Tuesday, July 31, 2007

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.

Monday, July 30, 2007

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.

Friday, July 27, 2007

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??

Sorry, I Still Don’t Get It

Pfizer launched its first TV campaign for Exubera this past week in an attempt to breathe a little life into the stalled inhaled insulin brand. And with just $4 million in quarterly sales after 18 months on the market, Exubera needs all the help it can get.

But will the “Now I Get It” campaign be enough to put Exubera on a faster track? As we pointed out in an IN VIVO article in May, Exubera has some pretty major marketing hurdles: 1) it’s not clear that inhaled insulin is any more effective than the injectable stuff; and 2) there’s that pesky long-term pulmonary safety signal.

But perhaps the biggest hurdle is the size of the inhalation device. As big as a can of tennis balls, it’s not exactly something you’d like to whip out at a restaurant. Pfizer tries to dispel that notion in the commercial: a man is shown holding and closing the device while having a meal with a friend—but in such a way as to disguise the actual size of the thing.

The size problem isn’t new: as reported by The RPM Report, during FDA’s 2005 advisory committee review of Exubera, one panelist noted that despite the increase in “metrosexuals carrying purses,” the inconvenience of carrying the device may actually prevent patients from complying with their treatment regimen. Embarrassment also may be a factor: as the Pharma Marketing Blog points out, the inhaler looks like a large bong.

It’s also interesting to note that the commercial doesn’t ever discuss the convenience factor of inhaled insulin—in fact, the word “needle” is never uttered. But maybe that’s because for the majority of patients, inhaled insulin can’t replace injections. Instead, Pfizer sells Exubera as a treatment to help control blood sugar levels.

Inhaled insulin should be an easier sell, and with a number of other inhaled insulin products coming down the pike (all with smaller inhalation devices), Pfizer is running out of time. It’s a slick commercial, but it’s doubtful that the introduction of DTC ads for Exubera will help Pfizer overcome device envy.

But hey, don’t take our word for it: judge for yourself. To see a clip of the broadcast ad, click here, and tell us what you think.

Thursday, July 26, 2007

Merger Vaults Peripherals To Bigger Stage

Half a decade ago, the peripheral vasculature market was a clinical backwater for most cardiovascular device companies, who were more interested in the larger, more dynamic coronary area.

Now, the peripheral vasculature market is going Big Time.

This week’s merger of ev3 and FoxHollow Technologies reflects a new optimistic view of this space. The deal creates the largest peripheral vascular device company, one with a market cap of $1.7 billion on sales of around $600 million. But more importantly this combination establishes a single leader to push the peripheral market forward.

There is an irony to the success that both FoxHollow and ev3 have enjoyed in the peripheral market. Like other cardiovascular companies developing peripheral products, both Fox Hollow and ev3 were founded to focus on coronary applications, and only after finding that challenge to be too great did they eventually find their primary success in the peripherals.

FoxHollow’s success, in fact, is built on a technology—atherectomy—that has largely been shunted aside in the coronaries by the success of stents. The technology’s growing peripheral adoption is a vindication of sorts for company founder and current CEO John Simpson, PhD, MD, an angioplasty pioneer, who has long advocated that restenosis is best treated by taking the plaque out, not by putting a stent in.

Indeed, FoxHollow’s rapid growth, particularly as a public company, did much to change the thinking among CV device companies about the value of the peripheral market, while also reviving atherectomy: witness the emergence of new peripheral atherectomy players such as Cardiovascular Systems and Pathway Medical. Though FoxHollow’s market cap is no longer north of $1 billion, adoption of its technology remains strong, creating a compelling basis for this deal.

As successful as each was on its own, both companies were feeling the pressure to offer more broad-based product lines.

The ability to link atherectomy systems with ev3’s line of innovative stents and embolic protection devices potentially solves FoxHollow’s problem of being a one-product company and ev3’s issue of lacking a market-leading product. (FoxHollow does have an innovative service-based relationship with the drug company Merck, but that alliance does little to shore up its business with peripheral specialists.)

Indeed, the merger represents the logical conclusion of a product development and distribution collaboration the two companies initiated this past January linking ev3’s embolic protection device with FoxHollow’s atherectomysystem, (and discussed in a profile of ev3 that appeared this past February in IN VIVO).

For both companies, however, the collaboration was as much about market development as technology enhancement. As FoxHollow’s atherectomy technology evolved and the company’s ability to remove plaque grew more precise, it could expand the number and type of cases it treated, but in the process, issues regarding the potential need for embolic protection naturally surfaced. For ev3, the FoxHollow deal opened the door to take a technology, embolic protection, that had been used primarily in the coronary and carotid arteries and develop it for peripheral applications. Combining with ev3 should also help FoxHollow expand in Europe, where ev3 has a strong distribution platform and FoxHollow hardly any at all.

