Wednesday, April 02, 2008

NEJM: The Market-Cap Executioner ... You're Next, ARBs

I received a call on Monday from a close friend of The RPM Report who started the conversation with: "So, has the New England Journal of Medicine ever destroyed as much market cap in two days as they did in the past 48 hours?"

Well, the issue in late May 2007, which contained cardiologist Steve Nissen's Avandia meta-analysis was not good for GlaxoSmithKline's market cap. Remember when GSK lost $13 billion in cap in a few days? If you forgot, click
here or here.

NEJM may be on its way to eclipsing the old record the magazine already owns. Of course, on Sunday, everyone was privy to the actual ENHANCE study results on Merck and Schering-Plough's Zocor/Zetia combo Vytorin. I couldn't help but think of
this when I contemplated how badly burned the companies must feel by the study results. As my blolleague (blog colleague) Chris Morrison pointed out earlier, Merck lost about $12 billion in market cap and Schering-Plough lost about $8 billion in market cap during early trading. Yuck. To see the results from ENHANCE, click here.

But one study that's getting drowned out in the ENHANCE frenzy is the ONTARGET study comparing angiotensin-receptor blockers (ARBs) against angiotensin-converting–enzyme (ACE) inhibitors. ONTARGET compared the ACE inhibitor ramipril (Altace) with the ARB telmisartan (Boehringer Ingelheim's Micadis, Bayer Schering Pharma's Pritor/Kinzal) and a combination of the two.

Here's what the investigators found:

"Telmisartan was equivalent to ramipril in patients with
vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit."
You can read the whole study, published in the May 31 NEJM, by clicking here. Wasn't the whole point of taking an ARB to reduce side effects?

An editorial in the same issue of NEJM written by John McMurray titled "ACE Inhibitors in Cardiovascular Disease--Unbeatable? " was pretty explicit in advising prescribers. Here's an excerpt:
As the fourth and largest comparative trial, the ONTARGET study confirms, beyond doubt, that angiotensin-receptor blockers (ARBs) are not better than angiotensin-converting–enzyme (ACE) inhibitors at reducing fatal and nonfatal cardiovascular events. Of course, physicians and patients might still choose to use an ARB if it is as effective as an ACE inhibitor but better tolerated or less costly.
Wow. Here are some of the ARBs on the market: AstraZeneca's candesartan (Alatacand), Sanofi-Aventis' irbesartan (Avapro), Sankyo/Forest Labs' olmesartan (Benicar), Merck's losartan (Cozaar), and Novartis' valsartan (Diovan). These are not nothing products: Novartis generated over $4 billion in sales from Diovan in 2007; Benicar accounted for more than $750 million in revenue in 2007 and is growing quickly in the US.

McMurray concluded by saying that ONTARGET together with an earlier study
"show that telmisartan and valsartan provide a benefit similar to that of a proven ACE inhibitor. ... However, because ARBs are more costly than ACE inhibitors and have more side effects, their primary value is as an alternative for patients who cannot tolerate ACE inhibitors because of cough."
McMurray ends with nixing an ARB/ACE combo:
"The addition of an ARB to an ACE inhibitor has no benefit and causes an increased number of adverse events in patients with arterial disease but seems to be beneficial in patients with heart failure, although the trials in heart failure did not test the addition of an ARB to a full dose of a proven ACE inhibitor."
To read the full editorial, click here.

There's been a lot of buzz around comparative effectiveness, a comparative center, the impact of comparative effectiveness on personalized medicine, so on and so forth. The ONTARGET study and NEJM editorial should prove to be an interesting marker of how comparative effectiveness will impact the commercial market.

We already
saw what ENHANCE did to Vytorin. And it wasn't pretty.

1 comment:

Anonymous said...

Published on

A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial

While it seems that pharmaceutical company sponsors of clinical trials usually end up with results that clearly favor their meds studied in their trial, there are rare exceptions, and Merck and Schering proved that with their disappointing ENHANCE Trial, which many have heard about through the media not long ago. The drugs studied were Vytorin, which was compared with Zocor.

Vytorin is a combination med for high cholesterol and contains Merck’s Zocor, which is now generic, and Schering’s Zetia, which works differently than Zocor, which is one of many statin drugs. Both Vytorin and Zetia are co-promoted by Merck and Schering. So, several years ago, an outcomes study was initiated to prove superiority of Vytorin over Zocor. The trial was named the ENHANCE trial, and possibly this trial was initiated because Zocor is generic now, and not a priority from a profit paradigm of its creator.

