Replies to post #57470 on Biotech Values

[DewDiligence]

After the Vytorin-induced sell-off, SGP is trading at a modest valuation relative to expected sales and earnings. If it falls much further, SGP could become an attractive takeover candidate based on the HCV franchise and the antiplatelet drug candidate (#msg-23899164).

On the other hand, SGP’s recent acquisition of Organon makes a takeover of SGP less likely than it otherwise would be, IMO.

[DewDiligence]

Vytorin, Zetia Are Losing Altitude Fast

[The share of TRx’s is down but, more important, the share of NRx’s is way down.]

http://blogs.wsj.com/health/2008/01/22/vytorin-prescriptions-decline-amid-scrutiny

>>
January 22, 2008, 4:15 pm
by Jacob Goldstein

Last week’s Vytorin trifecta of unflattering study data, media scrutiny and hit prescriptions of the cholesterol combo pill pretty hard.

Prescriptions for Vytorin fell about 9.5% to 359,659 in the week ended Jan. 18 according to an estimate from Verispan cited by Dow Jones Newswires. Prescriptions for Zetia (which comprises half of Vytorin and is also sold as a stand-alone drug) fell 12% to 258,619, Verispan said.

Market share as a percentage of new prescriptions for cholesterol drugs fell as well, according to Catherine Arnold of Credit Suisse. Vytorin’s share was 9.2% during the time period ended Jan. 20, down from 11.1% before the news broke. And Zetia’s share was 6.1%, down from 7.7%.

So now the question is whether that was a one-time dip or the start of a sustained decline for the drugs, which are co-marketed by Merck and Schering-Plough and had sales of $3.73 billion in the first nine months of 2007.

Schering CEO Fred Hassan said last week that the science behind the drugs is still solid. But DJ Newswires cites Leerink Swann analyst Seamus Fernandez, who estimates that prescribing levels for Zetia and Vytorin will decline by at least 15% in 2008 because of the study results.

Primary care docs who write the most prescriptions have shifted quickly toward generic simvastatin and away from Vytorin and Zetia to treat cholesterol, according to data from ImpactRx. Vytorin’s share of new prescriptions written by the influential doctors fell to 5% for the rolling seven-day period ending Jan. 21 from 11% the week before. Simvastatin’s share climbed to 43% from 33% on the same basis.
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[DewDiligence]

Vytorin Rebound Falters as Prescriptions Fall Again

[What rebound?]

http://blogs.wsj.com/health/2008/02/19/vytorin-rebound-falters-as-prescriptions-fall-again

>>
February 19, 2008, 4:21 pm
by Peter Loftus

So much for the Vytorin rebound.

Prescriptions for Merck’s and Schering-Plough’s cholesterol drug Vytorin and its statin-free stablemate Zetia declined last week, following two weeks of recovery after the long-awaited results of the Enhance study raised questions about their effectiveness.

Vytorin prescriptions for the week ended February 15 were off 7% to 327,698 compared with the previous week, according to data provided by Verispan. And the prescriptions were down nearly 18% from the week preceding the release of the study results on January 14. Zetia prescriptions declined 8% to 237,797 last week compared with the week before, and were off 19% from pre-Enhance levels.

Prescriptions had dropped for two weeks after the companies released the Enhance results. They then started to recover as the companies stepped up efforts to persuade doctors to resume prescribing them as they had before. In an earnings call last week, Schering-Plough CEO Fred Hassan, voiced his support for the medicines, saying, “The doctors generally knew that this was one of those media-driven situations.” [This was not one of Hassan’s finer moments, IMO.]
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[DewDiligence]

Tough Times for Vytorin May Be Just Beginning

http://www.forbes.com/2008/03/20/schering-merck-vytorin-biz-healthcare-cx_mh_0321enhance.html

>>
Matthew Herper
03.21.08

Full results of a controversial artery-imaging study are due to be presented March 30 at the annual meeting of the American College of Cardiology (ACC), following an unusual 18-month delay in releasing the negative results of the study by drug makers Schering-Plough and Merck. The resulting controversy drew a congressional investigation and caused prescriptions for both drugs to slump 17%.

Shares of Schering and Merck plunged as investors fretted over the threat to a $5.2 billion cholesterol franchise. Zetia is a unique drug for lowering cholesterol; Vytorin combines it in one pill with the generic drug Zocor.