As the peripheral opportunity moves from the wings to center stage, this deal begs the question: won’t big CV device companies, particularly Medtronic and Abbott, who currently lack peripheral (non-carotid) vascular plays, see the same kind of opportunity in FoxHollow that ev3 prizes? But if breadth of product offering and, more importantly, a development effort focused on peripherals are important, it may make even more sense for the Medtronics and Abbotts and any other interested parties to let this deal close since a combined ev3/FoxHollow may be even more valuable to them down the road.

Evista Update

Lilly's response to my questions about the Evista press release (subject of a July 25 post):

"Following the July 24 meeting of the Oncologic Drugs Advisory Committee (ODAC), Lilly issued a press release containing factual information about the meeting’s outcome pertaining to Lilly’s osteoporosis drug.

'We believe that our actions were consistent with the laws and the consent decree,' said Anne Nobles, Vice President, Compliance and Enterprise Risk Management. 'Lilly takes very seriously our responsibility to abide by all the laws governing our business practices and are committed to ensuring our employees' actions reflect the highest legal and ethical standards of conduct.'"

Schwan Song

Roche’s announcement that Severin Schwan, the head of its Diagnostics division, is set to succeed Franz Humer as CEO of the Roche Group next March came just hours after we’d filed a story for the upcoming issue of IN VIVO looking at Roche’s recent acquisitions, including its ongoing $3 billion hostile tender offer for anatomic pathology specialist Ventana Medical Systems. Given his recent history in diagnostics, the Schwan news would’ve made an excellent punch line to the article, which talks about the firm’s belief in diagnostics and its bet that personalized medicine--an area where innovative platforms and molecular test content will play significant if separate roles—will be key to its long-term growth.

This past Monday, the IN VIVO Blog also cited a rumor that Novartis could be grooming Joerg Reinhardt, the head of its vaccines and diagnostics businesses, as successor to CEO Dan Vasella.

Is it a coincidence that both firms are turning to Dx veterans? Novartis doesn’t have an in vitro diagnostics business anything like the scope of Roche’s, nor does it have a life sciences research tools unit. But Novartis knows blood banking, to which it has applied a nucleic-acid test (NAT) based platform for virology testing. And like Roche, Novartis has a significant investment in targeted cancer therapies, for which companion diagnostics are assumed to play a vital part. (Ventana, for example, markets a molecular test to gauge patients’ potential to respond to Novartis’ Gleevec).

So maybe it's a good time to examine Roche’s strategy.

Unlike other Big Pharmas (including Novartis), Roche has dedicated itself to the in-house development of companion tests. Its molecular diagnostics unit has developed know-how around adapting microarray technology to clinical diagnostics--one of the most complex aspects of the approval process for drug-diagnostic tandems--via a series of collaborations with Affymetrix, leading to tests for mutations in the p450 and cystic fibrosis genes. Roche is applying the same tools to developing its own drugs, including a p53 diagnostic for a cancer drug that binds wild type p53. And before Roche took rights to Plexxikon’s PLX4032 cancer program, which inhibits a gene mutation present in roughly two-thirds of melanomas, the two companies had begun a diagnostics collaboration around a molecular test for the mutation. Indeed, one reason Roche paid so much for the Plexxikon compound was that the companion diagnostic could dramatically expand its market into solid tumors by targeting the same mutation in those far more common cancers.

Roche has the free cash to invest in its diagnostics businesses and is clearly aiming at personalized medicine as a principal way to bolster them long term – and importantly, also support the development of targeted drugs on its pharmaceutical side. On the conference call discussing the Ventana tender offer Schwan said flatly that Roche wants it for strategic reasons relating to its drug business. The Ventana deal “is very much driven by the synergies we have on the R&D side, by the development of targeted medicines. The real value is that we can leverage the different capabilities across the entire Roche Group,” he said. “The earlier you start the exchange of ideas between pharma research and diagnostics, the better chance you have to come in parallel with the development of a companion diagnostic,” added Roche CFO Erich Hunziker.

It’s long been held that pharma holds all the leverage when it comes to drug-diagnostics partnerships. But the demand for innovative test content to run on molecular diagnostics platforms is increasing: witness the recent upswing in deal-making, along with renewed VC interest in diagnostics. It suggests that the area's potential to drive health-care innovation by directing therapy more efficiently is finally being recognized. Even Abbott Labs noted this when, in the wake of the breakup of GE Healthcare’s bid to acquire Abbott's diagnostics businesses, Ed Michael, Abbott’s newly appointed head of diagnostics, commented to us that there are synergies between all of its diagnostics divisions--especially between the molecular and point-of-care testing businesses.

