While You Were Saying Goodbye to Summer

going, going, gone.

Outta here like a Ryan Howard shot to deep right field, vanished like Keyser Soze, Summer 2008 is now just a memory. Hey, at least football season has begun, right? Below, our roundup of what you might have missed while enjoying that last BBQ of the season.

• European Society of Cardiology: News came thick and fast out of this annual meeting in Munich. The results of a potentially important study of stents vs scalpels in treating clogged arteries are in, and surgery has come out on top. Lilly and Daiichi's prasugrel got a boost in diabetics prior to its 26th September FDA deadline. An analysis of the previously released Triton-Timi 38 trial showed that prasugrel was more effective than standard-of-care clopidogrel (Plavix) in that patient population, reports Reuters. Pronova/GSK's Omacor (fish oil) met both primary endpoints in a Phase III outcomes study in patients with heart failure, who were 9% less likely to die than patients given placebo. AZ's Crestor didn't fare as well in a similar population. Finally, Bayer said it would speed up development of rivaroxaban--putting a little extra pressure on Pfizer/BMS, whose rival candidate apixaban hit a snag last week, as we wrote about here. For more news out of the meeting, click here.
• Shionogi & Co. is the latest in a pretty long line of Japanese pharmaceutical companies buying up cheaper American firms to help expand into western markets. Shionogi bought Sciele Pharma for $1.1 billion ($31/share, a 61% premium to the stock's previous close) plus the assumption of $325 million in debt, the companies announced on Monday. Atlanta-based Sciele had revenues of more than $382 million in 2007, and specializes in women's health, cardiovascular disease, diabetes, and pediatrics. For more on Japanese Pharma appetites, see here, and look for a feature on these trends in an autumn issue of IN VIVO.
  
• Oncology expert Prof. Karol Sikora of CancerPartnersUK diagnoses the ills of the country's NHS and writes this prescription in The Sunday Times: "Radical structural change to the NHS is vital. Competition and choice drive up quality and access, so leading to greater value, just as we’ve seen in other consumer areas such as mobile phones, budget airlines and the high street. Sensible incentives linked to performance and outcomes are essential. Drastic reform, not more money, is now needed."
• Novacea, which begun a strategic review in May after Schering-Plough canceled an alliance around its entered an agreement to merge with Trancept Pharmaceuticals (nee TransOral Pharmaceuticals, click here for our admittedly old 2003 profile of the firm). The latter company, a privately-held specialty pharma that specializes in tweaking the pharmacokinetics of CNS compounds, has raised more than $70 million in venture funding but--surprise, surprise--has been unable in this climate to tap the public markets. If investors buy into this reverse merger, TransCept backers will hold 60% of the combined company, which, the companies say, will have enough cash to pursue FDA approval for and launch its Intermezzo lozenge formulation of the insomnia drug zolpidem (the now-generic Ambien).
• Lipitor ads are back after six months off the air, but you mean nasty bloggers won't have Dr Jarvik to kick around any more! According to the WSJ, Jarvik's out and heart attack survivor John Erlendson is in. What are the odds that he's a rower?
• In the latest installment of its A1 "The Evidence Gap" series, The New York Times asks why more than three million people still take Vytorin/Zetia every day, and notes that some prominent cardiologists are now calling for it to be taken off the market.
  
• The Guardian adds up the challenges facing Big Pharma and, well, that's pretty much it. Would have been nice to see some answers in there too.
  
• Speaking of The Guardian, Ben Goldacre's Bad Science (the book) is on shelves now (at least in the UK). Go on, buy one. And if you haven't already, click the link to his web site in our blogroll to the right to get a preview.
  

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.

While You Were at ACC

The weekend news in pharmaland was dominated by Vytorin (again--see below) and a few other stories coming out of the ACC meeting in Chicago. No surprise there, and no surprises in the NCAA Tourney, with four #1 seeds making it to San Antonio. In other more important news, it's Opening Day ...