The problem: The delayed study couldn't prove that Vytorin prevents artery disease that leads to heart attacks and strokes any better than Zocor does, although it costs four times as much. A trial actually measuring whether the Vytorin combo prevents heart attacks better than Zocor won't be out until 2011. In the meantime, the lack of clear data could leave the companies in a long, slow battle to hold on to their sales.

They argue the controversy is "media-driven," and Wall Street analysts have expressed hopes that a scientific discussion of data will convince doctors, quiet doubters and stabilize sales of Zetia and Vytorin. But critics will be on hand, including Harlan Krumholz of Yale University, who will be among the top cardiologists discussing the data at the ACC meeting.

Cardiologists are torn about what to think of the imaging study, called ENHANCE. Prediman K. Shah, at Cedars Sinai Medical Center, says the results are "inconclusive." But he cautions, "It's not an unimportant study. It certainly raises questions, but doesn't answer them."

If it turns out that Zetia doesn't prevent heart attacks in the 2011 study, Merck and Schering are conducting, "we have some explaining to do," Shah says.

William Boden, a top cardiologist at the University of Buffalo, still uses Zetia in rare cases and expects the big trial due in 2011 may vindicate it. But he warns his patients, "We don't really know if putting you on this additional drug will do anything more than make your numbers look better." He says the companies have "gotten a long-overdue pass on marketing a drug where there was no outcomes data."

Zetia, approved in 2002, works completely differently from drugs like Lipitor, Zocor and Crestor. The other medicines, called statins, work in the liver to lower blood levels of LDL, the "bad cholesterol." They also seem to have other benefits. Zetia works by preventing the absorption of cholesterol in food. Adding it to the other pills gives them an added LDL-lowering wallop with few side effects.

But some prominent doctors have questioned whether they can be sure that Zetia confers the same benefit as statins. Now, the ENHANCE study has given doubters ammunition.

Mounting Evidence

The first real convincing trial came in 1984, a test of the cholesterol-lowering drug Questran. It took seven years to prove a benefit from lowering cholesterol 8%. Sales of cholesterol drugs remained pretty low. Lopid, a cholesterol drug from Warner-Lambert, generated only $200 million in 1988. Merck introduced the first statin, Mevacor, in mid-1987; it generated $260 million in its first full year on the market.

"People regarded cholesterol as a major risk factor," says Boden. "But we didn't have very good treatments to lower it."

It was giant studies of the statins that finally convinced many doctors that lowering cholesterol saved lives. Mevacor and other statins were developed from genetic insights gleaned from patients with familial hypercholesterolemia. In 1994 and 1995, studies of Merck's Zocor, a Mevacor replacement, and Bristol-Myers Squibb's new Pravachol showed a striking 30% reduction in the risk of death for patients with established heart disease.

In 1998, cholesterol drugs were reportedly a $5 billion market. By 2000, that had tripled, according to drug data company IMS Health, and by 2002 they were the best-selling drug class in the world. The top dog was Pfizer's Lipitor. It was approved in 1996, getting a fast review because of its unprecedented ability to lower cholesterol in patients with the FH disorder that causes cholesterol levels of 300 or more. Within two years, Pfizer already had presented data showing that Lipitor prevented heart attacks and strokes.

But big studies to prove a statin reduces heart attacks and deaths are expensive and can take half a decade. So drug companies also pursued the approach of using ultrasound to measure the thickness of the wall of the carotid artery in the neck. Mevacor, Pravachol and Novartis' Lescol all have such ultrasound data in their product labels. A 2005 analysis in Current Controlled Trials in Cardiovascular Medicine concluded these imaging studies predicted how well the drugs would prevent heart attacks, strokes and deaths.

"No Valid Evidence"

When Zetia was approved in October 2002, cardiologists were starting to think that the lower they could get cholesterol with statins, the better. The refrain in studies, in company press releases and at medical meetings was that lower cholesterol is better. Some cardiologists argued that LDL levels should be brought down to levels seen most often in rural China. But many doctors were statin-shy because patients didn't like the muscle achiness and liver tests required with Lipitor, Zocor, and Pravachol.

Zetia seemed to represent a solution. Added to a low dose of a statin, Zetia lowers LDL as much as the top dose, with fewer side effects. Vytorin, approved in 2004, provided such a combo in a single pill, allowing patients to get it for one insurance co-payment. Sales ramped up fast. Zetia had annual sales of $900 million in 2004; Vytorin hit the same mark in 2005.

