Merck's IMPROVE-IT trial hits big, supports wider Zetia use
The results decreased the likelihood that the FDA would require outcomes data for PCSK9 inhibitors.
The results from the so-called IMPROVE-IT trial are expected to shore up Zetia/Vytorin sales, analysts said, after the first trial showing that a non-statin added to a statin reduces cardiovascular events. Doctors will now be more likely to prescribe Zetia (ezetimibe) and combo drug Vytorin, which pairs Zetia with the statin Zocor, as an alternative to statins such as in patients who cannot tolerate statins.
By how much, is the question analysts are asking. While Zetia was Merck's top-selling drug in 2013, generating US sales of $1.7 billion, a 19% increase over 2012, Vytorin sales fell 9% year-on-year to $865 million, according to IMS Health, and have decreased 48% since 2008, the year Merck released data from the ENHANCE finding no advantage for Vytorin over simvastatin in slowing the progress of atherosclerosis.
Not only are the latest results a positive for Vytorin in the near term; they lay the ground work for the success of an emerging class of lipid-lowering drugs, the PCSK9 inhibitors. In a Phase-III study, also announced at the American Heart Association 2014 Scientific Sessions in November, Sanofi and Rengeneron's PCSK9 alirocumab handily beat Zetia in a head-to-head comparison, reducing LDL cholesterol by 45% compared to 14% for subjects taking Zetia.
With the evidence that Vytorin reduces the chance for heart attack and stroke, FDA could be more inclined to accept LDL lowering as a surrogate end point in evaluating the PCSK9s, even without outcomes data of their own.
The 10-years-in-the-running, 18,144-patient IMPROVE-IT study of high-risk patients with acute coronary syndromes met its primary endpoint and all secondary composite efficacy endpoints.
Approved in 2002, Vytorin was widely expected to miss its goal as there have been no trials demonstrating the clinical benefit beyond lowering LDL. The trial showed patients taking Vytorin experienced significantly fewer major cardiovascular events than patients treated with simvastatin alone. Major cardiovascular events were measured by a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, re-hospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization.
Patients taking Vytorin experienced a 6.4% reduced relative risk for cardiovascular events, and LDL cholesterol levels 22% below those given simvastatin and placebo. In the study at seven years, 32% of patients taking Vytorin experienced a primary endpoint event, compared to 34% of patients taking simvastatin alone, Merck said.
Merck now plans to submit the data from IMPROVE-IT to the FDA in mid-2015 to support a new indication for reduction of major cardiovascular events for Vytorin and Zetia.
Tagging the results a “vindication” for Vytorin, Leerink analyst Seamus Fernandez wrote in an investor note that a cardiovascular benefit of above 6% “could support Zetia as the primary add-on therapy choice to statins—possibly adding it to CV treatment guidelines depending on subset analyses and Zetia's overall safety profile in the study.”
“Despite the legion of challenges weighing against IMPROVE-IT, the study succeeded in hitting its primary endpoint. This may be a reflection of the considerable power of the study, which we estimated could hit its primary endpoint with a relative risk reduction as low as 5% with sustained LDL reductions of 8-10 mg/dL,” Leerlink's Fernandez wrote.
Yet Sanford Bernstein analyst Tim Anderson wrote in a note of his own, “a relative risk reduction on the primary endpoint in the single digits would probably be viewed as underwhelming in terms of really making a major impact on patients lives.” The primary benefit of positive trial results comes from the removal of a “psychological overhang” on Merck's stock, he said.
The results will likely be “too little, too late” for Vytori/Zetia sales prospects, Anderson added, with both drugs scheduled to go generic in 2016.
What's more, most major statins are off-patent. And AstraZeneca's Crestor has been free of the controversy that has dogged Vytorin, matches Vytorin/Zetia in LDL reduction, has already demonstrated its benefit on outcomes, and “continues to dominate in terms of (formulary) coverage. Payers will likely continue preferring Crestor in this short window before generics arrive, unless Merck suddenly becomes much more aggressive on price,” Anderson wrote.
Vytorin's results also decrease the likelihood that the FDA would require outcomes data before approving the developing PCSK9 inhibitors, whose candidates include those from Sanofi/Regeneron, Amgen (evolucumab) and Pfizer (bococizumab), if a near linear relationship between LDL levels and cardiovascular event reduction is shown, analysists say.
“We fully expect LDL to regain its pre-eminent surrogate marker status with physicians and regulators globally,” Fernandez said.
The results go beyond the Merck drugs in “a reaffirming of the LDL hypothesis that was beginning to be questioned,” and that LDL levels should possibly be driven lower than guidelines have recommended (below 70 mg/dl), wrote Evercore ISI analyst Mark Schoenebaum.
“(Vytorin's) results add the first real data point to our understanding of the relationship between LDL reduction and outcomes at very low LDL levels,” Schoenebaum wrote.