So if pharma companies truly believe in the vision – and more to the point, the necessity -- of personalized medicine, and if the development of tandem drug-diagnostic combos is best started early in development, it makes sense they’d want their senior executives to have hands-on experience with the ins and outs of diagnostics development. Finally.

Wednesday, July 25, 2007

Even Cancer Ain't Exempt

No drug is exempt from FDA’s ultra-conservative stand, it seems, even those, like GPC Biotech’s satraplatin (Orplatna), that allegedly improve survival among cancer patients with few if any treatment alternatives.

An oncology advisory committee (ODAC) yesterday recommended that FDA delay considering prostate cancer candidate satraplatin for approval until overall survival data from the company’s 950-patient SPARC study is available. This recommendation came despite interim analysis strongly supporting the efficacy and safety of satraplatin, which was granted priority FDA review in April 2007.

Still, it wasn’t a complete surprise, at least since the rather negative FDA briefing documents released last week. These raised five “issues” including questions over the company’s assessment of pain progression, and, more importantly, over the definition and composition of one of GPC’s two key primary end-points used in the trial, progression free survival (PFS).

According to GPC’s “greatly disappointed” CEO Bernd Seizinger, GPC had communicated intensively with FDA throughout the application process and amended various aspects of the trials in accordance with FDA suggestions—including suggestions on what pain score to use. In sum, they’d done everything possible to make this work. (Listen for yourselves here.)

But FDA wasn’t having it. According to one analyst, “GPC walked into a complete stitch-up—FDA primed the advisory committee that they didn’t want this to happen.” Reading the briefing document, we’re inclined to agree.

Now, sources tell IN VIVO Blog that there’s no love lost between GPC and FDA—the ODAC meeting was “hostile and antagonistic,” according to one observer. Combine this with FDA’s overall caution (the last thing they want is to be hauled in front of the Senate for injudicious approvals) and you have a recipe for delay, if only temporary.

Still, GPC isn’t just an innocent victim here. Let’s go back to that issue of end-points. The briefing documents state that FDA had all along warned GPC that a PFS end-point may be problematic. Yet GPC failed to communicate this concern to the investment community.

That’s why analysts are so pissed—many had buy ratings on the stock, even after the review documents were released last Thursday. GPC shares fell 35% back then, and about the same again today. “Trust has been lost,” says one in London. “When it comes to the investment community, GPC are on their own.” (They can sulk in a corner beside Sanofi Aventis, which hasn't won any prizes for transparency among the investment community either, particularly with regard to Zimulti's rocky ride, on which we've reported extensively, including here.)

It’s a worrying time for the German biotech. All of a sudden, the overall survival data for satraplatin—which is the other primary end-point, alongside PFS--has become a make-or-break issue for the company. If it’s positive, the drug will probably still make it, although not in an accelerated fashion. If it’s not, the drug may not get onto the US market at all—which could prove fatal for GPC.

The rest of the sector has cause for concern, too, though (not to mention androgen-independent prostate cancer patients that have failed first-line therapy). This bleak little episode—besides showing up personal clashes between applicants and the agency, which, it seems, do matter—may mean that regulators’ caution is spreading beyond primary-care drugs like Avandia or the Cox-2s, where the main concern is safety.

Today, it seems, the tough hurdles can come from anywhere--including from non-safety-related issues like how pain is measured. Some might call this nit-picking.

Lilly’s Evista for Breast Cancer Prevention: Vindication or Provocation?

It looks like Eli Lilly & Co.’s raloxifene Evista is poised for approval for reduction of the risk of breast cancer. A Food & Drug Administration advisory committee voted yesterday to support use of the drug for that use in post-menopausal women at high risk of breast cancer, and—more narrowly—to support use for breast cancer prevention in post-menopausal women with osteoporosis.

The agency itself has until September to make a decision on Lilly’s pending supplemental FDA. But all signs point to an approval that, whatever else it means, will feel like vindication for Lilly.

Just 18 months ago, the company paid $36 million to settle an investigation into its promotion of Evista. The drug has been approved for use in osteoporosis for a decade. But in 2005 Lilly pled guilty to a criminal misdemeanor charge that it promoted the drug for breast cancer prevention and cardiovascular risk reduction. The conduct involved occurred in 1998; the company simultaneously settled related civil claims dealing with conduct that continued into 2000, but Lilly did not admit guilt.

