Good News for Amgen and J&J on EPO—but not for the Rest of Pharma

CMS: The Other Drug Safety Agency

Amgen and Johnson & Johnson got some good news when the Centers for Medicare & Medicaid Services finalized its proposed policy on coverage of erythropoietin stimulating agents (ESAs) in cancer patients. The final policy is about as good as it could be for the companies under the circumstances—much better than the agency originally proposed.

CMS agreed to continue to cover EPO in a number of important chemotherapy settings and also dropped some of the toughest dosing restrictions in the proposed policy. So the worst may be over for darbepoetin (Aranesp) and epoetin (Procrit) in the cancer market. Both Amgen and J&J reported sharp revenue declines for their respective brands during the quarter in response to safety concerns—and especially payment changes—but both expect growth to resume from the new, lower baseline.

CMS may have backed off from the most draconian aspects of its proposed limits on EPO coverage, but the agency is not backing off from the position that it does not have to defer to the Food & Drug Administration when it comes to responding to emerging drug safety issues.

In that sense, the final coverage policy is not a change from the agency’s initial proposal—and that is a message that the rest of the biopharmaceutical industry cannot afford to miss.

The RPM Report has written extensively about the activist role taken by CMS in the EPO safety debate. Simply put, there are now two agencies—FDA and CMS—that manufacturers have to consider when thinking about regulatory responses to drug safety issues.

CMS made it abundantly clear in the proposed EPO policy that it does not intend to wait for FDA to finalize its review of the safety issues before acting. And in the final policy, CMS is sticking to that position.

“CMS and FDA are separate agencies with different statutory missions, and operate under distinct legal authorities,” the final policy notes. “We are encouraged that the separate and independent analyses of the FDA and CMS have raised similar serious concerns about the use of ESA treatment in patients with cancer and related neoplastic conditions.”

“FDA deliberations are not public and their timeline for making changes (if any are made) in the labeling for ESAs is unknown. We believe the safety concerns that we have identified in this document required CMS to act quickly to protect beneficiaries.”

There are still plenty of regulatory hurdles ahead for ESAs. FDA hasn’t finalized labeling changes for EPO in response to the safety issues—and both FDA and CMS are just getting started on reviewing use of the agents in the renal failure market.

But one thing is clear: CMS is not going to take a back seat to FDA when safety issues arise.

Unusual Suspects: If Pfizer Decides to Really Rattle the R&D Cages

Yesterday, we listed a group of people -- we called them the usual suspects -- that we think Pfizer will try to woo if it ends up turning to an outsider to head up R&D. Today, we'll list some people who could do the job -- but you probably wouldn't think of them right away.

First off: Mark McLellan, former boss of FDA and CMS. The industry loves him; so do politicians. He was even relatively popular among the famously disgruntled FDA staff. But McLellan has just gotten huge funding for his Engelberg Center for Health Care Reform and, as Founding Director, he's not likely to abandon his post at what could be the center of US health policy.

Others qualify for the less-usual category because they’ve spent their careers in research, not development, and because they haven’t had the top R&D job. Michael Dohlsten who runs discovery for Boehringer Ingelheim. “A change agent,” says one recruiter. “He’s just that good.” Likewise, Allen Oliff, GlaxoSmithKline’s discovery boss. Or Marc Tessier-Lavigne, an academic for two decades before joining Genentech in 2003, now playing #2 in research to Richard Scheller.

Indeed, Tessier-Lavigne’s academic career is a particularly intriguing model for Pfizer. If Pfizer "wants to break the mold," says one recruiter, giving a scrub to its tarnished scientific self-image, why not go with an out-and-out academic – which is exactly what Merck and Novartis did in hiring, respectively, Peter Kim and Mark Fishman? Kim’s success at Merck certainly argues for the direction.