But that year, Rodney Hayward, a clinical researcher at the University of Michigan's School of Public Health, wrote that cardiologists may have gone too far in assuming lower is actually better. Patients at high risk of heart attacks do better on high doses of statins, he wrote in a 2005 issue of Annals of Internal Medicine, but it hasn't been proved that how low their LDL goes predicts their risk of heart attacks or strokes.

He also warned, "There is no valid clinical evidence to suggest that using treatments other than statins to pursue proposed LDL cholesterol goals is safe or effective."

Pfizer conducted 12 big studies to prove Lipitor's benefit, and AstraZeneca started three imaging trials and three trials measuring hard outcomes like heart attack and stroke. Merck and Schering started only one imaging study and three outcomes trials. A second imaging trial, with Steven Nissen of the Cleveland Clinic, was planned but never begun.

The most important study, due in 2011, is a 12,500-person trial to show whether adding Zetia to Zocor predicts heart attacks, strokes and heart procedures. The study was announced two years after Zetia was approved and started one year after that.

The Problem With ENHANCE

ENHANCE, involving 720 patients, began immediately in June 2002 and was modeled on an imaging study that had worked for Pfizer, called ASAP, conducted by John Kastelein of the University of the Netherlands. The patients in ASAP had FH, the genetic cholesterol disease. LDL, the bad cholesterol, was cut 50% on Lipitor, compared with 41% on Zocor. But while artery thickness increased by 0.036 millimeters on Zocor, it actually decreased by 0.031 millimeters on Lipitor.

ENHANCE was supposed to repeat that success, this time comparing Zocor and Vytorin. But it didn't. After delaying the release of the results for more than 18 months, the companies finally revealed data showing no statistically significant benefit in using the more expensive Vytorin. One explanation is that the patients in ENHANCE had been better treated and had less atherosclerosis, making it harder to prevent plaque buildup. Another is that lowering cholesterol with Zetia in addition to Zocor didn't provide a benefit in terms of slowing atherosclerosis.

"The full data will hopefully put in full perspective that there weren't any harmful effects at all," says A. Michael Davidson, executive medical director at Radiant Research. "This was a population that was so well treated that there wasn't really any opportunity to see any difference."

He says that FH patients are no longer a good population to use in these studies. He points out that LDL lowering is a main driver of the benefit of these drugs.

The danger to Merck and Schering this week isn't simply that the full data from the study will cause doctors to decide Zetia doesn't work. More doctors may decide they don't have enough data and use other drugs instead while they wait for the big trial the companies are conducting. Zetia and Vytorin will remain blockbusters, almost certainly. But if a significant minority of doctors find the ENHANCE results unconvincing, the drug makers will face strong headwinds, and a fast-growing brand could not only stagnate but also shrink.

This is what was happening to Vioxx, because of safety concerns, before Merck yanked it. And it's what happened with the schizophrenia drug Zyprexa, from Eli Lilly, as prescriptions in the U.S. dropped because of concerns about weight gain and high blood sugar. And the companies spent a lot of their time defending these franchises when they needed to look for new opportunities for growth.

One person who won't be convinced by ENHANCE: Eric Topol, the noted chief of translational medicine at Scripps Health in La Jolla, Calif. He still wants to see clear data on how Zetia affects heart attacks, strokes and deaths, and doesn't understand why it took so long to embark on a big study to prove it.

Doctors have been "hanging in suspense for years, unnecessarily," Topol says. "It's still conceivable there would be improvement in outcomes. Until we have that data, the jury is out."
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[DewDiligence]

Whither Vytorin? Consider Canada

http://blogs.wsj.com/health/2008/03/31/whither-vytorin-consider-canada

>>
March 31, 2008, 4:47 pm
by Jacob Goldstein

With all the Vytorin buzz in the past day, one interesting take has flown under the radar. At the same time the New England Journal of Medicine published the study that’s caused all the fuss, the journal also published a comparison of the use of ezetimibe in Canada and the United States.

Ezetimibe is the active ingredient in Zetia, and it’s one of the two drugs in each tablet of Vytorin (a statin is the other).

