While You Were Eating Beignets...

It's the first weekend in December and that means it's time once again for the American Society of Hematology meeting. This year, reps from biotech and pharma travel to N'awlins to make news--or at least issue press releases--before the last year of the first decade of the 21st century comes to a close.

And for the foodies/cultural mavens in the industry, how can you blame them? Where else can you indulge in chicory coffee, beignets (essentially fried dough, but the French makes it sounds waaaay better), and gumbo, while also soaking up the music scene?

If you weren't at ASH, you were likely debating the merits of football's popularity contest, aka the Bowl Championship Series, or Tim Tebow's oscar-winning performance after the Gators lost to Alabama. Or maybe you were engaged in that annual ritual now closely tied with propping up the national economy...filling recycled, reusable bags with unnecessary plastic items manufactured in China.

Away from food, footballs and rituals: this week's dealmaking got off to a healthy start, with Celgene announcing it was buying private firm Gloucester Pharmaceuticals for $340 million in cash, plus up to $300 million in future US and international regulatory milestones. The deal further strengthens Celgene's cancer franchise--more specifically, its blood cancer franchise--as Gloucester's romidepsin (Istodax), a histone deacetylase inhibitor, was approved by FDA in November for cutaneous T-cell lymphoma.

Not that Celgene's early Monday morning shopping should overshadow our hand-picked selection of the weekend events that happened while you were searching in vain for a $10 Zhu Zhu hamster... (Fuhgedabout it!)

New Yorker's Atul Gawande analyzes the current health care reform bill under review in the Senate. The fact that there is no grand master plan for curbing costs is actually a good thing, he argues. (If you haven't read Gawande's latest, you should. He's required reading in the West Wing.)

The WSJ reports Obama went to the Hill to urge the Dems to stay united as the Senate debated a proposed compromise option to the public plan. Meanwhile NYT's Prescriptions Health Blog outlines the advantages of a hybrid plan, the Federal Employees Health benefits Program.

There's lots for Sharfstein and Hamburg, the FDA's dynamic duo, to keep an eye on as they promote their safety first agenda. This weekend news surfaced that a Fresno, CA-based company recalled 22,723 ounds of ground beef potentially linked to salmonellosis; and then there was the NYT article on the safety of plasma products.

Also in the NYT this weekend, a story on the outsized pricing of cancer med Folotyn. The article is sure to spark renewed debate from payers about reimbursement for high priced meds that add just a few months of life. That's bad news for pharmas looking to cash-in on this specialty market.

ASH-related headlines: Cell Therapeutic's pixantrone increases median survival by 3.3 months in patients with relapsed/refractory NHL; Onyx/Proteolix presented updated Phase IIb data from studies of their next-generation proteosome inhibitor, carflizomib; privately-held Gloucester Pharmaceuticals presents additional data on newly approved ISTODAX in cutaneous T-cell lymphoma.

It wasn't just cancer at ASH; new data about next-generation blood thinners from Johnson & Johnson and Boehringer Ingelheim were reported at the meeting in conjunction with an article in the NEJM.

(Image by flickrer and[w] used with permission through a creative commons license.)

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.

FDA’s “Roadside Bombs” and “Insurgents”

“Roadside bombs” and “insurgents” aren’t typically found in FDA’s regulatory lexicon. But that’s how FDA’s former drug center director Carl Peck described the situation the agency finds itself in right now.

Peck, speaking at the Food and Drug Law Institute’s annual meeting March 27, was referring specifically to a study making headlines today in the New England Journal of Medicine. The study, authored by well-known Harvard researcher Daniel Carpenter, looked at new molecular entity approvals between 1950 to 2005 and found that drugs approved close to the prescription drug user fee deadline ran a higher risk of being withdrawn and receiving a “black box” warning compared to those drug approved earlier in the cycle.

“The conclusion is that drugs approved just before PDUFA deadlines are less safe than those approved well before,” Peck pointed out after a solid criticism of “ambitious politicians” and “media competing for sales-enhancing headlines” (the IN VIVO blog is obviously not shackled by this particular criticism since the blog is free…remember that, people).

More specifically, drugs approved two months before the PDUFA deadline carry a 5.5 excess risk of being withdrawn and a 4.4 excess risk of getting a “black box” warnings. To read the NEJM abstract, click here.

FDA isn’t taking this one sitting down.

“FDA has tried to confirm the numbers that are in that article and we have been unable to,” Center for Drug Evaluation & Research deputy director Douglas Throckmorton commented at the FDLI meeting. “The numbers we have gotten are considerably different.”

The Wall Street Journal first reported that FDA was sending a protest letter to NEJM related to the study findings. To read the story, click here. Throckmorton says the discrepancy between FDA figures and Carpenter’s figures aren’t negligible. “We need to know what those numbers really are before we try to interpret them and we have a group within the FDA that’s working to try to understand where that difference is because it’s considerable.”

Throckmorton also pointed out what everyone in the biotech and pharmaceutical industries already know: almost every single new drug approval occurs at or just before the user fee deadline date. “The small fraction of products that aren’t—it’s an important fraction to look at—but whether that’s a balanced representation of what we’re doing” is debatable.

The CDER deputy highlighted that this is one particular research question that has a “right answer” and isn’t up for interpretation.

In other words, this isn’t likely to be a study to go the route of Avandia and other drug safety issues that never produced a general consensus. Judging from Throckmorton’s comments, the agency appears confident that it has the right numbers, not the academics. If that’s the case, chalk one up to FDA. Finally.

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.

Avandia and Rezulin Redux

We told you about the dangerous parallels between GlaxoSmithKline's diabetes drug Avandia and Warner-Lambert's now-dead TZD Rezulin.

The New England Journal of Medicine has published a piece on making the same connection by Jerry Avorn, a Harvard Medical School professor. I think this quote from Avorn says it all on how he feels about FDA's advisory committee vote (almost unanimous) July 30 to keep Avandia on the market:

"The decision was more suggestive of Rezulin redux (and of Redux) than it was of resolve."

You all remember Redux don't you? To read the whole Avorn piece, click here. As always, your comments are welcome.