So in terms of an academic, why not…Pete Schultz of Scripps, also the director of the Genomics Institute of the Novartis Research Foundation, a prolific company creator (Affymax, Kalypsis, Syrrx and Ambrx, among others), and—by various accounts—intensely ambitious? Probably not—say headhunters: tough personality for a corporate job.

There are certainly a bunch of young research stars—though our headhunters were unwilling to give us their best ideas here. But there’s a problem for Pfizer with this route: Peter Kim was able to understudy for a few years with the previous R&D boss, Ed Scolnick. Tessier-Lavigne is understudying now. A new young academic joining Pfizer won’t have the same chance since LaMattina leaves in December -- and no internal candidate would want to take a temporary coaching job in the corner office.

So what do we think will happen?

Up to now, Kindler & Co. haven't strayed far from the corporate nest in replacing top commercial and business development management. So it's not likely they'll do anything different with R&D, particularly given the sales job they'll have to do to attract a really capable outsider. Our money's on the top internal candidate, Martin Mackay.

FDA Advisory Committee Votes to Keep Avandia on the Market

FDA's joint advisory committee voted (22-1) to keep GlaxoSmithKline's diabetes drug Avandia on the market with a black box warning for patients at higher cardiovascular risk. All the votes came with the caveat for stronger warnings.

But they voted 20-3 that Avandia increases the cardiac ischemic risk in type 2 diabetes. What an odd vote.

We don't think it means very much and that Avandia, for all intents and purposes, is dead. See our previous post below. What do you all think?

The Nail in the Coffin on Avandia

It doesn't matter what the committee votes now.

The final blow to GlaxoSmithKline's diabetes drug Avandia was not delivered by FDA whistleblower and director for science and medicine in the office of surveillance and epidemiology David Graham, although he gave the most persuasive presentation during the morning session of today's advisory committee meeting on the troubled product. It was his boss, drug safety director Gerald Dal Pan.

Graham gave the last presentation before lunch and predictably came to the conclusion that Avandia should be pulled from the market. He went through a detailed, half-hour talk explaining why he came to his conclusion, using a combination of results from long-term, placebo controlled studies, and meta-analyses to show rosiglitazone's benefits did not outweigh its cardiovascular risks.

"There is no evidence, none whatsoever, to support the benefits of rosiglitazone with these outcomes," Graham said refering to a host of cardiovascular adverse events including heart attack. He paralleled the Avandia situation to Warner-Lambert's Rezulin, saying it had cardiovascular risks other drugs (read Takeda's Actos) in the class did not have. Rezulin was pulled for showing fatal liver toxicities other drugs in the class did not have (read our earlier post).

Everyone expected that from Graham. But it was Dal Pan's endorsement of Graham's findings that effectively killed this drug, even if it does stay on the market with a black box warning. If Glaxo's legal team wasn't already in crisis management mode, they certainly will be now.

Dal Pan was noticeably reserved about the meta-analysis finding of a 43% increased risk of heart attack linked to Avandia during an early July Congressional House hearing. He was not ready at that point to make any determination on Avandia. Now, he has reached his conclusion: it should be pulled. The benefit/risk profile of Avandia "is not favorable" Dal Pan concluded.

Best case scenario for Glaxo, Graham says, is that Avandia was responsible for 40,000 excessive cardiovascular events in 6.5 years since 1999. Graham puts the real number at 80,000 excess cases. A real nightmare, if true.

Dal Pan gives credibility to Graham's findings that did not previously exist. The only reason the Office of Drug Safety did not make a formal withdrawal recommendation is that the whole drug safety team had not had a chance to review the analysis as of yet, according to Graham.

There is clearly a line in the sand between the Office of New Drugs and the Office of Surveillance and Epidemiology (drug safety) within FDA's Center for Drug Evaluation & Research. OND wants to keep it on the market, OSE wants it off. CDER office of drug evaluation II director Robert Meyer argued eloquently against Graham and Dal Pan's conclusions, adding that he himself had not decided on the appropriate "regulatory action."

