Replies to post #60789 on Biotech Values

[iwfal]

One more comment on Jupiter - consistent with my belief that statins act at least as much through CRP related pathways as LDL I predict that the HR will be equal to or better than for any of the LDL based trials of statins at moderate doses (Jupiter did not use the highest dose of Crestor). I.e. a reduction in events of more than 30%.

[DewDiligence]

Heart Disease: Not About Cholesterol?

[Crestor has a decent chance to become the largest-selling drug of all time.]

http://www.businessweek.com/bwdaily/dnflash/content/apr2008/db20080414_688906.htm

>>
AstraZenaca's Crestor study finds that statins may help prevent heart attacks because they control inflammation, not because they lower cholesterol

April 15, 2008
by John Carey

The idea that lowering cholesterol is the key to preventing heart attacks and cardiovascular disease has taken a couple of big hits recently. The first came on Mar. 30, when a panel of cardiologists recommended that Zetia and Vytorin, cholesterol-lowering drugs marketed by a joint venture of Schering-Plough (SGP) and Merck (MRK), be used only as a last resort. The reason: A clinical trial adding Zetia to other cholesterol-reducing drugs had failed to show a benefit.

But in the furor over Zetia and Vytorin, an equally dramatic but largely unnoticed development occurred the next day. On Mar. 31, AstraZeneca (AZN) announced that it was halting early a 15,000-patient trial of its cholesterol-lowering drug, Crestor—because the drug was working better than expected. The surprising twist: When the patients started taking the drug, their "bad" cholesterol levels were already very low—so low, in fact, that drugs normally would not have been recommended or used. Yet patients on the drug had fewer heart attacks than those untreated in the trial, which was dubbed Jupiter, and the benefit showed up much earlier than expected. "It was stunning to have Jupiter stopped so early," says Dr. James Liao, a researcher in the vascular medicine unit of Brigham & Women's Hospital in Cambridge, Mass., the lead research center for the trial. "It suggests a new paradigm. These drugs may be working in ways other than lowering cholesterol."

That's a heretical notion, given the overwhelming message from doctors, companies, and the media that high levels of bad cholesterol can lead to an early grave and must be reduced. According to national treatment guidelines, everyone's LDL (or bad cholesterol) levels should be brought under 130 mg/dL, and in many cases, lowered as close to 100 as possible.

Nonbelievers

Yet there have always been doubters about the almighty importance of cholesterol levels, and there is evidence that LDL may be only a part—and a small part—of the story. Half of all heart attacks and cases of cardiovascular disease occur in people with normal or even low levels of LDL, for instance. And the Zetia trial showed that different types of cholesterol-lowering drugs don't bring the same benefit. In that trial, the additional LDL reduction from adding a second drug, Zetia, to the standard statin-type drug, which works differently in the body, seemed not to help patients.

Dr. Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham & Women's Hospital and a professor of medicine at Harvard University, was one of those who thought something else must be going on. The evidence, he believed, pointed to a major role for inflammation in causing cardiovascular disease. He became a proponent of testing blood for a biological marker of inflammation, called C-reactive protein (CRP). Could inflammation be a better indicator of risk than cholesterol levels, he wondered? Maybe statins such as Lipitor work, in part, by reducing inflammation.

Ridker convinced AstraZeneca that it was worthwhile for the company to fund a major trial to test the idea. After all, there was little risk and lots of potential gain for the Anglo-Swedish drugmaker. Its drug, Crestor, had been late to the cholesterol-lowering game, and it lagged behind other drugs in the same "statin" class, such as Pfizer's (PFE) Lipitor. But if the trial showed that Crestor worked in patients with low cholesterol, then it could reach a wider market than the other statins. Instead of just selling it to people with high cholesterol, it might also be used in those with high CRP or other indications of inflammation even when they had normal or low cholesterol. That's a potential expansion of the market by some 25 million to 30 million Americans. "The trial was originally conceived to see how important a factor inflammation is in cardiovascular disease," explains AstraZeneca Chief Executive David Brennan.

The trial Ridker launched was huge: 15,000 patients with high CRP levels. Their average cholesterol level: 108, which is very low. Half the volunteers got Crestor; half got a placebo. Ridker designed the study so that, if the drug reduced events like heart attacks by 25%, the benefit in those getting the drug would be noticeable in 3½ years. "Our expectation was that the trial would take until 2010 or 2011," says Brennan.

