Merck Uses Legal Threats To Stifle Negative Advice About Zetia And Vytorin In Italy Reply

In response to repeated legal threats, a public health doctor in Italy has withdrawn advice to curtail use of a controversial drug. The drug, ezetimibe, is a key ingredient in Zetia and Vytorin, which is manufactured by Merck. The cholesterol-lowering drug has been the subject of fierce controversy because it has never been shown to improve clinical outcomes. Despite the controversy, in 2013 the drugs had combined sales of more than $2.6 billion.

MSD Italy, the Italian arm of the company, sent two “cease and desist” letters to Alberto Donzelli, who is “the head of education, appropriateness, and evidence based medicine at the public health authority of Milan (Milan Healthcare),” according to The  BMJwhich published a news report of the affair.

Click here to read the full post on Forbes.

 

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FDA Approves Novel Merck Drug To Prevent Heart Attacks And Strokes Reply

The FDA today approved vorapaxar (Zontivity), Merck’s once-troubled platelet receptor antagonist, to reduce the risk of myocardial infarction (heart attack), stroke, cardiovascular death, and revascularization procedures. The drug is approved for use in people with a history of MI or peripheral arterial disease. The approval represents an amazing turnaround for a drug that had experienced nearly as many ups and downs as an amusement park roller coaster.

Click here to read the full post on Forbes.

 

FDA Advisory Panel Votes In Favor Of Approval For Merck’s Vorapaxar Reply

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 10-1 in favor of approval for vorapaxar, Merck’s novel thrombin receptor antagonist. The “roller coaster ride” cliché might have been invented for this drug, which was the subject of tremendous early hopes followed by major disappointments and, finally, a subsequent revival.

Click here to read the entire post on Forbes.

 

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(Photo credit: Wikipedia) 

 

 

 

Packaging Defect Leads Merck To Recall All Lots of Liptruzet In US Reply

Merck said today that it was recalling all lots of Liptruzet, its combination of the cholesterol-lowering drugs ezetimibe and atorvastatin, in the US. The company said the recall was due to a packaging defect which could potentially allow air and moisture to affect the quality of the drug, though the company said “the likelihood of the packaging defects decreasing the effectiveness of Liptruzet on a patient’s lipid profile or negatively impacting the safety of the product is remote.” To date there have been no adverse events or product complaints reported to the company.

Merck is recalling the drug from US wholesalers but is not asking patients or pharmacies to return their stock. The company said that patients may continue taking the pills already in their possession.

Today action will deplete the current supply of the drug in the US, the company said. The company said it will resupply the drug “as soon as possible.”

 

Merck’s Vorapaxar Gets Positive FDA Review Reply

A few years ago a novel antiplatelet agent from Merck seemed all but dead. Vorapaxar, a thrombin receptor antagonist, was widely thought to have no future after unacceptably high serious bleeding rates were found in two large clinical trials studying the drug in a wide variety of acute and chronic cardiovascular patients. But hopes for the drug resurfaced with a new analysis of one of those trials, the TRA2P trial. Now the FDA appears willing to give the drug a renewed lease on life.

Click here to read the full story on Forbes.

 

Possible New Lease On Life For Two Cardiology Drugs From Merck And J&J Reply

Early next year an FDA panel will review a new drug from Merck and a new indication for Xarelto (rivaroxaban), Johnson & Johnson’s highly successful new oral anticoagulant. Both drugs have had a rocky road getting to this stage and their success is by no means assured, but the announcement of the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee suggests that the companies have made progress resolving earlier problems.

Merck’s new drug application for vorapaxar (Zontivity is the proposed trade name) will be discussed on January 15 for the proposed indication of reduction of atherothrombotic events in patients with a history of myocardial infarction (MI).

On January 16 the panel will discuss the supplemental new drug application for J&J’s Xarelto (rivaroxaban) to reduce the risk of thrombotic cardiovascular events in patients in the first 90 days after suffering acute coronary syndrome.

Click here to read the full story on Forbes.

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Why Is Actelion Suppressing Phase III Data? 2

I highly recommend a terrific article by Ian Parker in this week’s New Yorker about Merck’s efforts to develop a novel insomnia drug, suvorexant. Normally I don’t write about non-cardiology topics but I want here to call attention to one small, almost tangential detail buried in the middle of the story. It’s not about the Merck drug but about another orexin antagonist from Actelion, almorexant:

“At the time, Jed Black, the Stanford sleep specialist, was on a two-year leave of absence, working full time on almorexant, the rival drug made by Actelion. Phase III trials of the drug were under way. This work has not been published, and Black cannot discuss it, although he recently described almorexant as having ‘an absolutely remarkable profile’ that was likely to outperform zolpidem in sleep maintenance.