But that doesn't mean much anymore. Whether or not it stays on the market, GSK's Avandia is dead.

Round Up the Usual Suspects: Who Will Run Pfizer R&D?

As soon as John LaMattina announced he was stepping down as head of the world’s largest pharmaceutical R&D organization, speculation over his successor bubbled over.

According to insiders, the top internal candidate is Martin Mackay, who spent most of his nearly 12 years at Pfizer on the discovery side; he’s only been running development since the beginning of the year.

But all the insiders and outsiders we spoke with think that Pfizer CEO Jeff Kindler will need to look externally, too (we understand he's using Spencer Stuart on the search).

Insider or outsider, however, he'll want someone who can straighten out the maze--cultural, bureaucratic, and physical--created from Pfizer's series of acquisitions. Not just the big ones, Warner-Lambert and Pharmacia, but also the myriad of biotechs, plus Pharmacia's acquisitions, too--many of which hadn't been fully integrated when Pfizer bought it.

Perhaps unsurprisingly, not a lot of names dropped from the trees we shook (mostly recruiters at a variety of white-shoe firms). “Who would want that job?” they chorused. Most obviously, Pfizer’s got an enormous challenge in replacing Lipitor in 2011 – a no-win situation, they said, even if the new guy creates the sleekest, best-looking R&D organization in the industry.

Or could there be a way out after all? We think maybe there could. Granted, if Vytorin and generic Zocor continue to munch away at Pfizer’s share of the statin business at the current rate, Pfizer could see $11 billion Lipitor turn into a $5 billion drug several years before patent expiration. In that case, Pfizer stock could reach the floor pretty soon. That's bad news for lots of employees (the layoff program will speed up) but it's good news for a new R&D chief (and his stock options): starting at the bottom is better than starting on a downward slope.

Plus, given all the corporate motivation provided by the loss of billions in revenue, the R&D boss would clearly be allowed to make some big changes--something that stymied previous R&D chiefs, in particular Peter Corr, who was pushed out of the job.

What's more, there are plenty of people who would simply love the ego boost that comes from managing a $7.4 billion budget.

So, we asked, which outsiders is Pfizer likely to approach? Our sources put them into two groups: the usual suspects and the less usual ones. In this post, we'll go through the former group. Tomorrow, we'll consider the less likely candidates.

Bob Ruffolo, Wyeth’s by-the-numbers R&D boss. He’s certainly shaken up the organization, but no one expects him to budge before he sees some of the fruits of his restructuring.

John Patterson, now a board member and head of development at AstraZeneca, the driver behind the effort to root out AZ’s nearly fatal NIH syndrome, and the architect of the industry’s most ambitious business development program.

Joerg Reinhardt, now CEO of Novartis Vaccines and Diagnostics, and the former development chief. But Reinhardt is joined at the hip with CEO Dan Vasella and probably will be his successor, say the jungle drums.

Jeff Leiden, former head of research and COO at Abbott, now a partner at Clarus Ventures (not, like the other senior folks at the fund, a "managing director" -- whatever that distinction means). Was a star academic physician (and a founder of several biotechs) before joining Abbott and would certainly add a start-up shine to Pfizer.

All of these folks would be relatively safe choices for Pfizer--execs with street cred. But Pfizer will need to do a terrific sales job to get any one of them.

While You Were in Springfield

D'oh! It's back to the daily grind. IN VIVO Blog picked up on a few stories you may have missed over the lazy summer weekend.

• Pretty soon they'll be putting it in the water. A couple pieces in the UK Guardian over the weekend about the potential fluoridization of statins in the UK. Followed up this morning, here, is the plan's downside.
  
• GPC Biotech continues to deal with the wake of its satraplatin review. Late Friday night the company reported the first class-action lawsuit it will face. And over the weekend Reuters reported that GPC's largest investor, SAP co-founder Dietmar Hopp, increased is stake in the company to more than 14% as its shares have slipped.
  