• The publication (in the NEJM) and presentation (at ACC) of the long-awaited Enhance data did little to improve the current prospects for Merck/Schering-Plough's Vytorin/Zetia franchise. At ACC an expert panel put together to discuss and debate the results essentially suggested the drugs were used waaaay too much, and that "people need to go back to statins." (The pharmacos' response to the publication/presentation is here, The Pink Sheet Daily has the story here, the NYT weighs in here, and the WSJ story is here.) On Friday, the companies said they were expanding the Improve-It outcomes study everyone is waiting for, and results won't be available until 2012. UPDATE: Merck off about 12% ($12bb in market cap), Schering-Plough down 27% ($8bb) in early trading.
  
• Two Vancouver-based RNA interference drug and delivery companies are merging, and Alnylam and Roche has each promised them a $5 million wedding present. Tekmira Pharmaceuticals (a spin out of Inex Pharmaceuticals) and Protiva Biotherapeutics said Sunday they were combining their RNAi therapeutics and delivery businesses, retaining the Tekmira name and Toronto stock exchange listing. Alnylam and Roche each committed to buy $5 million in Tekmira stock at $2.40/share at the close of the deal, nearly triple Tekmira's Friday closing price of $0.87. Alnylam will have access to the combined company's liposomal delivery technologies (which under the agreement will be sublicensed to Roche and Regulus, the micro RNA JV set up by Alnylam and Isis) and Tekmira will secure a license to Alnylam's IP to develop seven siRNA drugs under its InterfeRx program.


• The AP notes incoming Lilly CEO John Lechleiter's penchants for perambulation and blogging, though we imagine these things are tough to do simultaneously. Throw in addressing Lilly's current woes and this guy's got a full schedule (though the most recent prasugrel data should put a spring in his step). Walk the walk with the Boston Globe.

Photo by flickr user Atelier Teee used under a creative commons license.

Botox, Friday Afternoon Press Calls and the Nissen Effect

Blaming the media will never go out of fashion, at least not when it comes to drug safety scares.

Here is Schering-Plough EVP Carrie Cox, summarizing the battle to rebuild Vytorin after the ENHANCE debacle during its earnings call February 12: "Physicians ... understand that the furor around ENHANCE is largely a media driven event."

And GlaxoSmithKline’s recap of the Avandia meltdown of 2007: it resulted from a “distortion of the media” about the risk profile seen with the Type 2 diabetes drug, outgoing CEO JP Garnier said February 7.

There is no question that front-page headlines and national news broadcasts can do immediate and lasting damage to even the most well-established brands, damage that may go far beyond any appropriate medical response to new data.

But that only begs the question: what prompts some safety scares (or, in the case of ENHANCE, a failed efficacy trial) to create a media feeding frenzy, while others seem to pass with barely a ripple?

One answer, to borrow a phrase from religious themed bumper stickers, could be WWSNS: What Will Steve Nissen Say? There certainly does seem to be a strong correlation between the Cleveland Clinic cardiologist’s reaction to new data and the amount of play it gets in the media.

Wall Street seems to believe in the Nissen effect. In a February 11 note, Wachovia’s Larry Biegelsen argued that investors over-reacted to an “early communication” about a potential safety issue involving Allergan’s Botox. The issue, announced by FDA February 8, involved serious adverse events primarily associated with off-label use of Botox in children with cerebral palsy. Investors worried that a safety scare could significantly impact Botox widespread cosmetic use.

Not to worry, says Biegelsen. An “ENHANCE-like impact” on Botox use is “unlikely in our view.” Why? Well, for one thing, “Dr. Steve Nissen has not spoken out against Botox,” the way he did against Vytorin.

Talk about a case where silence is golden.

Biegelsen, of course, knows it isn’t quite as simple as that. Nissen’s silence is one of four factors the Wachovia analyst sees as reassuring differences between the Botox safety issues and the ENHANCE fallout. Only one is under the control of the sponsor: “There does not appear to have been any delay in the reporting of the serious adverse events.”

The other three involve reactions by external parties who have no formal regulatory role: (1) Nissen’s silence; (2) “Congress has not started an investigation into the handling of the Botox data”; and (3) The media coverage of Botox is more benign than the coverage of the ENHANCE data.

How so? “We couldn’t find a story in the print version of the New York Times on Saturday, whereas ENHANCE was front page news the day after the results were released.”