After several years passed, a disappointment arrived for the sponsors of this trial, which was first brought to the attention of Schering in March of 2007, yet the results existed since the spring of 2006, I believe upon information and belief.

The disappointment is that Vytorin lacked anticipated benefit or superiority over Zocor. Since about 1 million scripts were written for both Vytorin and Zetia every week in 2007, combined with what I believe was about 5 billion in revenue for these two drugs that year, this was a problem for the drug makers, meaning a fear of shareholder reaction. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs with Schering, I understand.
Being the responsible corporations both companies are, of course, alterations occurred after such events were discovered that fractured numerous rules and regulations with clinical trials, possibly in illegal and unethical tactics.

The trial sponsors delayed the release of the trial results for secrecy reasons, it has been speculated. Results from the trial existed, yet were not disclosed at the time of their discovery. After several months of possessing these trial results that were only known to the manufacturers, they created or implemented some atrocious tactics to improve the trial’s unimpressive results following the original results of this ENHANCE study. At the end of 2007, the companies changed the primary endpoint of the trial, which is what the results were measured upon during the entire course of the trial. Sort of like sorting cards to make a good hand not dealt to you. Anyway, since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually as they had been anticipated for quite some time, and while such trial manipulation was occurring and results were being kept secret, Schering stated that continued data analysis from the trial results was the etiology for the delay.

With clinical trials, case report forms are used to record data from the trials, and are created in a manner where further analysis is not normally necessary, as such forms are quite clear and often not subject to interpretation as implied by the trial sponsors, one could conclude. So at the end of 2007, both Merck and Schering got the attention of relevant government officials who contacted both companies regarding this ENHANCE trial due to such suspicions on the facts known and presented, and an investigation began into the activities of both companies regarding this trial at that point.

This became a catalyst for the ENHANCE trial results to be finally released at the beginning of 2008, which caught the attention of major media organizations, as expected. In the spring of 2008, a very large cardiology meeting was held, where the audience was told, I understand, to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, it has been said that a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin by prescribers, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades, starting with Mevacor in the 1980s. Of course and as expected, Merck and Schering were not pleased, nor were they surprised at the review of Vytorin at this particular meeting. The following month after this cardiology meeting, Schering’s earnings dropped by 48 percent, as I recall. Also during much of this year, Schering in particular blamed the media for amplifying the situation regarding the ENHANCE trial.

Now, these cholesterol drugs promoted by Merck and Schering, Zetia and Vytorin, were aggressively marketed in a number of ways, including investing I believe about 200million dollars in 2007 for DTC ads for these products. To add to this, and soon after both meds were launched, reps from both companies made inferences to doctors about outcomes regarding plaque accumulation and how Vytorin was superior in that area, which, of course, this ENHANCE trial proved it is in fact not the case whatsoever. It did not matter, apparently, to both Merck and Schering that such claims were is entirely void of proof, which is not unique to any pharma rep, in my opinion. No remorse or regret from the makers of these drug makers, either, which did not shock many. Yet what is known now is that these companies, as stated by other researchers, performed junk science with their deliberate manipulation of this ENHANCE trial using such tactics. Also, last year, Zetia and Vytorin had about 20 percent of the cholesterol lowering market. It does not seem that there will be an increase of this percentage because of this scandal. Possibly if they presented the truth, the future of these meds might be better than what is anticipated presently.

Worst of all regarding this ENHANCE trial scandal is the harm caused to both doctors and patients. The ENHANCE trial concerned and confused both of these participants in the health care system. Furthermore, it’s likely they were devastated by being so clearly misled by the marketing of both Merck and Schering regarding the false benefits of Vytorin they were led to believe by the companies that promoted them- the health care providers in particular.

This whole situation is another example of the progressively frequent discovery of corruption of the scientific method by placing profits over the well-being of patients, which harms the well being of patients. In addition, most were shocked by Merck behaving in such a way in particular because of what use to be their excellent reputation as an ethical pharmaceutical company. And this alone shows the progression and infiltration of such damaging ethical atrophy that desperately needs to be stopped and corrected for the sake of others- for everyone.

Don’t just say something. Have something to say- to the right people, with conviction and with others who share your views.

“Waste no more time arguing what a good man should be. Be one.” --- Marcus Aurelius

Dan Abshear

Author’s note: What you have read is based upon information and belief. Thank you