The study compared the use of ezetimibe in Canada, where it’s available only as Zetia, and the United States, where it’s available in both Zetia and Vytorin, through 2006. The researchers found that in Canada, the drug accounted for only 3.4% of all prescriptions for lipid-lowering drugs, compared with 15.2% in the United States.

While the fact that Vytorin’s not available in Canada had something to do with that, it’s probably not the whole explanation. After all, Canadian doctors can essentially give patients Vytorin by prescribing both of the drug’s constituent parts, Zetia and simvastatin.

So why the big difference? The big marketing push for Vytorin in this country probably played a role; direct-to-consumer advertising for prescription drugs of the sort common here is prohibited in Canada.

Also, the authors point out, some big Canadian formularies have taken a pretty restrictive stance toward Zetia, limiting its use to patients who either can’t get to their cholesterol goal on a statin alone, or who can’t take statins. Those rules sound a lot like the recommendations that have been coming out lately in this country on the use of Zetia and Vytorin.
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[DewDiligence]

Cost Controls Help Merck Beat Forecast

[1Q08 saw the initial impact—but not the full impact—of the ENHANCE study on Zetia and Vytorin sales. Today, MRK lowered 2008 guidance for its 50% share of the income from the Zetia/Vytorin JV with SGP by a whopping $700M.]

http://www.reuters.com/article/marketsNews/idINN2141452620080421

>>
Mon Apr 21, 2008 12:40pm EDT
By Ransdell Pierson

NEW YORK, April 21 (Reuters) - Merck & Co (MRK) on Monday reported better-than-expected quarterly earnings as tight cost controls offset plunging sales of an osteoporosis drug now facing generic competition and slowing sales growth of its Vytorin and Zetia cholesterol fighters.

"Merck's revenue came up a little below expectations, but their cost control was good," said Edward Jones analyst Linda Bannister.

An unexpectedly low tax rate in the quarter also boosted Merck's results, and helped the company reaffirm its 2008 earnings forecast of modest growth, Bear Stearns analyst John Boris said.

The company said it earned $3.3 billion, or $1.52 per share, compared with $1.7 billion, or 78 cents per share, in the year-earlier period.

Excluding special items, Merck earned 89 cents per share. Analysts on average expected 86 cents per share, according to Reuters Estimates.

The items included $2.2 billion received from AstraZeneca as a result of a complex arrangement reached in February between the two partners, under which Merck will keep its rights to certain AstraZeneca medicines.

Merck said global sales rose 1 percent to $5.82 billion, but would have fallen 3 percent if not for the weak dollar, which raises the value of overseas sales when converted back to U.S. currency.

Combined sales of cholesterol drugs Vytorin and Zetia rose 6 percent in the quarter to $1.2 billion, their growth held back by the failure of Vytorin to cut artery plaque in a closely watched study whose results were announced in January.

Vytorin combines Merck's older Zocor treatment with a medicine called Zetia that prevents the intestines from absorbing cholesterol. The combination drug and Zetia are sold through a 50/50 joint venture of Merck and Schering-Plough Corp (SGP).

Merck said it now expects income from joint ventures and affiliates this year of $2.3 billion to $2.6 billion, or $700 million less than its earlier forecast, as publicity from the failed Vytorin study continues to dampen demand for it and Zetia.

Merck and Schering-Plough have come under fire for their handling of the Vytorin study, with critics alleging they improperly tried to change the main goal of the trial while it was under way, and delayed results of the failed study.

The companies recently received subpoenas from New Jersey's attorney general seeking documents related to the clinical trial and the sales and marketing of Vytorin, Merck said on Monday.

Global sales of asthma treatment Singulair jumped 10 percent to $1.1 billion.

Even so, Morningstar analyst Damien Conover expressed concern that Singulair garnered only 1 percent growth in the United States from previous double-digit gains, amid reports of a possible link between the drug and mood and behavioral changes, including suicidal behavior.

Januvia, a new diabetes pill, had quarterly sales of $272 million -- putting it on track to become a blockbuster product -- compared with $87 million in the year-ago period.

But sales of osteoporosis treatment Fosamax, plunged 37 percent to $470 million, as most formulations of the medicine began facing generic competition in the lucrative U.S. market.

Sales of company vaccines rose 9 percent to $986 million, reflecting a slowdown in earlier sizzling growth for Gardasil, Merck's product to prevent infection by forms of the virus that cause cervical cancer.