Instead, the benefit was so obvious that the trial was stopped in March, more than two years early, so that patients getting the dummy pill could also benefit. Continuing the trial would have been unethical since it would have denied the benefit to those still on the placebo. The company says it will make the actual data public this fall at a scientific meeting. But the effect is surprisingly large. For the reduction in heart attacks to have been seen so early, the benefit in these patients is as high, or higher, than the benefits seen in patients who start with high bad-cholesterol levels. The implication is remarkable: The main reason why blockbuster statins work may not be because they lower cholesterol, but because they reduce the inflammation that leads to heart attacks. "I think statins do work, but maybe not because they lower LDL," says Liao.

Body Chemistry

Liao's own research has proved that statins have other biochemical effects than lowering cholesterol. Most important, they reduce the amount of an enzyme called Rho-kinase. That, in turn, dials back damaging inflammation in arteries. When Liao knocks down the level of Rho-kinase in rats, they don't get heart disease. And in new, still unpublished work, he has showed that simply reducing Rho-kinase in certain immune system cells is enough to reduce heart disease in rats.

Depending on details of the data from the Jupiter trial, it may be possible for AstraZeneca to convince the Food & Drug Administration that Crestor should be approved for people with low cholesterol but high levels of inflammation in their arteries. That could turn the drug, now a $2.7 billion-a-year best-seller, into a mega-blockbuster. Without FDA approval, the company can't yet market the drug for this new use, "but we think it will take the science in a certain direction, towards inflammation," Brennan says. A year's supply of the 20mg Crestor dose used in the Jupiter trial costs just under $1,200 when purchased online. If just 5 million more people went on the drug, that would represent an additional $5.2 billion for AstraZeneca—a nearly 200% boost from current sales. And if 10 million in the potential market expansion of 25 million to 30 million people were to take Crestor, the company would add some $11.8 billion in additional annual sales.

One hurdle, however, is exactly how that inflammation should be measured. CRP is seen as a bit of a blunt instrument, since it varies considerably among people and requires multiple tests to establish a true reading. The body's immune system kicks into high gear at the first sign of injury or disease, be it a head cold or broken bone, and inflammation increases. In addition, Ridker has been criticized for having patented the test for CRP at the same time that he is pushing for more widespread testing—a conflict of interest. Others, such as Liao, believe that other biological substances, such as the Rho-kinase enzyme, might end up being a better marker.

Either way, the Jupiter trial adds to the growing evidence that the American obsession with "bad" cholesterol levels may be misplaced. In the coming years, doctors and patients may become far more concerned with how inflamed our arteries are.
<<

[DewDiligence]

Crestor JUPITER Data Could Be a ‘Game Changer’

[#msg-28510348 is a good background piece on this topic.]

http://blogs.wsj.com/health/2008/10/30/a-strong-season-for-astrazenecas-cholesterol-drug-crestor

›October 30, 2008
by Jacob Goldstein

AstraZeneca reported stronger-than-expected earnings this morning, largely on a big jump in sales of its cholesterol drug Crestor. And the drug could soon get yet another boost from the widely anticipated results from a study of cholesterol treatment.

The AstraZeneca financed study, known as Jupiter, enrolled more than 15,000 basically healthy people with modest amounts of bad cholesterol (the average LDL level was 104), but high levels of a common marker of inflammation [CRP].

Researchers aimed to see whether Crestor lowered the risk of major cardiovascular events such as heart attack and stroke; the study was stopped early in March because of “unequivocal” benefits for patients who received the drug, but the full results have yet to be released [#msg-28053790].

Those data are likely to be one of the big stories next month at the American Heart Association’s big scientific meeting, where the study will be presented in full. If the data are a home run, they could prompt doctors to prescribe Crestor to millions of basically healthy people who aren’t currently taking cholesterol drugs, Forbes reports.

“It’s potentially a game-changer,” Steve Nissen, a high-profile cardiologist who is often skeptical of the drug industry, told Forbes. “There could be a much larger population of patients that may benefit than are currently treated.”

Even without the Jupiter results, Crestor sales are growing — which is particularly impressive given that Lipitor, Pfizer’s dominant cholesterol medicine, has been losing sales to generic competitors. AstraZeneca said this morning that the company sold $922 million worth of the medicine in the third quarter, up from $691 million during the year-earlier period. In the U.S., sales of the drug rose 23%. The gain is probably due at least in part to worries about the safety and efficacy of Vytorin, the cholesterol pill co-marketed by Schering-Plough and Merck.‹

[DewDiligence]

CRP Is Just a ‘Bystander’ in Heart Disease

http://www.nytimes.com/2009/07/01/health/01heart.html

›July 1, 2009
By GINA KOLATA

A blood protein that only a short time ago was thought by some to be more important than cholesterol in heart disease now appears to be little more than a bystander.

