New Drug Of The Year: LCZ696 from Novartis
Old Drug of the Year: Ezetimibe
Not-So-Funny Drug of the Year: Ivabradine
After all the waiting and all the controversy it turned out to be pretty simple. The IMPROVE-IT trial did what it set out to do and reached its primary endpoint. The benefit wasn’t very big or impressive but it will be enough to put to rest concerns that ezetimibe might have been an expensive placebo or that LDL might not be a reliable surrogate endpoint. The IMPROVE-IT results will also provide comfort to companies developing the next generation of cholesterol drugs, since their approval may have depended on validation of LDL as a surrogate endpoint.
The Improved Reduction of Outcomes: Vytorin Efficacy International Trial, presented Monday morning at the American Heart Association meeting in Chicago, randomized 18,144 high-risk patients within 10 days of an acute coronary event to either ezetimibe or placebo on top of a statin….
The presentation of the eagerly awaited IMPROVE-IT trial, scheduled for Monday at the American Heart Association meeting, won’t be accompanied by a simultaneous publication in the New England Journal of Medicine. Although no one except for a small group of insiders knows for sure, this news may have important implications.
In a series of studies analyzing blood samples from nearly 100,000 people, Sekar Kathiresan and colleagues identified 15 rare mutations that block the activity of a single gene — called Niemann-Pick C1-Like 1 (NPC1L1). The mean LDL level was 12 mg/dL lower in mutation carriers than noncarriers. There were just 11 carriers of the mutations among 29,954 people with CHD versus 71 carriers among 83,140 people without known CHD (carrier frequency: 0.04% vs. 0.09%). This worked out to a 53% reduction in CHD risk for mutation carriers.
The IMPROVE-IT trial will be big news when its results are finally presented on November 17 during the annual meeting of the American Heart Association. The results of the trial–underway for nearly a decade– have been long and eagerly awaited by everyone interested in cardiovascular medicine. The trial could impact the future sales of a key Merck drug, ezetimibe, though because it is nearing the end of its patent life the commercial significance is somewhat limited. However, IMPROVE-IT will also have very important implications beyond its specific effect on one drug franchise and could influence the fate of several new drugs now being investigated and may even alter the entire drug development and evaluation process.
Here’s some background information and links to useful resources.
Results of the eagerly-awaited and highly controversial IMPROVE-IT trial are finally going to be revealed. The American Heart Association has announced that the trial will be presented by Chris Cannon on November 17 at 11:51 AM (central time) in Chicago at the group’s annual scientific sessions . IMPROVE-IT compared the effect on cardiovascular outcomes of the statin simvastatin with Vytorin (the combination of simvastatin and ezetimibe, manufactured by Merck) in more than 18,000 patients with acute coronary syndromes.
Both Vytorin and IMPROVE-IT have been the subject of considerable controversy.
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 BMJ, which published a news report of the affair.
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.”
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.
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…
The FDA has finally completed its review of ENHANCE that it started in January 2008. It’s finding: there was no difference in clinical outcome between the vytorin-treated and the simvastatin-treated patients in clinical outcomes, though vytorin, as expected, had greater efficacy in lowering cholesterol. The FDA advises patients that, pending the results of IMPROVE-IT, “patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about these medications.”
None of this should come as a surprise to anyone reading this blog, I suppose.
Click here to read the FDA statement.