Merck said it continues to expect 2008 earnings, excluding items, of $3.28 to $3.38 per share. That reflects tepid growth of no more than 6 percent, as Fosamax generics take their toll.
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[DewDiligence]

Vytorin update (the other big pharma story today):

Worldwide 2Q08 Vytorin sales were down 14% year-
over-year, but things could get even worse as Vytorin
missed its primary endpoint in the SEAS study (see
below) and also showed a possible cancer link. MRK
and SGP shares were hammered again (during regular
trading and again in the AH session) and MRK has taken
the unusual step of revoking all earnings guidance.

http://online.wsj.com/article/SB121662823157969873.html

›Vytorin Hits Another Bump

By PETER LOFTUS and LAUREN POLLOCK
July 21, 2008 7:00 p.m.

In the latest setback for cholesterol drugs marketed by Merck & Co. and Schering-Plough Corp., a new study suggested Vytorin failed to show a benefit in people with a heart-valve problem.

It was the first study to show what effect the companies' jointly marketed cholesterol drugs had on clinical outcomes such as heart attacks. Previous studies have primarily measured the drugs' effects on cholesterol levels and artery thickness.

The outcome could put further pressure on sales of Vytorin and sister drug Zetia, which already have taken a hit this year because a previous study raised questions about their effectiveness.

The study, known as "SEAS," found no significant difference between treatment groups for cardiovascular events associated with aortic valve disease and heart disease, which was the primary endpoint of the study. In addition, there was no significant difference for the secondary endpoint of the prevalence [sic] of aortic valve disease events. The drug combination did produce a statistically significant 22% reduction in atherosclerotic events alone.

The study also found the drug combination appeared to reduce the risk of coronary artery disease events in patients with mild to moderate aortic stenosis, but not the rate of progression of aortic valve disease. The use of the drug combination in patients was generally well tolerated and safe.

The researchers found a higher rate of cancer cases in people taking the combination of simvastatin and Zetia, versus the placebo group, but that the difference could have been due to chance. Researchers also said an analysis of other, ongoing trials of Vytorin or Zetia do not suggest an inreased [sic] risk of cancer.

Merck shares were off 6.2% at $35.33 in 4 p.m. composite trading on the New York Stock Exchange, while Schering-Plough dropped nearly 12% to $18.95.

After the market close, both Schering-Plough and Merck reported second-quarter results.

Schering-Plough's profit dropped 19%, hurt in part by results from its cholesterol-drug joint venture with Merck. Net income for the quarter was $436 million, or 24 cents a share, compared with $539 million, or 34 cents a share, a year earlier.

Excluding $1 billion in accounting charges related to the company's purchase of Organon BioSciences and other items, per-share earnings rose to 45 cents from 41 cents. Net sales rose 55% to $4.92 billion, including sales from Organon, which Schering-Plough purchased in November.

In the company's statement, Schering-Plough Chief Executive Fred Hassan said the company remains "confident in Vytorin" as a treatment for high cholesterol levels.

Merck reported net income of $1.77 billion, or 82 cents a share, up from $1.68 billion, or 77 cents a share, a year earlier. Revenue fell a 1% to $6.1 billion. Combined world-wide sales of Zetia and Vytorin, as reported by the joint venture, were $1.2 billion, down 9% from a year earlier. [Standalone Zetia sales were down 3%, and Vytorin sales were down 14%.]

Addressing the study results, Merck Chief Executive Richard Clark said: "We are moving quickly to fully assess the potential implications of the data for our cholesterol joint venture." The company said that in the meantime it is suspending its 2008 financial outlook.

U.S. Prescriptions for Vytorin Sag

Vytorin is a combination of the drugs Zetia and simvastatin, which use different mechanisms to reduce levels of bad cholesterol. Both Vytorin and stand-alone Zetia are marketed by a joint venture of Merck and Schering-Plough; they had combined sales of more than $5 billion in 2007. Simvastatin, which belongs to an older class of cholesterol drugs known as statins, is marketed under the brand Zocor by Merck but since its 2006 patent expiration has been available as a cheap generic pill from several manufacturers.

U.S. prescription volumes for both Vytorin and Zetia have declined since January when Merck and Schering-Plough released results of the "Enhance" study, which showed Vytorin was no better than simvastatin alone at slowing clogging of the arteries, despite producing a greater drop in levels of bad cholesterol. Generic simvastatin sales have surged.

