Editor’s Note: The following guest post by Michael McCaughan originally appeared on The RPM Report, a highly valuable resource for biopharmaceutical executives on FDA, CMS and public sector issues published by Elsevier Business Intelligence.

Vytorin: Yesterday’s News? 

By Michael McCaughan

Merck’s cholesterol drug is poised to add a unique claim to improve outcomes in as many as 19 million Americans, even though there still isn’t data to answer critics about whether ezetimibe actually adds clinical benefit to conventional statin therapy. Why doesn’t anyone seem to care?

There was plenty of room in the press row during the Endocrine & Metabolic Drugs Advisory Committee’s Nov. 2 meeting to review Merck’s ezetimibe (Zetia/Vytorin) for a new claim to reduce major vascular events in patients with kidney disease.

In fact, there was plenty of room everywhere—except at the committee table (which had 17 panelists and half a dozen FDAers) and for the very crowded rows reserved for the sponsor.

This is hardly the first time an advisory committee met with some danger that the panelists would outnumber the audience. But this wasn’t a sleepy outpost like allergenic extracts, or a complex regulatory matter with limited impact like last year’s safety review of fosphenytoin.

This was a meeting to consider an important new indication for a blockbuster brand in a potentially vast patient population.

And it wasn’t just any medicine: this is Vytorin, the drug that was once ubiquitous in highly praised TV ads—and then equally prominent as one of a series of high profile blockbusters taken down by concerns about outcomes. When Merck reported that the ENHANCE study failed to show benefit of the ezetimibe/simvastatin combo versus simvastatin alone, the drug became national news, lumped in with Vioxx and Avandia as case studies of a broken regulatory system. (See “The Unsung Vytorin Victim: Primary-Care Marketing,” The RPM Report, February 2008.)

Then came a safety scare, when another trial (SEAS), was stopped over an excess incidence of cancer in the ezetimibe arm. FDA concluded that the signal was probably a false alarm, but theZetia franchise has been in the doldrums ever since—although, with global sales in excess of $4 billion annually, it is still a very big product line.

Assuming the new claim (based on the SHARP study) is approved, it will be the first explicit outcomes claim in the Vytorin and Zetia label. That alone makes this meeting a big deal.

The indication itself is potentially huge. The SHARP study was designed with no lipid entry criteria, so this is a claim that relates to a condition (chronic kidney disease) regardless of LDL levels.

Physicians will surely consider LDL and other risk factors when treating, but still: by the estimate of the SHARP study sponsors, there are as many of 19 million Americans covered by Merck’s proposed claim. (And, according to the study investigators, treating all of those patients would prevent 400,000 major atherosclerotic events). So this was a medically and commercially important event.

Now, based on the outcome of the advisory committee, Merck probably won’t get a claim that broad. As reported in The Pink Sheet DAILY here, the panel agreed unanimously that the data support a claim of reduced vascular events in patients with CKD but not on dialysis; the panel voted 10-6 against approval in dialysis, although a couple of committee members who voted no said they would have voted yes for an indication that encompassed the entire SHARP population.

We’ll see what FDA makes of that advice, but this is clearly a case where the breadth of the claim doesn’t matter all that much to Merck. What matters is having some form of labeling that counters the view that ezetimibe does something beneficial for patients beyond lowering a number on a lab test.

Steve Nissen Not Convinced

As important as the vote was the tone of the meeting: the panel supported the claim with minimal discussion of the past questions about safety and efficacy of ezetimibe as an add-on cholesterol therapy.

There was only minimal acknowledgement of the still unanswered question about whether ezetimibe actually adds anything to the benefit from lipid lowering with simvastatin (or any other statin). The SHARP study did not include a simvastatin only arm (except for a one-year period to permit safety comparisons to the ezetimibe combo).

So it is perfectly possible that the SHARP study only demonstrated that statin therapy does in fact have a role in patients with CKD. Among those who read the study that way is Cleveland Clinic Cardiology Department Chair Steve Nissen, who almost single handedly turned the ENHANCE trial into national news in 2008.