In addition to paying the fine, Lilly entered into a consent decree prohibiting it from promoting Evista for breast cancer prevention without formal FDA approval.

Not that you would know that from reading Lilly’s press release announcing the advisory committee vote. Underneath a headline announcing the advisory committee vote, Lilly includes what starts out sounding like a disclaimer but ends up sounding like a claim of effectiveness for the new use: “EVISTA is currently indicated for the prevention and treatment of osteoporosis and may provide an important option for postmenopausal women at increased risk for breast cancer.”

Now that sentence is surely unobjectionable on its face. But it definitely counts as bold talk from a company that just signed a court order saying it is “permanently enjoined from directly or indirectly promoting Evista for use in preventing or reducing the risk of breast cancer…unless and until it is authorized to do so by the FDA by the approval of a supplement to the New Drug Application for Evista.”

Especially when you consider that the DoJ investigation included, among other allegations, claims that Lilly promoted the off-label use through its press releases about Evista. (Read the Justice Department’s summary of Lilly’s conduct here.)

Of course, the consent decree includes other provisions, notably one stating that “nothing in this Decree shall be construed to limit or expand the rights of Eli Lilly under the First Amendment of the Constitution.”

When it comes to off-label promotion, that is precisely the question: what are the rights of drug companies like Eli Lilly under the Constitution? Free speech advocates argue that companies have the right to engage in scientific discourse about their products, even if they are talking about uses not approved by FDA. After all, if raloxifene works to prevent breast cancer, millions of women would benefit from knowing that as soon as possible.

Prosecutors see it differently: the FD&C Act prohibits promotion of unapproved uses of drugs, and they have gone after many companies for promoting their drugs beyond the label. There have been several recent settlements (with the Evista case one of the first) in which manufacturers have accepted that premise—explicitly or implicitly—rather than fight the charges in court.

In our next issue, The RPM Report will be taking an in-depth look at the current state of uncertainty in industry after the recent wave of settlements.

As the advisory committee vote indicates, Lilly’s statement that Evista “may be an important option for post-menopausal women at increased risk for breast cancer” is undeniably true. But it was undeniably true a decade ago too. And that didn't keep Lilly out of trouble.

Now, here’s a thought: Johnson & Johnson made headlines recently when it offered a money back guarantee to the UK National Health Service on its cancer therapy Velcade, promising to pay back the government if the therapy doesn’t prove cost effective.

Maybe Eli Lilly & Co. should take a page from that playbook. But instead of offering a refund to the US government, maybe Lilly should ask for its money back from the Department of Justice. Justice.

Tuesday, July 24, 2007

Dissin' Steve Nissen?

The New York Times ran an interesting profile of the Cleveland Clinic's Steve Nissen on Sunday in light of his "controversial" meta-analysis finding over a 40% increased risk of heart attack for diabetes patients on GlaxoSmithKline's drug Avandia.

I interviewed Dr. Nissen a few months ago. Check out our July issue of The RPM Report called "Inside the Mind of a Serial Drug Killer" to find out what makes him go, what would make him stop and what he thinks is driving some members of Congress to criticize his efforts. Note, the Times may have higher circulation than The RPM Report , but we had the better headline.

But don't take our word for it. Here are a couple of excerpts:

The RPM Report: What would make you stop doing this type of work in the area of drug safety?

Nissen: It is all of our jobs, not just the FDA’s job to do this. Those of us in the physician community owe it to our patients to give equal balance and weight to positive and negative findings about drugs, and so should the FDA. Even if the FDA were doing an outstanding job, it’s still the responsibility of independent scientists to do these sorts of things, so it really isn’t about the FDA.

The RPM Report: So creating two drug centers—one for premarket review and one for postmarket surveillance—would not stop you from doing this kind of research. You feel this is a moral obligation.

Nissen: It is a moral and ethical obligation; it’s just about good science, it’s a scientific obligation. Science is about pursuing the truth and wherever that leads you. If we had very, very good regulatory agencies looking after this, there may be fewer opportunities to turn these things up.

How did we find out about fen-phen? There was an independent group of physicians that began seeing fen-phen patients with valve abnormalities. They said, “Oh my God, this is a potentially serious problem, let’s publish it,” and they did a great thing, they probably saved a lot of lives; they’re heroes.

The RPM Report: Why is there such a visceral reaction to you and the research you are doing? FDA’s meta-analysis of Avandia studies showed similar findings as your meta-analysis.