Several prominent U.S. cardiologists have called for curtailed use of Vytorin and Zetia in the wake of the Enhance study, citing the lack of definitive proof that the drugs' effect on cholesterol translates into reduced risk of heart attacks and stroke, versus simvastatin alone.

Merck and Schering-Plough have countered that Vytorin and Zetia are effective for the primary use approved by U.S. regulators -- to lower levels of bad cholesterol. They note that the concept of lowering bad cholesterol is generally accepted as a way to reduce risk of heart attacks and related disease.

The Enhance study also sparked probes by members of Congress and federal and state investigators partly because the companies waited nearly two years to release the results after the study's completion in 2006. The companies have said it took awhile to analyze the results due to data-quality problems.

The SEAS study tested Zetia and simvastatin in about 1,870 Europeans with a heart-valve problem called aortic stenosis. The condition, which involves narrowing of the heart's aortic valve, affects about 3% of people older than age 75. The study measured whether the combination of Zetia and simvastatin -- the equivalent of Vytorin -- reduced the need for aortic-valve replacement and cut the risk for heart attacks and related disease, versus a fake pill, or placebo.

History wasn't on the side of Vytorin and Zetia in this patient population. A previous study, published in The New England Journal of Medicine in 2005, showed that Pfizer Inc.'s Lipitor statin drug didn't halt the progression of aortic stenosis or induce its regression.

A larger study, "Improve-It," is under way to test whether Vytorin reduces the risk for heart attack and related disease in a broader patient population, but results aren't expected until about 2012.

Merck and Schering-Plough had been scheduled to report second-quarter results Monday morning, but they postponed the announcement until after the market close because of the impending announcement of the SEAS study results.‹

[DewDiligence]

Ouch—Zetia and Vytorin are continuing to lose share.
(Figures from SGP’s SEC filing in thousand of US Rx’s.)

 
                                       Zetia+Vytorin 
        Zetia  Vytorin  Zetia+Vytorin  Market Share 
 Nov08   893    1,086      1,979          10.3% 
 Oct09   978    1,207      2,186          10.6% 
 Sep08   969    1,202      2,171          10.9% 
 Aug08   984    1,249      2,233          11.2% 
 Jul08 1,038    1,339      2,376          11.7% 
 Jun08 1,022    1,330      2,351          12.2% 
 May08 1,067    1,412      2,479          12.5% 
 Apr08 1,079    1,428      2,507          12.8% 
 Mar08 1,201    1,619      2,820          14.3% 
 Feb08 1,183    1,607      2,790          14.7% 
 Jan08 1,375    1,851      3,226          15.7%

http://sec.gov/Archives/edgar/data/310158/000095012308017796/y73451exv99w1.htm

[DewDiligence]

FDA says: “Keep taking Zetia and Vytorin despite the doubts—at least for the time being.”

http://finance.yahoo.com/news/FDA-backs-Vytorin-after-apf-14009173.html

[DewDiligence]

1Q09 Vytorin/Zetia sales fell 30% year-over-year in the US, although sales are still growing in other countries. Isn’t it odd that docs in other countries don’t seem to care about the ENHANCE study? Comments?

[DewDiligence]

(MRK) This analyst is not exactly going out on a limb:

http://finance.yahoo.com/news/Analyst-Mercks-Vytorin-sales-apf-3357123240.html?x=0&.v=4

Sales of Merck & Co.'s blockbuster cholesterol drug Vytorin likely will continue to fall amid rising competition from rival brands and generic versions in the same class of pills, [Bernstein] analyst [Tim Anderson] predicted Friday.

LOL

[DewDiligence]

MRK, Glenmark settle Zetia patent case:

http://www.merck.com/newsroom/news-release-archive/product/2010_0510.html

Under the settlement, Glenmark gets to launch a generic Zetia in Dec 2016, only four months before the expiration of the challenged patent in Apr 2017. Glenmark evidently did not like its chances in a patent trial.

A side question: Will anyone still be using Zetia in 2017?