Of course, that last point is not entirely good fortune for Allergan. As we pointed out, FDA issued the “early communication” about Botox on Friday afternoon—part of what is becoming a pattern at the agency. (A safety update on Pfizer’s emerging blockbuster Chantix came out the week before Botox, and FDA’s first response to ENHANCE came the week before that.)

It so happens that Friday afternoon is the time least likely to generate significant news coverage. FDA swears there is no deliberate strategy to bury drug safety events. (At least, they assured Pharmalot of that—you can read more here.)

It certainly is plausible that FDA didn’t get all its ducks in a row to issue the early communications until Friday afternoon. We’ve talked to media savvy FDAers over the years (both in the press office and elsewhere) who routinely lament the review divisions’ habit of issuing approval letters at or after the close of business, often on Fridays, thereby all but assuring that even the most important new drug approvals would not be covered in the national news broadcasts, and sometimes even receive scant notice in newspapers.

The fact is that if FDA is not taking the news cycle into account when making safety announcements, it should be. Overblown safety scares do not serve the public health, so FDA certainly could justify Friday afternoon announcements as a way to better ensure that important new information gets into the public sphere in a more measured fashion.

On the other hand, the news media is the best way to amplify an urgent safety message. If that is the goal, the agency is better served by getting the news out early in the day and early in the week whenever possible.

In fact, that’s what FDA did on Monday February 11, when it announced that Baxter is suspending production of heparin due to severe adverse events--an announcement with urgent public health implications.

As far as we know, Dr. Nissen didn't weigh in on that one...

Who's Sorry Now? Not Feeling So Good Edition

Nature reports today that a peer reviewer for the New England Journal of Medicine leaked to GlaxoSmithKline that big old Avandia meta-analysis that has been the bane of their existence since it was released in May 2006. (Our coverage of the Avandia debacle can be found here.)

University of Texas Health Science Center professor of epidemiology Steven Haffner, MD, explained to Nature: "Why I sent it is a mystery. I don't really understand it. I wasn't feeling well. It was bad judgement."

Brian Vastag writes in Nature that Haffner faxed the article 17 days ahead of publication to GSK's Alexander Cobitz, whom he had worked with on an earlier trial of Avandia. What happens from there is unclear--though it's not like GSK effectively got out in front of the news, the 17-days head start may have helped them provide a relatively prompt interim analysis of its RECORD study, which was published in the NEJM in June to try to stop the bleeding.

We will likely have more on this later, once the dust settles. For now, we bring you another edition of "Who's Sorry Now?"

• Steven Haffner to NEJM: Sorry I leaked the Avandia study, but i had a serious cold that day.


• Senator Grassley's office to Nature: Sorry we broke your embargo on the Avandia news today, but we aren't feeling so hot today ourselves.


• American Heart Association and American College of Cardiology to patients: sorry we forgot to disclose our potential financial ties to Merck and Schering-Plough, but there's a wicked flu going around the office.


• Phillies to Mets: Sorry you're spending all that money on Santana, but you're still not winning the NL East this year. Cough.

Survey Says?! Too Little, Too Late

Lets have another quiz. The above chart illustrates ...

a. Reaction to last night's State of the Union address
b. The results of the IN VIVO Blog poll about Schering-Plough and Merck's reaction to critics of the Enhance study
c. Both

Lets not get too carried away though. Although we all know that you IVB readers are smarter and better informed than your average bear, only a very small minority of you (compared to how many visits the site gets) decided to vote. Slackers!

(It'll take a whole mouse-click but if you can muster up the energy you can find our ongoing Vytorin coverage here.)

While You Were Almost Upsetting

We've been told by certain football (soccer) fans that there are not enough allusions to the beautiful game in our weekend roundups. So as equal opportunity sports enthusiasts we thought Saturday's FA Cup fourth round near-upset of Premier League giants Liverpool by the part-timers from the curiously named Havant and Waterlooville away at Anfield warranted a mention. (And hey it's the NFL's ridiculous weekend off anyway.)

Even though they lost 5-2, this team of teachers, builders and trash collectors (not sure if there are any pharma bloggers on the team, but who knows maybe the mysterious Insider from Pharmagossip plays for them) led twice and gave one of the top teams in Europe quite a scare, at least in the first half.