Nissen: Right. Part of the problem is this is not about me. One of the issues is sometimes when you don’t like the message; it’s easier to attack the messenger. It’s to be expected, but we’ve got to keep everyone focused on the science. I was very restrained in that [Avandia] hearing, I didn’t attack back. I simply said: this is what we did, this why we did it, this is why it’s important, and I’m going to stay on that message because it’s the right thing to do.

The RPM Report: Rep. Darrell Issa (R-Calif.) seemed particularly unnerved by your analysis and the process you took to get it published?

Nissen: He was wrong about the statistics, you cannot calculate an effect size if there are no events [studies with no heart attack events were excluded from Nissen’s meta-analysis]. He had been briefed by people giving him campaign contributions and that happens to be GSK. I looked it up. The three people on the attack at the hearing were very heavy recipients of GSK campaign money.

For the rest of the interview, subscribe to The RPM Report. Also, Nissen will be speaking at our annual FDA/CMS Summit in December in Washington, D.C. in case you want to hear him in person.

Speaking of Avandia, there is a July 30 fact-gathering meeting between FDA and Glaxo (Takeda, which markets Actos, is an invited guest) regarding the cardiovascular profile of the diabetes drug. While something conclusive could come out of that meeting, it's highly doubtful. So we'll just have to wait and see whether Nissen and his meta-analysis are vindicated for finding risks that hadn't been previously uncovered or his findings were rushed, sloppy and wrong. Stay tuned. It could be a while.

Monday, July 23, 2007

Confused Communications

I suppose it’s tempting to try to spice up the news during slow summer months. But Northwest Biotherapeutics should have known better than to issue a press release earlier this month declaring its delight in being “the first company to reach the market with a personalized therapeutic vaccine for brain cancer.”

The release stated that Switzerland’s Institute of Public Health had issued an Authorization for Use for the product. Exciting news, it seemed. The wires and papers picked it up. Even VCs and analysts were fooled--London-based house brokers Collins Stewart issued a report that talked about “history in the making”, with this first approval for “a new class of product called personalized vaccines.” This, the analyst said, was a “high value event.”

So in flocked the investors—Northwest’s stock, listed on the OTC bulletin board in the US and on London’s AIM since June this year, more than tripled.

Trouble is, it wasn’t an approval at all. The ‘news’ was an import-export authorization for the product in Switzerland, and one with conditions attached, which the company is still fulfilling. Northwest won’t seek product approvals in the US and EU before 2009.

All of this was clarified in a release issued a week later (why not clarify it properly in the first one?) prompting the stock to fall back to where it started.

Now, we’re not saying Northwest set out to deceive or confuse—you can judge that one for yourself. But we are saying that positioning an import-export order as equivalent to “reaching the market”—which is what Northwest did—is just silly. And suggesting, as the second release did, that the media is to blame isn’t very clever either.

Yes, cancer vaccines are indeed an exciting, promising area where a handful of companies may be on the cusp of a breakthrough. (Dendreon’s Phase III Provenge, an active cellular immunotherapy treatment for prostate cancer, received an approvable letter from FDA in May 2007.)

But the sector already has to battle with the disappointment caused by over-optimistic mainstream press reports about cures for cancer and Parkinson’s disease being around the corner. It doesn’t need its own members fuelling that fire. Nor does it need another report of misleading behavior, whether in promotional activities or in corporate communications.

Northwest has come back from the edge once already—it was saved by VC fund Toucan Capital after bombing out following its December 2001 Nasdaq listing. This episode won’t reassure its new investors. It wouldn't be surprising at all if the SEC took a long look at the announcements, given the share price movements. Nor will it help anyone else in the space, either—least of all the brain cancer patients with only a handful of inadequate treatments currently available to them.

While You Were Moving to Higher Ground

Ah, England in summertime.

For our UK readers, we hope you avoided the flooding. Here are a few stories you may have missed whether you were evacuating or simply focused on the last Harry Potter ...
  • And then there was one. Of Europe's five big pharma, only Novartis' Dan Vasella will have survived as CEO by next summer, Reuters reports. Roche's recent decision to replace Franz Humer at CEO with Severin Schwan may also put pressure on Novartis to likewise split its chairman/CEO positions. Word on the street is that Vasella may groom vaccines head Joerg Reinhardt as a successor.
  • They grow up so fast. Tysabri turns one today, sort of. The MS therapy returned to the US market one year ago. Elan and Biogen Idec estimate 14,000 patients receive the infused treatment.
  • The quick brown fox jumps over the lazy catheter (or something like that). EV3 is buying Fox Hollow for $780 million in cash and stock. The companies have been working together in peripheral artery disease since early 2007. More to come on this story.
  • And the New York Times profiles the Cleveland Clinic's Steve Nissen. Naderesque? OK, maybe consumer rights crusader Nader, not election swaying Nader.