• A new use for those old pills. The AP reports on drug-disposal companies that can turn pharmaceuticals into energy.


• Finally, a big day for Avandia today ... more to come on the IN VIVO Blog.

Avandia and Rezulin: Parallels that Should Make GSK Nervous

History doesn’t repeat itself but it does rhyme. That old Mark Twain saying must be making GlaxoSmithKline sweat as Avandia is starting to look more and more like another Rezulin. By our reading of the tea leaves, Avandia is in much more peril than anyone seems to realize.

GSK is hunkering down for continuing assaults on its number two drug, battered initially by Cleveland Clinic’s Steve Nissen whose meta-analysis showed a 43% increase in heart attack risk for Avandia patients compared to control.

During the company's second quarter conference call, CEO JP Garnier clearly was using the "If you sound like a winner, you are a winner" strategy when it came to discussing Avandia with investors, analysts and media.

"We are still encouraged [about Avandia] because we have seen...a lot of evidence recently," Garnier said of the data GSK has submitted to the agency in advance of a Monday advisory committee fact-gathering meeting. "The evidence is supportive of Avandia's risk/benefit ratio, and of its effect on cardiovascular safety."

GSK is hyping a 400,000-patient epidemiology study of patients on Avandia and Takeda's Actos among other treatments that apparently bodes well for the diabetes drugs.

Glaxo has said that they simply have been unsuccesful in boiling down their message on Avandia to a "7-second soundbyte" which is the reason for the more than 45% decline in new Avandia scripts. " In the US, the media has ... had more of an impact on physician and patient impressions than the data itself," GSK's pharma operations chief David Stout said on the call.

Clearly, the message from GSK is: We stand behind Avandia. Unfortunately for the company, there are some discouraging parallels between their diabetes drug and Warner-Lambert's Rezulin.

Warner-Lambert pioneered the glitazone class, but Rezulin caused liver toxicity that ultimately led to its withdrawal. A recap of the regulatory history suggests some uncomfortable parallels with Avandia and the concerns about cardiovascular safety.

Two months after it got to market in 1997, FDA slapped Rezulin with a stricter warning on its packaging (thanks to 35 post-marketing reports of liver injury). At that point, 500,000 patients were already on the drug. Several "Dear Doctor" letters later, FDA's Endocrine and Metabolic Drugs Advisory Committee reviewed the liver tox issues, and recommended keeping Rezulin on the market, but only for patients not well-controlled on other diabetes drugs. One year later, the drug was taken off the market when reports kept coming in.

For Avandia, the toxicity is different--cardiovascular rather than liver--but the slow motion, repeated regulatory reactions are similar.

Avandia labeling was rewritten to strengthen cardiovascular safety warnings in 2001, and the company issued a "Dear Doctor" letter on the topic at that time. The concerns were raised more directly in the context of the review of Avandia for an indication for use with insulin; that use was ultimately approved in 2003. The Nissen paper now has put the regulatory machinery into fast forward, and an advisory committee will discuss Avandia's fate on Monday.

All of that is uncomfortable enough, but there is another parallel to the end of Rezulin emerging at the worst time for GSK: a Senate Committee is raising concerns that FDA reassigned a medical officer who wanted to put stronger warnings on Avandia.

If that sounds familiar, it should. In early March 2000, FDA senior medical officer Robert Misbin wrote a letter to Rep. Henry Waxman (D-Calif.) expressing frustration over FDA's handling of Misbin's attempts during the previous two months to convince the agency's Center for Drug Evaluation & Research that Rezulin had to be withdrawn from the market. Misbin asserted that FDA officials had stopped him from releasing information related to deaths of Rezulin patients.

One other thing: Misbin was the primary reviewer on Avandia and was taken off of the review several years ago. (Apparently, he's not the whistleblower this time around -- for more speculation on who the whistleblower might be, see the next post.)