What else was going on this weekend?

• Vytorin snafu: New York State AG Andrew Cuomo piles on. More at Pharmalot.
  
• Ben Goldacre highlights a few recent studies about publication bias (including one concerning SSRIs from last week's New England Journal of Medicine). Your indispensible Bad Science is here.
  
• Our Vytorin poll is closing today. Vote here.

FDA Gets Out in Front on Vytorin, Defends LDL Endpoint

The Food & Drug Administration is weighing in on the Vytorin controversy via an "early communication" on the study results.

Given the hue and cry over the drug since Merck and Schering-Plough finally disclosed disappointing data from the ENHANCE trial January 14, many may wonder how FDA can say it is "early" with its response. After all, didn't Steve Nissen, the United States Congress, and seemingly every media outlet in the country already tell us what to think?

As far as Vytorin goes, the FDA announcement indeed is decidedly anti-climactic. The agency summarized the results already made public by the company, and said it would review the data fully once it is submitted by the sponsor. On a media call, Office of New Drugs Director John Jenkins said it may be another couple of months before the data is submitted, and up to six months before the agency completes its review.

And, Jenkins added, it is not like there is much to expect from the regulatory review itself. Vytorin is already clearly labeled as not showing any demonstrated benefits in long term outcomes data. The agency will be looking carefully for any new safety information in the data, Jenkins said, but it is not aware of any red flags at this time.

So not much new there.

But there is an important way in which FDA is getting out in front of the Vytorin story. One of the primary messages of the early communication and the media call was to try to diminish speculation that the ENHANCE trial calls into question one of the basic tenents of cholesterol therapy: the focus on LDL levels as a key marker for treatment.

The agency's main message: it remains confident that LDL reduction is a fully validated surrogate endpoint as a basis of approval for cholesterol treatments--and that LDL reduction is an appropriate therapeutic goal for physicians and patients. (Recall that the Schering-ENHANCE study failed to show the expected benefit of combination therapy with Vytorin versus single-agent simvastatin, despite showing significantly better LDL reductions.)

"It would be premature to embark on any systematic change in how we approve lipid-lowering drugs," Jenkins said. "We have a long track record" of success in basing approvals on LDL, he noted.

In fact, Jenkins added, LDL reduction is a much more fully validated than the arterial plaque endpoint used in ENHANCE.

"It is tempting to think of" changes in arterial plaque "as a direct measure of what these drugs do," Office of Medical Policy Director Robert Temple added. But "that may not be the best measure." He noted that statin drugs show improved outcomes in a matter of months--before any measurable changes in arterial plaque are observed.

"The surrogate that really works is LDL cholesterol," Temple stressed. "I'm very concerned that this will lead to people becoming indifferent" to their LDL levels, rather than seeking treatment.

That message may or may not help Vytorin in the marketplace--but it is great news for all cholesterol drug development companies.

The Best Defense Is a Good Offense, Or Something Like That

Merck and Schering-Plough put out a release a few minutes ago responding to critics of ENHANCE and the trial results' fallout:

WHITEHOUSE STATION, N.J. & KENILWORTH, N.J.--(BUSINESS WIRE)--Merck and Schering-Plough said today that they strongly object to mischaracterizations about the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial. “While the ENHANCE trial was time consuming and took longer than originally anticipated to complete, our companies acted with integrity and good faith in connection with the trial. We took numerous actions to assure the quality of the reading of the ultrasound images,” said Thomas Koestler, Ph.D., president, Schering-Plough Research Institute.

And from there it gets more defiant. So, dear readers, what do you think? Read the whole release. Is this an effective defense for Merck and Schering-Plough? Please take our poll:

Vytorin: Two Sources of Angst for DTC

Rep. John Dingell is one source of cholesterol nightmares for Big Pharma advertisers

Schering-Plough and Merck are halting their direct-to-consumer television ads for Vytorin, surely a sound decision given what appears to be a continuing free fall in use of the combination cholesterol therapy after the disclosure of the ENHANCE study results.

Advertisers are worried about the impact on regulation of DTC in general. An excellent piece in Advertising Age spells out some of the concerns.