[DewDiligence]

Vytorin/Zetia finally catches a break, but will it matter?
This study compared Vytorin to placebo, so it isn’t
known if the Zetia portion of Vytorin made any difference.

http://finance.yahoo.com/news/VYTORIN-ezetimibesimvastatin-bw-283295457.html?x=0&.v=1

›VYTORIN Significantly Reduced Major Vascular Events in Patients With Chronic Kidney Disease in a New 9,000-Patient Investigational Study

Saturday November 20, 2010, 12:51 pm EST

DENVER, Colo.--(BUSINESS WIRE)-- In a new investigational study of VYTORIN® (ezetimibe/simvastatin), the cholesterol-lowering medicine from Merck (known as MSD outside the US and Canada), VYTORIN 10/20 mg reduced the incidence of first major vascular events -- defined as non-fatal heart attacks or cardiac death, stroke or any revascularization procedure -- by a highly statistically significant 16.1 percent compared to placebo (p=0.0010). This was the pre-specified primary endpoint of the study. The SHARP (Study of Heart and Renal Protection) study involved more than 9,000 patients who, on average, had advanced or end-stage chronic kidney disease (CKD), and is the first prospective clinical study in patients with CKD to demonstrate the benefit of lowering LDL (bad) cholesterol on major vascular events. The results were presented today during Renal Week, the American Society of Nephrology's annual meeting, by Professor Colin Baigent, F.F.P.H., F.R.C.P., and Dr. Martin Landray, Ph.D., F.R.C.P., the principal investigators of SHARP, from the Oxford University Clinical Trial Service Unit (CTSU), Oxford, England.

"This is an important study," said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. "Patients with CKD have a high risk of ischemic vascular disease and increased rates of heart attack, stroke, other cardiovascular events and revascularization procedures. In SHARP, the investigational use of VYTORIN significantly reduced the risk of these events in a spectrum of patients with chronic kidney disease -- and this was the first demonstration that an LDL-cholesterol lowering medicine could do so."

Merck plans to seek regulatory approvals for the use of VYTORIN in patients with CKD based on the results from the SHARP study. VYTORIN is currently indicated as adjunctive therapy to diet for the reduction of LDL cholesterol in patients with primary hypercholesterolemia or mixed hyperlipidemia.

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.

SHARP is the largest prospective study of LDL-lowering in patients with CKD

SHARP is the largest clinical trial of VYTORIN conducted to date, and enrolled a total of 9,438 patients under the care of a nephrologist for chronic kidney disease. One-third of patients were undergoing dialysis therapy for end-stage kidney disease at the time of entry, and the remaining patients were pre-dialysis patients with advanced CKD with an average estimated glomerular filtration rate (a measure of kidney function) of 26.5 ml/min/1.73m2. Patients with a prior history of myocardial infarction or a revascularization procedure were excluded from the study. At randomization, the average LDL cholesterol of all patients enrolled in SHARP was 108 mg/dL.

Patients were initially randomized in a ratio of 4:4:1 to receive VYTORIN 10/20 mg daily versus placebo versus simvastatin 20 mg alone (for purposes of assessing drug safety). After one year, patients initially allocated to simvastatin alone were re-randomized to either VYTORIN 10/20 mg daily or placebo for the remainder of the study period. Patients were followed for a median of 4.9 years.

The protocol-specified primary endpoint for the study was the incidence of first major vascular events, defined as the composite of non-fatal heart attack or cardiac death, stroke or revascularization procedure in the two groups randomized to VYTORIN or placebo at study initiation. (This analysis did not include patients initially randomized to simvastatin alone for the first year.) In the intention-to-treat analysis, VYTORIN reduced first major vascular events by 16.1 percent compared to placebo (p=0.0010). In the group that received VYTORIN (n=4,193) 15.2 percent of patients had a major vascular event, compared to 17.9 percent of patients taking placebo (n=4,191).

In addition, in the full study population of patients, including patients who took simvastatin alone for the first year and were then re-randomized to either VYTORIN or placebo, VYTORIN reduced first major vascular events by 15.3 percent compared to placebo (p=0.0012). The rate of major vascular events in patients taking VYTORIN (n=4,650) was 15.1 percent, compared to 17.6 percent of patients taking placebo (n=4,620).

