken some people (drug companies) out of the game," said Harrington, director of Duke's clinical research program. "I actually think that's a good thing."
As a result, there have been incremental improvements but not paradigm shifts, he said.
"There has been an indisputable slowdown of new technologies making their way to the market, in part because we have been so successful," Harrington said.
In 2004, the FDA approved a pair of drugs that were destined to become the dynamic duo of direct-to-consumer marketing: Vytorin (ezetimibe/simvastatin) for treatment of hyperlipidemia and the prescription omega-3-acid Lovaza for treatment of elevated triglycerides.
But neither drug was proven to reduce cardiovascular deaths, heart attacks, or strokes and, in the case of Vytorin, ultrasound imaging evidence would emerge after it got on the market showing that it did not slow the progression of atherosclerosis.
Whether those drugs would be approved today is unknown.
What is clear is the field has suffered some disappointments, especially with the promising, but still unrealized potential of drugs that raise HDL cholesterol.
A few years ago, those drugs were expected to be the new wave of cardiovascular research.
But in late 2006, the field was dealt a huge setback when Pfizer halted a large clinical trial of the promising experimental drug torcetrapib because of patient deaths. While the drug raised HDL cholesterol, it also raised blood pressure, a dangerous side effect for heart patients.
Pfizer had hoped to sell torcetrapib in combination with its blockbuster Lipitor, which lowers LDL cholesterol.
Stunned by the trial, in 2008 Pfizer said it was abandoning internal efforts to develop new heart disease medicines.
As it turns out, the world's largest drug company again is testing the waters, although it may be several years before it is known if its research initiative will become a major new therapy.
Back in the Game
Pfizer is one several companies trying to design new heart drugs by looking at how human genetic variation affects heart disease risk.
Specifically, it is targeting a gene known as PCSK-9, which is involved in regulating levels of LDL cholesterol. Although that genotype represents less than 1% of the population, people with a specific mutation of the gene have extremely low levels of LDL cholesterol and show no signs of heart disease, said Tim Rolph, PhD, head of cardiovascular disease research for Pfizer.
Pfizer is looking at whether the function of the PCSK-9 gene can be blocked, possibly by injecting an antibody into people to see if they get similar protection.
Rolph said the research has as much potential as cholesterol-lowering statin drugs, which reduce heart attacks and strokes by more than 30%, but any such drug likely would not reach the market until 2020.
Another setback to the field came in 2008 when Merck learned that the FDA would not approve its HDL-raising compound without additional trial data. But the company is continuing its research on the drug, a combination of extended release niacin and the anti-flushing agent laropiprant (Cordaptive).
Earlier this month, a Merck cardiovascular disease research official wrote that failures of once-promising drugs has profoundly affected the industry's willingness to invest in cardiovascular research and shifted its focus to other fields such as oncology.
"We cannot afford to abandon the development of novel, preventive (cardiovascular disease) treatments," Andrew Plump, MD, PhD, a Merck vice president and head of cardiovascular disease research, wrote in Nature Reviews.
In an interview, Plump said it was disheartening that some companies were leaving the field of cardiovascular disease research.
He said Merck had several large clinical trials going on, including a 25,000-person worldwide trial of Cordaptive that will directly measure whether it reduces heart attacks, strokes, and coronary deaths. The trial is expected to be completed by the end of 2012.
In addition, the company is testing its own drug from the same class of HDL-raising agents as Pfizer's failed torcetrapib. In an earlier study, Merck's drug, anacetrapib, raised HDL cholesterol by 140%, but without raising blood pressure.
Oddly, the main measure of the 1,600-person phase III trial is not how much it raises HDL cholesterol, but how much it lowers LDL cholesterol. The drug does both. The trial's results will be presented here Wednesday.
The Warfarin Alternatives
"There are little islands of activity, but it's not what we need," Plump said, referring to the overall state of heart disease research.
One of those research niches that, so far, has been a major disappointment is the field of anti-obesity drugs.
In 2008, a 19,000-person worldwide clinical trial of the drug rimonabant was halted early because of concerns about suicide and other psychiatric side effects. That, plus the fact that the drug had no real benefit in reducing heart attacks, strokes, or cardiovascular deaths.
The one bright side of cardiovascular disease research has been the development of new anti-coagulant drugs.
Last month, the FDA approved dabigatran (Pradaxa) for the prevention of strokes and blood clots in people with a type of abnormal heart beat known as atrial fibrillation that affects two million Americans. Other companies are developing similar drugs.
Dabigatran reduced strokes compared with warfarin, but, unlike warfarin, dabigatran does not require continual monitoring with blood tests, nor does it require a special diet.
Another large clinical trial that will be reported here involves rivaroxaban, another potential replacement for warfarin. While dabigatran is a direct thrombin inhibitor, rivaroxaban is a factor Xa inhibitor.
"We've been waiting for a new anti-coagulant for 54 years since warfarin was approved," said Christopher Cannon, MD, a Harvard cardiologist and researcher with the TIMI Study Group.
Cannon said there have been several positive developments, especially with drugs to raise HDL cholesterol and improve other lipids as well as anti-coagulants. "There is a lot going on," said Cannon, who is heading up the anacetrapib clinical trial.
Others, including Sanjay Kaul, MD, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, see the prescription bottle as being half full. "I don't expect any major inroads," he said.
HDL-raising drugs, if they work, are six to 10 years away, said Kaul, who also has served as an FDA advisory panel member.
Kaul is a consultant to Hoffman-La Roche and one of the national coordinators for the company's trial of another HDL-raising drug, dalcetrapib. The 15,600-patient trial won't be completed until 2013.
Raising HDL is a lot more complicated than it seems, he said, and there may be more unforeseen side effects.
Stein reported that he serves on Data and Safety Monitoring Committees for Abbott, Lilly, and Takeda.
Kaul said he owns stock in Johnson & Johnson and serves as a consultant for Hoffman-La Roche.
Cannon reported research funding from Accumetrics, AstraZeneca, GlaxoSmithKline, InteKrin Therapeutics, Merck, Takeda; an advisory and ownership relationship with Bristol-Myers Squibb/Sanofi Partnership, Novartis, and Alnylam; honorarium for development of independent educational symposium from Pfizer; and clinical adviser and equity in Automedics Medical Systems.
Harrington reported receiving consulting fees/honoraria from WebMD, AstraZeneca, Schering-Plough Baxter, Otsuka Maryland Research Institute, Merck, The Medicines Company-sponsored TheHeart.org program, Regado, Luitpold, sanofi-aventis, CSL Behring Novartis, Lilly-sponsored Filming for Future Educational Programming, as well as research grants from Portola, Schering-Plough, Bristol-Myers Squibb, GlaxoSmithKline, Merck Millennium, AstraZeneca, The Medicines Company, and Baxter.