But just as the ads themselves highlight the "two sources of cholesterol," we think there are really two sources of concern about DTC raised by Vytorin.

The first is regulatory. Attacks on DTC are not going away, so advertisers are right to worry that any ammunition used against one ad can threaten tougher regulation for all. In this case, the Energy & Commerce Committee is already asking the sponsors and FDA to explain why the ads continued running long after the ENHANCE trial was complete.

But the second is more fundamental: the impact that the DTC advertisements themselves had in turning the failed ENHANCE trial into a commercial disaster for the sponsors. You can debate the medical significance of the ENHANCE findings all you want, but you can't debate this: the very success of the DTC campaign in establishing Vytorin as a consumer brand helped make the failed trial much bigger news than it might have been.

Congress doesn't open investigations of drugs no one has heard of. And national newscasts don't cover equivocal study results for drugs no one knows either.

DTC advertising is expensive and controversial. It also can be highly effective at building a brand and driving prescription growth. Any accurate calculation of the risks and benefits to a particular brand, however, has to consider the potential that an advertiser can be a victim of its own success. That surely is one of the lessons of Vytorin.

Vytorin: In this Case, Best to Ignore History

Are the experts right? Or is this another example of the wisdom of crowds?

Analysts are pooh-pooh’ing the Vytorin/Zetia affair. Tim Anderson of Sanford Bernstein wrote that ENHANCE will “likely only have a muted impact on Vytorin prescription trends given the limitations of the study, but some prescriber business may be lost on the margin contingent on much negative coverage ENHANCE continues to receive.” Catherine Arnold at Credit Suisse in a note on Friday talked about investors reactions as “excessive and disengaged from the fundamentals.”

So far, the market isn't listening. Merck’s stock was down last week 10%; Schering-Plough’s 23%.

Docs aren’t paying attention to the analysts either. Daily data from ImpactRx show steep declines in new scrips. Notes ImpactRx analyst Bob Caprara: if you look at 2-day averages, Vytorin has lost 75% of its new patient starts and was still trending down last Friday. If you continue to draw that line, Vytorin could easily lose 35% of its 2008 projected sales, he says.

Admittedly, Caprara notes, that’s a big if. Schering and Merck might be able to counter the negative press. Arnold argues that “there are no sound historical comparisons for a drug coming under this much fire for a disappointing efficacy study, especially when the study looked at an unvalidated surrogate endpoint, tested the drug against a strong active comparator and showed equivocal results.”

Maybe. Other drugs have faced a barrage of criticism and recovered – most notably, as Arnold points out, AstraZeneca’s Crestor. But we’d submit the Vytorin situation is no Crestor redux, and Crestor’s antagonist, FDA's internal gadfly David Graham, is no Steve Nissen (we blogged about one of Nissen’s attacks on the drug here). In the first place, Graham could point to no single trial to define his point. Vytorin’s critics now can. And that woefully-late-to-report trial looks to those with a suspicious caste of mind (including the New York Times editorial page and US legislators) like it was suppressed.

Then there’s the lower-is-better argument that the drug industry has used so effectively to boost one statin over the previous while driving sales in the category beyond the wildest dreams of its creators – first Merck, with Zocor over Bristol-Myers’ Pravachol, then Pfizer, with Lipitor over Zocor, then AZ with Crestor over Lipitor; and now Merck and Schering with Vytorin over Lipitor and Crestor. When you think about it, there ain’t all that much data comparing head-to-head outcomes data on the most powerful drugs – Vytorin’s IMPROVE-IT trial vs. Zocor won’t report out till at least 2010; the Crestor vs. Lipitor study not until 2011. And while Arnold is right that the ENHANCE study focused on a surrogate endpoint – atherosclerosis as measured by intima-media thickening – it’s an endpoint a lot closer to a real clinical endpoint than mere cholesterol reduction.

But whether Vytorin sales slump permanently or not, the real message is that primary-care risk is now off the charts, exacerbated by Big Pharma’s addiction to DTC advertising. In fact, we think the risk will bite a virtually permanent discount from the share price of firms whose earnings now or will flow largely from primary care products, particularly those – like Vytorin – which treat asymptomatic diseases.