Results on Major Atherosclerotic Events Also Presented

Based on information from clinical studies of other LDL-lowering medicines that became available after the original SHARP study protocol was implemented in 2003 and before the study ended, the independent SHARP Steering Committee determined that the most relevant "key outcome" for the study should be the incidence of first "major atherosclerotic events." Major atherosclerotic events were defined as the combination of non-fatal heart attack, coronary death, ischemic stroke or any revascularization procedure; this analysis excluded non-coronary cardiac death and hemorrhagic stroke from the protocol-specified primary endpoint of major vascular events. (The Steering Committee's rationale and statistical analysis plan are discussed in a paper published on-line in the American Heart Journal). In the intention-to-treat analysis, VYTORIN also reduced first major atherosclerotic events by 16.5 percent compared to placebo (p=0.0022). The rate of first major atherosclerotic events in patients taking VYTORIN (n=4,650) was 11.3 percent, compared to 13.4 percent in patients taking placebo (n=4,620).

In the first year of the trial, VYTORIN 10/20 mg lowered LDL cholesterol by 40 percent compared to placebo, while simvastatin 20 mg lowered LDL cholesterol by 28 percent versus placebo; the reduction achieved by VYTORIN was 30 percent greater than that achieved by simvastatin alone. After two and half years of treatment, which was approximately mid-way through the study, VYTORIN lowered LDL cholesterol by 32 mg/dL, or 30 percent from baseline, compared to placebo.

The researchers noted that the reduction in major vascular events and major atherosclerotic events based on the LDL-cholesterol reduction achieved with VYTORIN in SHARP was consistent with reduction of outcomes that would be predicted based on the recently published Cholesterol Treatment Trialists’ (CTT) meta-analysis of large-scale statin trials. The CTT analysis, published online in The Lancet, examined the relationship between LDL-cholesterol lowering and reduced rates of cardiovascular events.

One of the secondary endpoints for SHARP was the progression to end-stage renal disease (ESRD) among patients who were not yet on dialysis at the start of the study. A patient was considered to have progressed to ESRD if they started long-term dialysis or proceeded to kidney transplantation following randomization. On this endpoint, there was no difference between VYTORIN and placebo; 33.9 percent of patients receiving VYTORIN (n=3,117) proceeded to ESRD, compared to 34.6 percent of patients on placebo (n=3,130).

VYTORIN 10/20 mg Safety Profile Over the Nearly Five Years of Follow-up

In terms of assessing safety in SHARP, the researchers assessed reports of serious adverse events as well as adverse events that were pre-specified: cancer, myopathy with levels of creatine phosphokinase (CK) >10 x but =40 x upper limit of normal (ULN), and reports of myopathy with CK >40 x ULN, hepatitis, persistently elevated liver enzymes (ALT/AST >3 x ULN), complications of gallstones, other hospitalizations for gallstones, and pancreatitis without gallstones.

Overall, the safety profile of VYTORIN 10/20 mg in this study was consistent with the profile described in the current approved label.

VYTORIN (n=4,650) was comparable to placebo (n=4,620) in the incidence of cancer and cancer-related deaths: cancer was reported in 9.4 percent of patients taking VYTORIN versus 9.5 percent of patients taking placebo (p=0.89); mortality due to cancer was reported in 3.2 percent of patients taking VYTORIN versus 2.8 percent of patients taking placebo (p=0.20).

For other safety analyses that were pre-specified, VYTORIN was also comparable to placebo in the incidence of CK > 10 x but = 40 x ULN (0.4 percent for VYTORIN versus 0.3 percent for placebo), CK >40 x ULN (0.1 percent in each group), hepatitis (0.5 percent for VYTORIN versus 0.4 percent for placebo), persistently elevated ALT/AST>3 x ULN (0.6 percent in each group), complications of gallstones (1.8 percent for VYTORIN versus 1.6 percent for placebo), other hospitalizations for gallstones (0.5 percent for VYTORIN versus 0.6 percent for placebo) and pancreatitis without gallstones (0.3 percent for VYTORIN versus 0.4 percent for placebo).

"Merck is proud to support clinical trials such as SHARP and we thank the Oxford University and the thousands of patients and health care professionals who participated in SHARP for their contributions to this study to address this important medical question for patients with CKD," Kim said.‹

[DewDiligence]

MRK’s Januvia/Janumet franchise is now selling at a $4.2B annualized rate:

http://finance.yahoo.com/news/Merck-Announces-First-Quarter-bw-3035206367.html?x=0&.v=1

The Januvia franchise has filled the hole from declining sales of Vytorin/Zetia in the past few years.

Who said old-fashioned blockbusters are dead?