But, in early 2011, Actelion announced that it was halting the drug’s development, because of an undisclosed possible safety issue. Merck’s scientists speculated about the nature of the concerns, and feared for the future of suvorexant. Black said that the problem was ‘straightforward,’ but that Actelion had decided to pause and take its time. ‘I don’t think almorexant needs re-tinkering at the molecular level,’ he said, implying a problem of drug delivery. Black, who is back at Stanford, suspects that almorexant will be launched, and is certain that such drugs will eventually become dominant. (GlaxoSmithKline recently published results, from Phase II studies, of its own orexin antagonist.)”

The time frame is not entirely clear, but it appears that Actelion has been actively suppressing phase III data about almorexant for several years at least.

Click here to read the full post on Forbes.

 

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FDA Approves Combination Of Ezetimibe And Atorvastatin Reply

The FDA has approved a new combination drug from Merck for lowering cholesterol. The drug, which will carry the brand name of Liptruzet, is a combination of two previously approved cholesterol-lowering drugs, ezetimibe and atorvastatin.

Merck said the new drug (pronounced “LIP-true-zett”) would be commercially available starting next week. Liptruzet will be available as a once-daily tablet combining 10 mg of ezetimibe with either 10, 20, 40, or 80 mg of atorvastatin. In clinical trials Liptruzet lowered LDL cholesterol from 53% to 61%, depending on dosage.

Click here to read the full post on Forbes.

 

HPS2-THRIVE Coming Attraction: First Look At What Went Wrong With Niacin Reply

In a few weeks, on March 9, the main results of the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study will be presented in San Francisco at the annual meeting of the American College of Cardiology. These results have been eagerly awaited since Merck’s brief announcement in December that the trial had not met its primary endpoint and that it would no longer pursue approval of Tredaptive, the combination of extended-release niacin and laropiprant, in the US. The trial was designed to assess whether adding the niacin/laropiprant combination to standard statin therapy in high risk individuals would further reduce vascular events.

Now, serving almost as a coming attraction for the main event at the ACC, an important substudy from HPS2-THRIVE has been published in the European Heart JournalThe paper discusses the trial design, the pre-specified muscle and liver outcomes, and the reasons for stopping treatment during the trial.

Click here to read the full story in Forbes.

European Heart Journal

The Big Gamble of CETP Inhibitors 2

Merck has invested a substantial amount of money on the CETP inhibitor anacetrapib. Chemist and veteran pharma blogger Derek Lowe suspects that the company might as well have plunked the money down in a casino.

In a provocative new post, Lowe wonders if big pharma, in its desperation, has abandoned rational research in favor of, essentially, gambling. He notes that CETP is “a drug target that has incinerated a lot of money over the years” and wonders whether any of the compounds will “ever make it as a drug?” The failure of past CETP inhibitors, torcetrapib (Pfizer) and dalceptrapib (Roche), along with the recent failure of Tredaptive (Merck), “illustrate how little we know about this area [HDL].”

Read the rest of the post on Forbes.

 

Merck Starts To Suspend Worldwide Availability Of Tredaptive Reply

In the wake of the negative HPS2-THRIVE study announced last month, Merck said today that it was beginning to suspend the worldwide availability of Tredaptive, its combination of extended-release niacin and laropiprant.

Click here to read the full story on Forbes.

Merck’s Combination Of Ezetimibe And Atorvastatin Back On NDA Path 1

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A combination tablet containing the cholesterol-lowering drugs ezetimibe and atorvastatin is back on the path to possible FDA approval, according to Merck, which already markets Zetia (ezetimibe) and Vytorin, the combination of ezetimibe and simvastatin. Merck has repeatedly stumbled in its efforts to gain FDA approval of the proposed new drug, which has been dubbed “Son of Vytorin.” The new drug application (NDA) submission was first rejected by the FDA in 2009 and, again, last year.

Merck said yesterday that the FDA had accepted Merck’s resubmission of its NDA, which included additional data provided by Merck in response to the FDA’s rejection of the application last year. Merck said it also planned to pursue approval of the drug in other countries.

Despite its potent cholesterol-lowering effects, the clinical benefits of ezetimibe have never been demonstrated, prompting furious debates about the proper role of surrogate endpoints. Last year the FDA rejected a new indication for Vytorin and  Zetia (ezetimibe alone) in chronic kidney disease patients, as the independent effect of ezetimibe had not been assessed in SHARP, the pivotal study for the indication. Results of the IMPROVE-IT trial, expected this year, may finally resolve the question of whether ezetimibe is beneficial.
Click here to read the Merck press release…

HPS2-THRIVE: No Benefit, Signal Of Harm For Niacin Therapy 3

The largest-ever study of niacin has failed to show a clinical benefit for niacin and even found a strong signal of harm. Merck announced today that the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study did not meet its primary endpoint. In that study, the combination of a statin and Merck’s niacin compound, Tredaptive, a combination of extended-release niacin and laropiprant, an anti-flushing agent, was compared to statin therapy alone in 25,673 patients at high risk for cardiovascular events.

After a median followup of 3.9 years, the combination of niacin and laropiprant “did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy,” according to Merck. Even more troubling, the company reported that there was “a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.”