There are several reasons why. First, with the general lack of head-to-head outcomes data – and understandably little appetite among Big Pharma for financing it pre-approval –payors will increasingly look to switch their insured populations towards generics. And this is particularly easy with asymptomatic conditions like hypercholesterolemia because patients have very little practical reason to care. Their disease doesn’t hurt; the drugs provide a merely theoretical benefit. At least diet and exercise make you look better.

Second, these drugs are the easiest ones to attack. There are no patient cholesterol or hypertension or diabetes lobbies that can compete with breast cancer or AIDS or Alzheimer’s. The makers of the big primary-care drugs are easy targets for politicians – and evidently more frequent targets, too (thanks in part to the backswing of the double-edged DTC sword Big Pharma has been wielding so aggressively). Merck and Schering will be asked to explain themselves to Congress (and no doubt FDA will be obliged to hold an advisory committee as well). That means more headlines and more questions. As we wrote here, it won’t help that the Energy & Commerce Committee, which is investigating Vytorin, is also investigating Pfizer’s Lipitor DTC campaign.

And you add those headlines to the fact that the drugs don’t actually make people feel better – and a compliance problem the drug industry has always struggled with will grow worse.

Let us return to Catherine Arnold’s point: “there are no sound historical comparisons for a drug coming under this much fire for a disappointing efficacy study.” Exactly. History -- the rear-view mirror -- isn’t where we should be looking to understand the meaning of the Vytorin story.

Photo 'Crowd listening to T.R. speak, Chicago' from Library of Congress, via Flickr

While You Were Losing Your Resolve

Allegedly this is the time of year that most of us begin to let those New Year's resolutions slip. (Already? Weak!) Trip to the gym or grab a beer to watch the conference championship games? We watched football--but then again we were smart enough not to make any resolutions this year. Pack and Charger fans, better luck next year.

Just a couple notes from a cold and quiet Sunday. If you're taking the day off in observance of Martin Luther King Jr. Day, enjoy the long weekend.

• Start saving for a super bowl ad: Merck and Schering-Plough defend Vytorin and Zetia in some full-page ads on Sunday. Will doctors and patients respond? We'll have some data on their early reactions to the Enhance kerfuffle later today.


• Lupus, unmasked: Scientists writing in the New England Journal of Medicine and Nature Genetics describe unearthing genetic variants in at least six distinct regions of the genome related to the autoimmune disease systemic lupus erythematosus. Reuters' roundup is here.

The Man Pharma Loves to Hate

It’s the headline lay media outlets love to report: “High-Cost Cholesterol Drug Combo Shows No Benefit Over Lower-Cost Generic Statin.” From a health care reporter’s perspective, nothing is more juicy than a study that shows that a cheap generic drug is more effective than a expensive new medicine. Especially when the study is sponsored by a drug company.

And that story is made even better is when Steve Nissen goes on national television to say things like this: “My advice to physicians is to not use these drugs...for first-line indications anymore. These should really be relegated to drugs of last resort until we have some evidence that they produce a health outcomes benefit.”

But that’s exactly what happened to Merck and Schering-Plough’s hot new cholesterol combo, Vytorin. The drug, which combines another relatively new drug, ezetimibe (Zetia) with generic simvastatin, was found to have no effect on the accumulation of plaque in the arteries, and may even increase plaque growth.

Yikes. No wonder Schering and Merck waited two years to release those findings. Wall Street certainly showed its displeasure: Schering’s stock price fell 8% yesterday, and Merck’s shares slipped 1.3%. And Merrill Lynch downgraded its rating on Schering’s stock, from “buy” to “neutral.”

But Merck and Schering aren’t just in hot water with investors. The companies released the data after Bart Stupak (D-Mich.), chairman of the House Energy & Commerce Committee, opened an investigation into the delay. Now Stupak is sure to haul Merck and Schering executives up to Capitol Hill to testify at what surely will be a very public, very messy hearing.

“In light of today’s results, which were released nearly two years after the Enhance trial ended, it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data,” Stupak said in the statement. Stupak, of course, was the man behind the Ketek hearings last spring, when FDA’s David Graham returned to Capitol Hill to revive his role as a drug safety whistleblower. So he’s not exactly friendly with Big Pharma.