All in all, Monday's advisory committee meeting doesn’t look good for Avandia. Even if the medical officers keep quiet, FDA will not be presenting a united front to the committee. That's because the agency is once again going to let its most prominent whistleblower, director for science and medicine in OSE David Graham, make a formal presentation. Graham most recently helped ensure that Merck's Arcoxia died a painful public death before an FDA advisory committee. FDA has apparently concluded that they have to let Graham speak at these meetings rather than wait for him to go to Congress to make his presentations. (Here is our coverage of the Arcoxia debacle.)

On Avandia, Graham has already made his position clear in FDA briefing documents. He argues that the current postmarketing studies (in particular the key RECORD study) can't, statistically, demonstrate a heart attack risk related to Avandia: they're underpowered. In other words, the current scientific evidence is all FDA is going to get to make their decision on the future of GSK's drug. Anyone want to venture a guess at where Graham will stand on Avandia?

And its not like FDA won't let the discussion go into whether the drug needs to be pulled. Quite the opposite. Here is one question posed to the committee: "Does the overall risk-benefit profile of Avandia support its continued marketing in the US (VOTE requested)? If yes, please comment on what FDA should do to maximize the risk-benefit considerations (e.g., limit to certain patients, incorporate a boxed warning….)"

That question means FDA is thinking awfully hard about whether this drug should stay on the market. You could argue that they added the question for political cover in order to leave it on the market, but I'm not buying it. I think they really want to know the experts' opinion.
And what will that opinion be? Nissen himself has said Avandia should remain on pharmacy shelves. NIH's Malozowski told us that he didn’t think FDA would pull it. “They will probably add a warning for a subpopulation of patients and a contraindication for its use with insulin."

I also asked Tom Garvey, a former FDA reviewer who runs his own drug development consulting business, what he thought. He concurs with Malozowski. Sort of.

Rezulin could be pulled off the market with less risk, he argued, because there were two other marketed drugs without Rezulin’s liabilities. Moreover, "the absolute risk found by Nissen is small (if, indeed, it exists) and the benefit conferred by Avandia is not inconsequential, especially in certain types of type II diabetics.”

But then he added, surprisingly: “All of this having been said, I too get the sense that the drug is probably doomed."

In short, as with Rezulin, an FDA advisory committee could recommend keeping Avandia on the market, in a limited way—while, in parallel, the political and historical momentum builds to yank it off. On the scientific front, the data isn’t clear. Nissen's meta-analysis has come under intense fire, but his results were confirmed by FDA's own meta-analysis, and they had access to a much larger data set. Meanwhile, GSK's RECORD study has been inconclusive on the heart attack risk question.

But the political front will evolve in its own way. And if history really is rhyming, if not precisely repeating itself, FDA will have a hard time keeping Avandia on the market.

So Who Is the Avandia Whistleblower?

The Senate Finance Committee loves FDA whistleblowers. And it sounds like they have found another one as part of their investigation of the review of GlaxoSmithKline's diabetes drug Avandia.

In a July 24 letter from Senate Finance Committee leadership to FDA, Chairman Max Baucus (D-Mont.) and Chuck Grassley (R-Iowa) reference a primary reviewer that was taken off the Avandia review for voicing safety concerns about the drug.

Previously it was revealed that the former Deputy Director of the Division of Drug Risk Evaluation in the Office of Surveillance and Epidemiology (OSE) Rosemary Johann-Liang, who recently left the agency, had been verbally reprimanded for recommending that a black box for congestive heart failure be placed on Avandia. Now Baucus and Grassley allege a second reviewer was taken off the review.

"During a recent interview with Finance Committee staff," their letter says, "a senior medical officer in the Office of New Drugs (OND), who at one point was the primary reviewer for Avandia, told staff investigators that s/he was told to stop participation in the review of potential cardiovascular safety problems associated with Avandia. Since 2005, the senior medical officer believed that there was enough evidence to support a black box warning regarding the risk of CHF."