Ball-and-stick model of the niacin molecule, a...

Merck said it was now no longer planning to seek approval of Tredaptive in the United States. The drug’s initial application for approval in the US was rejected in 2008. HPS2-THRIVE was designed to answer criticism from the FDA and other experts about the lack of any evidence demonstrating clinical benefit.

Tredaptive (also known as Cordaptive in some places) is approved in some countries outside the US. Merck said it is “recommending that providers not start new patients” on the drug. It is unclear whether the drug will remain on the market in these places.

Although niacin, a natural vitamin, has been used for decades to raise HDL, a clinical benefit has never been demonstrated. In 2011 the NIH’s  AIM-HIGH trial found no benefit for extended-release niacin. Critics said the trial was underpowered and otherwise flawed. HPS2-THRIVE, most agreed, would provide a more definitive test of the effect of niacin.

HPS2-THRIVE adds to the string of failures associated with trials of HDL-related therapies, although some hope remains for CETP inhibitors, despite the failure of two large clinical trials. It appears likely that the results of HPS2-THRIVE will also impact the use of existing niacin products. Bernstein analyst Timothy Anderson said it may “cause some collateral damage to AbbVie’s Niaspan.”

Responding to the breaking news, Steve Nissen said he had three initial thoughts about the trial:

What were the “non-fatal serious adverse events” that showed a statistically significant increase?

Did the study fail because of niacin or laropiprant?

We will need to decide whether to withdraw patients from niacin.

Update: Here’s a terrific comment posted below from cardiologist John Osborne:

Also don’t forget that this trial did not have a cut-off for HDL, so that patients could have any level of HDL and still get into this trial, not just patients with low HDL where presumptively the greatest benefit would be seen, according to the HDL-raising hypothesis. We will need to see how this sub-group responded, which was a pre-specified sub-group analysis. As far as the vague “excess of non-fatal serious adverse events”, it is no surprise given the known issues with the use of niacin, such as flushing (even occasionally to the point of causing vasodilation resulting in rare syncope), hyperuricemia, gout and gout flares, peptic ulcer disease, and hyperglycemia. If these non-fatal adverse events were higher int the niacin-laropriprant arm, I would not be at all surprised. If, however, we saw an excess of non-fatal strokes, as a tendency was seen in AIM-HIGH, that would be much more concerning. Obviously science and medical care cannot and should not be based on lay press reports and we need to see and digest all the data from this trial when it comes out. Stay by your radios (and Internet feeds), my friends!

Update #2: James Stein sent the following comment:

HPS did not THRIVE!  I am disappointed.  It suggests that in people on a statin with well controlled LDL and non-HDL cholesterol levels, adding niacin may not reduce CVD risk.  I still think niacin is a useful drug for those who can’t reach goals on statins or who can’t take them, and for selected patients with combined dyslipidemia.  However, this may be as much about laropiprant as it is about niacin. I am especially concerned about the increase in non-fatal serious adverse events in the group that received extended-release niacin/laropiprant. You may recall that the idea for using laropiprant was to improve the tolerability of niacin by blocking flushing. However a close look at the laropiprant data for its effectiveness as a flushing blocker showed that at the dose it was being used at, it was not significantly better than adult dose aspirin.

More worrisome, pre-clinical Merck research showed an off-target effect of laropiprant on platelet DP1 receptors. Bleeding times were not prolonged, so the meaning of this off-target effect is unclear, but this is evidence that the drug may affect more than just the DP1 receptor on dermal blood vessels.   We know DP1 receptors also are on neurons and lung tissue, among other places.  We in the lipid world need to be very humble about off target effects – even if we can’t explain them with our current knowledge base.

Click here to read the Merck press release…

Bleeding Problems Continue To Bedevil Merck’s Novel Antiplatelet Agent Vorapaxar 1

In the large TRA-2P  study of more than 26,000 patients with  MI, ischemic stroke, or documented peripheral vascular disease, the novel antiplatelet agent vorapaxar significantly reduced the primary endpoint of CV death, MI, stroke or urgent coronary revascularization. But vorapaxar treatment resulted in a significant increase in bleeding, including intracranial hemorrhage.

The fate of vorapaxar now appears to be uncertain, as the company said it will review data from the drug’s two large clinical trials with the investigators of the trials and external experts to inform the company’s next steps.

The full results of the TRA-2P  (Thrombin Receptor Antagonist in Secondary Prevention of atherothrombotic ischemic events) trial are scheduled to be presented in March at the American College of Cardiology. Merck today released the top-line results in a press release.

TRACER, the large ACS trial with vorapaxar, was terminated early last year due to similar safety concerns. As reported here last year, at the same time TRACER was stopped the TRA-2P trial was modified. TRA-2P investigator Eugene Braunwald said that vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial because of an increase in intracranial hemorrhage in these patients.

On his blog on Forbes Matt Herper provides some additional perspective on this story.
Click here to read the press release from Merck…