That’s all bad enough for Schering and Merck. But Nissen, head of cardiology at the Cleveland Clinic, twisted the knife in a bit deeper, appearing in virtually all major news outlets to blast the efficacy of Vytorin and Zetia. (In fact, we would challenge anyone to find a major news story that didn’t quote Nissen.)

Nissen became the go-to guy on cardiovascular drug safety following his unauthorized meta-analysis of GlaxoSmithKline’s Avandia data. With Vyotrin, he adds the mantle of Dr. Efficacy. Here’s what he told NBC’s Today show: “It was a shocking result for the medical community, and it suggests that this mechanism of cholesterol lowering produced by Vytorin and Zetia is simply ineffective at providing any benefits to patients.”

It was comments like those that led to the anti-Merck and Schering “hysteria” on Wall Street, according to Sanford Bernstein analyst Tim Anderson. “In isolation,” Anderson says, “the results probably would have led to a share price rise for SGP and MRK, but largely due to negative comments from prominent cardiologist Steve Nissen, share prices declined.” (Well, either that or analysts underestimated, and continue to underestimate, how bad these results really are--particularly for Schering-Plough, and especially as those same analysts estimate that "about 70 percent of Schering’s earnings depend on Zetia and Vytorin," according to this morning's New York Times.)

Either way, the reaction confirms our belief that Steve Nissen has become a pretty powerful force, and why our colleague, Ramsey Baghdadi, labeled him as a “serial drug killer.” (For Ramsey’s profile of Nissen in The RPM Report, you can find it here. Those who aren’t yet subscribers can sign up for a free trial to read the story.)

There is an important distinction in Nissen’s role in Avandia and Vytorin: he isn’t taking down Vytorin with his own analysis, but using the visibility gained from Avandia to publicize what he sees as a drug that provides minimal efficacy. But given the sharp drop-off in Avandia prescriptions after Nissen got involved, you can guess where Vytorin and Zetia scripts may be headed—especially once AstraZeneca (Crestor) and Pfizer (Lipitor) start using the data in sales calls.

And finally, for those of you that thought the DTC advertising nightmare was somewhat over, think again. Here’s Nissen on Katie Couric’s “Eye to Eye” last night: “We see no evidence of benefit from this very heavily advertised, very heavily used medication.” If that's not an open invitation for more attention from Capitol Hill, we don't know what is.

Nissen Weighs in on ENHANCE

You know what he's going to say ...



Remind you of this?

ENHANCE Interrogation Technique

So what was our colleague Ramsey Baghdadi's "little birdie" talking about when s/he said to expect "something big" to get released this week?

Maybe it was yesterday's encore public throttling of Avandia in the Journal of the American Medical Association. That study concluded that older (age 66+) patients on Avandia had "an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other combination oral hypoglycemic agent treatments."

But we're not so sure--the sequel is rarely as good as the original, and why would anyone be whispering to a journalist about a study that was probably available on an embargoed basis anyway.

Perhaps instead our avian friend was referring to the latest chapter in the ENHANCE saga? Yesterday Schering-Plough's Fred Hassan and Merck's Dick Clark got some mail from the House Committee on Energy and Commerce, and it wasn't a Christmas card.

The letter, from committee chairman John Dingell (right) and subcommittee on oversight and investigations chair Bart Stupak, both Michigan Democrats, questions the companies' delay in releasing data from the ENHANCE study, which concluded in April 2006. ENHANCE was designed to compare the efficacy of Vytorin (ezetimibe [Zetia] plus simvastatin) and simvastatin alone.

Merck and Schering-Plough have five billion reasons to hope Vytorin does a better job of preventing plaque buildup in the arteries than now-generic simvastatin, and a combination of the significant and multiple delays in releasing data from the 720-patient trial, a delay in registering the trial with clinicaltrials.gov, and the apparent manipulation of the trial's primary endpoint drew the Congressional attention.

As the WSJ's Health Blog reports, both companies are still reviewing the letter and have yet to repond. For now, they say the data will be released at next March's American College of Cardiology meeting. Meanwhile, Dingell and Stupak contend the pharmas have some explaining to do.

But who knows, maybe that little birdie has something else up its sleeve.