Who's the whistleblower? We first spoke with Robert Misbin, a primary reviewer on Avandia and Bristol-Myers Squibb/Merck's developmental/dead diabetes drug muraglitazar (Pargluva). Misbin was a whistleblower on the first glitazone, Warner-Lambert's withdrawn Rezulin. Is he the reviewer in the letter? "I don't think it's me," he told us. The Senate Finance Committee also says it's not him.

That is a bit of a head scratcher. Misbin sure sounds like the guy, based on the Finance Committee's description of the reviewer as having six years of experience with the class. Misbin supported approval of the drug, but noted his concerns about cardiovascular safety at the time. And he was taken off the Avandia review--but not in 2005. That happened in 2002.

Next, we talked with former Avandia primary reviewer Saul Malozowski, now a senior advisor on endocrine physiology in NIH's National Institute of Diabetes and Digestive and Kidney Diseases, who left FDA in 2001. "Nobody under my direct supervision was ever removed from any task in either Avandia or other drugs," he said via email. "I hope you have access to my review of this drug where I underscored the potential pitfalls in the documentation provided and the dangers that patients with cardiac condition could encounter. I also was concerned about the weight gain." So he wasn’t the whistleblower either.

The only other person suggested to us as a possibility is Johanna Zawadzki, who still is a medical officer at the agency in the metabolic and endocrine division and worked on the Avandia review. But even the person who mentioned her as a possibility doesn't think she matches the description in the Finance Committee letter. We were unable to get Zawadzki on the phone.

So who is it? Any guesses??

Sometimes the Bear Gets You: Idenix Pharmaceuticals Edition

Idenix Pharmaceuticals announced this morning that FDA had placed a clinical hold on its Phase II valopicitabine hepatitis C polymerase inhibitor.

FDA made its decision following an assessment of the overall risk benefit profile observed in clinical rials to date, according to Idenix CEO JP Sommadossi, who addressed analysts on a conference call today. "We were very surprised," he said, adding that along with its partner Novartis, Idenix is evaluating its options. "But i am not optimistic about further development of valopicitabine in the future," Sommadossi added, and later re-emphasized.

So what happened? "FDA looked at all of the Phase IIB data ... and concluded that the GI side effect profile was not commensurate with the antiviral activity we were seeing," said Doug Mayers, CMO. Idenix, the executives said, had seen similar signals such as nausea and vomiting, but were eager to play with the doses of valopicitabine in further trials in an attempt to find a workable risk/benefit profile. FDA had different ideas.

Valopicitabine, previously dubbed NM283, was the furthest-along HCV polymerase inhibitor in clinical development and the first of a next-generation set of targeted HCV therapies. The polymerase class hasn't received as much attention as HCV protease inhibitors, which have been the subject of some pretty sizeable deals--Vertex's alliance with Johnson & Johnson and Intermune's alliance with Roche, for example. But Idenix had maintained that the future of HCV antiviral therapy would be combination, a sentiment shared by many, and so pushed ahead with development despite only moderate clinical success with the compound.

The biotech's partner Novartis must have agreed; the companies have a broad alliance whereby Novartis gets first right of refusal on any Idenix compound when it hits Phase II. For valopicitabine, Novartis had to pony up more than half a billion dollars to maintain its share of the drug. Novartis owns upwards of 57% of Idenix.

Today's news is the second clinical hold placed on a Novartis-in-licensed HCV candidate this year. Last summer FDA halted trials of Anadys' ANA975 drug, a TLR-7 agonist in Phase Ib, after a preclinical toxicology study unearthed a potential safety signal.

HCV dealmaking has definitely been a hot space, and will likely continue to be so despite this spate of clinical difficulties. For our roundup of drugs in development for HCV, see this late-2005 IN VIVO story.

UPDATE: Idenix shares are off about two bucks, or 35%, at about 11:30a.