Friday, July 20, 2007

Inverness' String of "I do's"

Inverness Medical Innovations certainly has no problems with commitment.

The Waltham, Mass-based diagnostics company—still in the process of integrating Biosite Inc., for which it paid $1.6 billion—grabbed a 51% stake in Diamics Inc., developer of a molecular based cervical cancer diagnostic.

The privately held Diamics took considerably less bling, requiring roughly $6 million in a staged investment, according to a release on the deal. But still it goes to show the Inverness isn’t allowing the megamerger with Biosite to take its eyes off the prize of building a broad portfolio of diagnostics the ole' fashion way--buying them. (By our count, this is number nine--or 8.51 if you consider the equity stake.)

While the Biosite deal (as well as the pending acquisition of Cholestech Corp.) gives Inverness’ cardiovascular practice a significant boost, (for an overview on Inverness check out your July IN VIVO), the Diamics deal falls closer to Inverness’ roots—women’s health care. Diamics is developing “a line of products designed to improve the effectiveness of cervical cancer screening and make the procedures less painful for patients,” according to the release. For a full profile on the company, check out last October’s START-UP Magazine.

Although Wall Street analysts say they don’t expect Inverness to make any major purchases in the future, the company has the firepower and desire to continue inking deals like this one.

Thursday, July 19, 2007

Adimab gets backed by Polaris and SVLS

IN VIVO Blog has learned that Tillman Gerngross, professor at Dartmouth and the founder of GlycoFi (and part of the brains behind that company's yeasty glycoengineering platform), and Dane Wittrup of MIT (who has pioneered the use of yeast for displaying libraries of antibodies and ab fragments) have started up a new antibody play with lead backing from SV Life Sciences and Polaris Venture Partners, called Adimab.

Gerngross tells us that the concept behind Adimab stems from the financial and organizational hassles that Big Pharma must endure to bring the necessary continuum of antibody-related know-how in house. The process, from soup to nuts, requires a host of technologies often licensed from disparate sources. "They need to have deals to get display technology, affinity maturation technology, protein expression technology, you need to line up a long series of technologies, and wind up with a royalty stacking issue and a very complicated set of relationships," he says.

Adimab--which stands for Antibody Discovery Maturation Biomanufacturing--is developing a platform that's deliberately engineered to minimize and potentially eliminate third party royalties, offering a one-stop-service-shop to a select few Big Pharma partners.

Gerngross declines to get into specifics of IP, and though he admits that it's complicated, he remains convinced that Adimab has found a way to engineer a technically superior and economically favorable approach to antibody discovery. Sticking to one system, yeast, should allow Adimab to move more quickly from discovery through antibody selection, he says.

"We're not pretending to be the only ones in this space," Gerngross says. "But we're building a business that will service pharma better than anyone else and on that could very quickly trigger an acquisition."

Adimab's as-yet announced Series A will bring in roughly $6.2 million to get the ball rolling. Its backers--which happen to be those same VCs that got behind GlycoFi from that company's outset--are aiming for another GlycoFi-like return: VCs invested a total of about $35 million since 2000 in that company, which Merck bought last year for $400 million.

We'll have more on the newco in the next START-UP.

Hillary Clinton's FDA

Slow summer so far. Not a lot going on. Washington is ready to go on its August hibernation. So I thought I would drop this quick note to jumpstart some watercooler talk before everyone goes to the beach.

Democrats are champing at the bit at their chances of regaining the White House in 2008. While there will be trench warfare over Medicare Part D drug prices and universal healthcare, one area that's sure to change (I'm not going out on a limb here) is personnel.

While the candidates themselves probably don't have a clear idea of who they would choose to lead key government agencies, they at least know who they like and who they trust on certain public policy issues.

Therefore, I found it interesting to see who Hillary Clinton had standing beside her during a campaign appearance "block party" in Washington, D.C. in June. It was Susan Wood, former women's health head at FDA, who resigned from the agency in protest over the delay in approving the switch of the morning-after pill from prescription to OTC. Wood stood next to Clinton, along with many other prominent women, including former Secretary of State Madeline Albright, during the outdoor event, which took place in the heart of downtown. Wood has not been shy about her support for Clinton. And neither has Clinton been shy in her support for Wood. During FDA Commissioner Andrew von Eschenbach's confirmation hearing before the Senate Health Committee, Clinton singled out Wood, in attendance, for her courage in resigning her post over the morning-after pill.