“I don’t agree with the committee’s decision,” Nissen told us. In his view, the SHARP study showed “not much effect, if any, in dialysis.” In the non-dialysis patients, “all of the benefits were in patients with elevated cholesterol who” would already be indicated for a statin, Nissen asserted.

SHARP is “just one more study that shows people with high cholesterol benefit from a statin,” he said. “The jury is still out” on whether ezetimibe actually contributes anything to statin therapy beyond a lower LDL number, he says.

Nissen’s view isn’t so far from what the committee concluded: a majority of the committee clearly had reservations about a dialysis claim based on SHARP, and no one in the committee room (or outside) argues that SHARP answers questions specific to the role of ezetimibe.

FDA clinical reviewer James Smith noted the ENHANCE study findings in his opening remarks to the committee, and stressed that a definitive answer to the question of whether there is some unique lack of benefit associated with LDL lowering by ezetimibe will await further data, including the IMPROVE-IT trial due to report in 2013.

And that is one big reason for the lack of attention to the meeting: the big news is still two year away.

Still a Big Opportunity

But it may be a mistake to equate the lack of excitement in the meeting room to the impact an explicit outcomes claim will have in the marketplace. Bear in mind: this will be a unique outcomes claim for ezetimibe; Merck will be the only company that can call on nephrologists with a message about reducing CV events in a trial focused specifically on their patients. There may still be doubts about the role of ezetimibe, but Merck’s competitors won’t have much opportunity to discuss them with specialists in kidney disease.

Merck may not have a claim to take to dialysis centers, but the pre-dialysis population is probably the more attractive piece anyway, since it is likely to be more accessible by traditional pharmaceutical promotion. Panelist Julia Lewis, MD, Vanderbilt University School of Medicine, observed that treatment in the dialysis setting is heavily driven by guidelines and payment policies, so a labeling claim alone may not be sufficient to make inroads (nor does its absence necessarily mean exclusion from use).

In the pre-dialysis setting, though, panelists were enthusiastic about the demonstration of benefits from lipid lowering, repeatedly thanking the SHARP study investigators for tackling a population that is something of a “quagmire.”

The study, incidentally, was designed and conducted by Oxford University and funded by Merck. That independence probably helped keep the tone of the meeting more positive.

Still, there is something odd about approving a unique claim for a combination therapy when there are still questions about the benefit of one half of the combination.

But during the November 2 meeting, the issue was broached only gently and nearly apologetically. Committee statistician Erica Brittain asked FDA whether it wanted any comment on the lack of simvastatin-only arm for efficacy. “I notice that none of the questions deal with it,” she told the FDA staff at the meeting, “so if we can just forget about it, that is fine, but I wanted to get your perspective

Endocrine & Metabolic Division Deputy Director Eric Colman responded by essentially defending the SHARP study design, observing that it was logical to try to use a low-dose statin to avoid known adverse effects in the renal insufficiency population in combination with ezetimibe to maximize the LDL reduction. He concluded that it would have been a “shot in the dark” at the time to guess that there might be reason to have a statin-only arm.

After that, there was only the briefest discussion by panelists about the lack of a direct comparison between combo and statin-only therapy, with no one arguing that the indication should be tabled pending a better understanding of ezetimibe’s role.

Even better for Merck, there were several statements during the review in the opposite direction, most notably a last-minute addition to the presentation by the FDA team that analyzed one-year efficacy data from the SHARP study that was intended to allow a safety comparison between simvastatin alone and simvastatin plus ezetimibe. While presented with caveats and clear reluctance, the one year data did play out in the right direction for Merck, with fewer major vascular events on the combo therapy compared to simvastatin alone.

That added level of reassurance probably helped the committee go along with the idea that a claim in this space would be appropriate.

Nissen, though, sees it differently. “This wasn’t a study that asked the right question.”

Nissen, of course, wasn’t on the committee; while he is a special government employee occasionally asked to sit on panels, he says he was not asked to join this one. He also says he has no plans to weigh in elsewhere, since he is only expressing an opinion based on his reading of the data, and “others clearly disagree with me.”

That suggests that the outcomes claim for Vytorin will continue to move with a very low profile. And that may be the best news of all for Merck.

Comments? Email the author at windhover-dc@windhover.com

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