Yes, Arbiter 6 Was A Small Study, But. . .

That isn’t really the story here, tonight, from AHA in Orlando. The “story” is 0-for-3.

If only 1 percent of Niaspan patients had cardiac events, and 5 percent of Zetia patients did, and the outcome was statistically significant — the 0-for-3 study streak [first ENHANCE, then SEAS and now Arbiter 6 - HALTS] looks particularly lethal, to the Merck cholesterol franchises.

Finally, if IMPROVE-IT is now essentially flying dead-stick, then I am uncertain that the expense of continuing to fund such a massive, longitudinal study can be justified.

CardioBrief’s Larry Husten — Some Bigger Open Questions

The New England Journal of Medicine has published Arbiter 6 — and it could scarcely be any worse, for Zetia. Niaspan’s a clear winner; increased risk of cardiac events in patients taking the Zetia arm. Larry Husten has much more — do go read all of his, at CardioBrief.

But this bit — from two former Merck/Schering-Plough joint venture PIs — may be the most troubling admission I’ve seen so far, tonight:

. . . .Kastelein and Bots raise the question whether we will ever find out the truth about ezetimibe: In their editorial they write that “the large number of hard clinical end points (>5,000) required to achieve sufficient statistical power in IMPROVE-IT makes it uncertain whether the trial will ever reach completion“. . . .

[Dr. Kastelein, my sharper readers will recall, was the PI on ENHANCE; Dr. Bots was brought in later, to evaluate the readability of the CIMT data in ENHANCE, and declared it "fine" -- "no better, or worse, than other similar studies' data", despite Merck/Schering-Plough's insistence that much of the ENHANCE CIMT data was poor.]

So — IMPROVE-IT (see my left margin count-down clock, still at least 1,506 days to go!) — May. Never. Reach. Completion.

Well — if that is remotely close to accurate, “game over“, for Vytorin/Zetia. IMPROVE-IT was to be the pair’s “last best hope“.

What Merck’s Dr. Pasternak USED TO SAY — About Niacin Additives

This is whole post is courtesy of an anonymous commenter, below. What many here may remember, is that as late as April of 2008, Merck was touting the potential benefits of its niacin additive program. Then, in early May of 2008, Whitehouse Station was told by FDA that its then-latest combination pill, laropiprant with a niacin additive (proposed to be called Cordaptive), was rejected by the FDA — it would not be approvable. [Merck officially claims it is still working on a niacin added combo pill, and negotiating with FDA about how to move forward.]

However, Dr. Pasternak’s remarks from the would-be Cordaptive candidate efforts are illuminating, and fascinating (compared to those he offered yesterday, by letter to the New York Times) — no more preliminaries, then — onto the fabulous anonymous commenter’s collection of Pasternak pull-quotes:

. . . .Interesting tune from Dick, and one that is very different from the past when Merck was trying to get FDA approval of Cordaptive (epic fail!):

“. . . .If approved, Cordaptive could be used by patients who cannot take statins or those who already take statins but need to further improve their cholesterol levels, Richard Pasternak, Merck’s vice president of cardiovascular disease research, told Dow Jones Newswires.” (Sept 4, 2007)

“I realized HDL has become tarnished because of torcetrapib, but Cordaptive uses a completely different mechanism,” Pasternak said. “In my mind at least, this does not tarnish the tremendous body of evidence that HDL is protective and low HDL is associated with clinical risk.” (Sept 2, 2007)

“Dr. Richard Pasternak, a senior Merck research official who helped conduct the trial, said the findings could trigger a rethink of treatment strategies.

“It’s a breakthrough because this comprehensive lipid therapy has not been available or achievable by most people. Physicians are reluctant to prescribe the agent (niacin) and patients are reluctant to take it,” he said in an interview.” (Sept 2, 2007)

“So I would think most people, excuse me, in this room are aware of the magnitude of the problem that we face with respect to cardiovascular disease in general and specifically dyslipidemia, while most people think about dyslipidemia in the context of an elevated LDL, it’s quite clear that other key lipid parameters, particularly HDL and to a certain extent triglycerides represent a therapeutic challenge and an unmet medical opportunity to improve the cardiovascular health, and Cordaptive in particular is an agent that is targeted to address all three key lipid parameters. Recall that as terrific as statins have been, and I used to be out as an academic cardiologist on the lecture circuit talking about what remarkable improvement in mortality and morbidity that it brought us but I think as we look back at that we have to recognize that the cup was only one-third full, or two-thirds empty, because statins only reduce mortality and morbidity only by 30 or 40%, so there is a tremendous burden that continues to exist and continues to search for treatment alternatives.

Niacin has been known for 50 years to have favorable lipid effects but despite these favorable lipid effects it’s been a challenge to get people to take Niacin on a regular basis no matter what form it’s come in, so despite these well known, well established favorable benefits both in terms of the lipids as I just mentioned but in terms of fairly robust outcomes over decades, the majority of patients who take Niacin experience flushing with Niacin.” (March 18, 2008)

[Posted by Anonymous, on] November 15, 2009 7:43 AM. . . .

A sincere debt of gratitude is owed to this anonymous commenter. Later today (Sunday brunch calls!), I’ll go get links to each of these statements, above — if they are available somewhere online.

Funny how Dr. Pasternak’s tune changes, depending on what agenda (niacin “breakthrough”: 2007-2008; niacin not so important: November 2009) he’s pushing, at any given moment.