Wood is now a research professor at the George Washington University School of Public Health and Health Services. Under President Hillary Clinton, would Wood go back to FDA? Would she consider the job of commissioner if Clinton calls her to duty? I asked her.

"The first is easy, I truly enjoyed working in government health policy for 15 years, and so would be happy to come back to FDA in the future if an opportunity ever arose," Wood said via email. "I haven't ever considered the second one, and it is so hypothetical I don't know how to answer it, sorry." I bet I know what she would answer to the second question, and it's this.

I wonder how the drug industry would react to a Susan Wood FDA?

Next: Sam Brownback's FDA

Wednesday, July 18, 2007

GE's Abbott Indigestion

Now that GE has pulled out of its proposed $8.13 billion all-cash deal for Abbott Diagnostics (ADD) and Abbott’s point-of-care testing business, will anyone else step up to the plate?

Perhaps the logical suitor is P&G, because from what we hear, only the makers of Pepto-Bismol could have treated the massive indigestion the parties were experiencing.

We believe the explanation that it fell apart because of the complexities involved in prying them—ADD, specifically—out of Abbott.

Some analysts have suggested that compliance issues and issues over the transfer of licenses also helped scotch the deal. But while there were literally thousands of transition services agreements that the parties were going to have to enter into, in the end, it appears that the degree to which ADD is integrated into the rest of Abbott, and how difficult it would therefore be to deliver it to a company that perhaps has a different culture, very much surprised both sides. And that pain was going to persist over a protracted integration period—“a lot longer than three years,” according to one insider.

What’s puzzling is that this would not be the first time such a diagnostics business was sold lock-stock-and-barrel to a health care generalist (Siemens, for example, managed to buy Bayer Diagnostics and immunoassay player Diagnostic Products last year). Nor is GE inexperienced at handling such moves (there's too many potential links to choose from for this one to even begin to know where to start).

So we have to ask: Were the cultures an obviously terrible mix? That’s very possible, and yes, it'd be interesting to contemplate what those differences may say about each company. We’ve also heard that the first marching order for Abbott now will be to improve the level of service to its diagnostics customers, which of course suggests GE may have uncovered something specifically troubling during its preparations.

In any event, the take-home is it’s unlikely that Abbott will be looking for another buyer for those businesses. And with the exception of Roche, which unlike Abbott, views diagnostics as intimately connected with its drug development ambitions and personalized medicine, there aren’t really any very large in vitro diagnostics (IVD) players left from whom GE could wring out efficiencies, exploit scale, and improve productivity in the IVD market the way it expected to with Abbott.

It may continue pursuing smaller, more targeted acquisitions in IVD and, like Abbott, certainly in molecular diagnostics. And with some of the premiums companies offered recently to companies with molecular content, like Biosite (63%, measured from the time of Beckman-Coulter’s initial offer for it before Inverness finally landed it), TriPath (58%, from Becton Dickinson), and Ventana (43% at the time of Roche’s recent hostile tender offer of $75 per share), an exit via acquisition is nearly impossible for those companies to resist at today’s prices, leading to a wave of consolidation that might only pick up more steam, now.

Who's Afraid of REMS Marketing Limitations?

Some coincidences can be very instructive and tell you a lot about the future.

RiskMAPs & black boxes don't necessarily spell doom

If Genentech’s current experience with its omalizumab (Xolair) allergic asthma therapy is any model, FDA's new risk minimization action plan (RiskMAP) authorities don’t look like necessarily a bad thing.

The safety issues facing the drug--an expensive therapy at the root of Genentech's recent acquisition of partner Tanox--were troubling, and resulted in a black box warning proposed in February by FDA and updated earlier this month.

Almost to the minute as the House of Representatives wrapped up its version of the FDA revitalization act (user fee reauthorization and drug safety reforms) last Wednesday evening, Genentech was explaining to a small group of financial analysts that one of the prominent, new regulatory powers being granted to FDA by Congress may actually be a boon to a threatened Genentech brand:

11 July, 6:00 PM at the Capitol: The House halts its truncated debate on the FDA Amendments (HR 2900), only one representative (New York Democrat Maurice Hinchey) speaks out against the well-managed bill. A final one-sided roll-call (403-16) passed the bill at 8:29 PM.

3:00 PM in South San Francisco: Genentech product development president Susan Desmond-Hellmann (right) tells a conference call on Genentech’s second quarter results that the company’s adoption of a new RiskMAP for Xolair will be a stabilizing event for the product and good for its continued growth. (Indeed the product's sales have been growing since the initial FDA warning anyway: Xolair sales were up 17% to $111 million in the first quarter when the safety alert was announced and up 14% in the second quarter to $120 million while Genentech and FDA were working out the specifics of the RiskMAP. The accepted plan was announced on July 2.)