The substance, C-reactive protein, or CRP, a marker of inflammation in the body, is unquestionably associated with heart disease: the more CRP in a person’s blood, the greater the likelihood of heart disease.

But in a paper to be published Wednesday in The Journal of the American Medical Association, researchers analyzing genetic data from more than 100,000 people conclude that their study “argues against” the notion that the protein causes heart disease.

Dr. David Altshuler, a professor of genetics and medicine at Harvard Medical School, said the distinction was important. If CRP caused heart disease, lowering it would protect people. But if it was merely associated with the disease, lowering CRP would have no more effect on health than quelling a shrieking fire alarm would have on putting out a fire.

Many believed CRP caused heart disease, especially after a widely publicized study released last year suggested that people with low cholesterol but high CRP levels had fewer heart attacks if they took a statin, a cholesterol-lowering drug that also lowers CRP.

That could mean that lowering CRP could prevent heart disease. Of course, it also could have been the cholesterol lowering that was protective, but many researchers argued that it was the reduction in CRP.

“There certainly has been a very vocal constituency in the idea that CRP causes or contributes to the development of heart disease,” said Dr. Daniel Rader, a lipid expert at the University of Pennsylvania. He noted that some companies were trying to develop drugs to lower CRP.

But Dr. Michael S. Lauer, director of the division of prevention and epidemiology at the National Heart, Lung and Blood Institute, said it might now be smart to abandon that search.

“It is likely that drugs or agents that specifically target CRP are not going to work,” Dr,. Lauer said.

The findings will not change current treatment. And one leading CRP researcher, Dr. Paul M. Ridker of Brigham and Women’s Hospital in Boston, director of last year’s study, called Jupiter, and the researcher most closely associated with the excitement over CRP, said the new study did not change anything for him.

Dr. Ridker, an inventor of a laboratory test for CRP who profits from its use, said that while the new results did not support causality, he did not think they definitely excluded it either.

Anyway, he said, it does not matter because the real issue is inflammation. CRP goes along with inflammation, and it is inflammation that is likely to be causing heart disease, Dr. Ridker said.

The thought is that white blood cells invade artery walls and release damaging chemicals, leading to plaque formation.

The new study, by Dr. Paul Elliott of Imperial College in London and 35 co-authors, used a recently developed technique that can get answers quickly about causality. Without it, the only method was what is seen as the gold standard in medicine: large clinical trials in which people are randomly assigned to take a drug, or not, and followed for years.

The new method, Mendelian randomization, “is changing the way we think about causality,” Dr. Lauer said. It only recently became feasible as researchers found genetic variants associated with proteins like CRP and developed tools to analyze data from what was, in this case, more than 100,000 people.

Different people produce different amounts of CRP, and the amount a person produces is determined by tiny inherited changes in the CRP gene. So in a population, there are people who just happen to produce more CRP throughout their lives and others who just happen to produce less. If CRP causes heart disease, those who make more would have more heart disease. That, however, is not what the study found.

“There was no association” between CRP genes and heart disease rates, Dr. Elliott said.

The association between CRP and heart disease must be reflecting something else. For example, if CRP levels go up when heart disease begins, because of inflammation in arteries, CRP levels would be higher in people with incipient heart disease. But CRP itself would be playing no role in heart disease risk; it was just marker of inflammation.

A smaller study of CRP, using the same method and published last October in The New England Journal of Medicine, came to the same conclusion.

But this second, larger, study was needed to convince heart experts, said Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital.

“It’s a very important question particularly in the context of the Jupiter trial,” Dr. Kathiresan said.

Dr. Rader, at Penn, said he still did CRP tests on selected patients and expected to continue. An elevated CRP level indicates increased risk, even if the protein does not cause the risk. Dr. Rader tests CRP to help decide whether to give a statin to patients with normal cholesterol but with a family history of heart disease. A high CRP, he said, could tip the balance, leading him to prescribe a statin.

Dr. Altshuler noted that part of the power of a Mendelian randomization study was that it could stop a hypothesis from prematurely becoming viewed as fact.

Ordinarily, science starts with an observation, like the one associating CRP with heart disease. That generates a hypothesis — that CRP causes heart disease. Then comes a trial, if there is a treatment, like a drug to specifically attack CRP, that people can be randomly chosen to take or not.

But it can be years or decades before the clinical trials are completed. In the meantime, Dr. Altshuler said, the hypothesis comes to be regarded as true. [Huh?]

And if the clinical trial contradicts the hypothesis, “some people are unwilling to question their beliefs, even if there was no evidence of causality to begin with,” Dr. Altshuler said.‹