Asked to comment on the commercial impact of the RiskMAP, Desmond-Hellmann characterized the company’s dealings with FDA and creation of a new safety program as a very positive effort. She said that the RiskMAP would help Genentech balance the needs of a very sick patient population with “a wish to protect them from adverse events.”

But RiskMAPs or REMS (as they are being called in the new legislation) have been signaled out by critics of the new legislation as one of the more threatening aspects of FDA’s new safety armentarium. An informal short-hand for describing the new authorities has already developed in pharma circles: the RiskMAPs allow FDA to “inform, nag and nudge, and impose limits.”

Not to Desmond-Hellmann or Genentech. Noting that many of the analysts might not be familiar with the procedures “because they are relatively new,” she portrayed the RiskMAP as a good way to work with FDA to supplement traditional labeling and provide more guidance to the medical community.

Both the Senate and House drug safety bills will make REMS more prominent by giving FDA more explicit authority to require extensive programs to alert doctors and patients to problems with new or already-marketed drugs. That authority includes requiring special messages to the medical community and patients, safety messages in ads, limited access restrictions, and follow-up surveys, registries and closer product surveillance.

Lets break down the elements of Xolair's RiskMAP:

Black Box Warning: The most onerous part of program is the box warning at the top of Xolair’s professional labeling.
Patient Medication Guide: Pateints are to be given a brochure starting with a direct mention of the analphylaxis risk before each injection.
Patient observation after injection: The RiskMAP stresses that physicians should keep patients in their offices for an adequate period of time after administration of the shot to watch for a reaction. FDA doesn't specify a waiting time but patients generally wait about two hours already, according to a 2005 study by Genentech's Xolair marketing partner Novartis.
Follow-up surveys: Genentech will follow-up with doctors administering the drug (mostly allergists and pulmonologists) and with patients to find out how the educational materials are working. In effect, the surveys just act to keep Genentech and Novartis more closely in front of the doctor and tied to the patient.
Two post-marketing studies: One will look for a skin test for use with Xolair to try to address the unpredictable nature of the side effect. This is an obvious step that the company would have likely undertaken on its own at the first sign of the increased rate of anaphylaxis. The second test is a version of closer product surveillance through an creation of an observational repository of cases of hypersensitivity reactions associated with Xolair and appropriate control cases. Again, this is a reasonable portective move to assure that the company will not be left at the mercy of FDA’s adverse event reports in the future.

Overall, the Xolair RiskMAP looks like a sound product protection plan that actually cements the company’s position with providers and assures that the product will be restricted to a very sick group of patients: a group which justifies the current high cost of the treatment. If FDA’s new authority makes more companies adopt plans like this, the industry could be headed into a period when postmarketing problems become resolvable and not the cause of sudden product withdrawals.

Tuesday, July 17, 2007

Honor for Langer

The IN VIVO Blog knows of at least one VC who won't rest until MIT's Bob Langer gets a Nobel prize.

But perhaps this will satisfy him for a while. Langer, whose lab has seen the birth of many successful start-ups, was presented with the prestigious National Medal of Science.

About the award from the National Science Foundation:

The National Medal of Science was established by the 86th Congress in 1959 as a Presidential Award to be given to individuals "deserving of special recognition by reason of their outstanding contributions to knowledge in the physical, biological, mathematical, or engineering sciences." In 1980 Congress expanded this recognition to include the social and behavioral sciences.

A Committee of 12 scientists and engineers is appointed by the President to evaluate the nominees for the Award. Since its establishment, the National Medal of Science has been awarded to 425 distinguished scientists and engineers whose careers spanned decades of research and development.
To see what sort of illustrious company Langer is in, go here.

We count Langer as one of those "needs no introduction folks." But if you need an introduction, go to his MIT site.

IN VIVO Blog is guessing this honor is a bigger thrill for Langer than this, but we might have a tough time choosing.

Congratulations to Dr. Langer.

Monday, July 16, 2007

The RPM Report has fancy new e-digs

Our colleagues from The RPM Report (and fellow bloggers here at The IN VIVO Blog) have a beautiful new web site over at, which we wholeheartedly encourage you to visit for the best analysis of biopharma regulation/policy/market access on these here internets.

While You Were Running with the Bulls

That's gonna leave a mark
A few notes from the weekend that was ...

(AP Photo/ Inaki Porto)

Friday, July 13, 2007

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.