Tysabri’s PML Count Climbs to 28, and Some Reflections From Biogen Idec’s Departing CEO

1/6/10Follow @xconomy

At least one more patient has been diagnosed with a rare, and potentially fatal brain infection after taking natalizumab (Tysabri), the hit drug for multiple sclerosis from Biogen Idec and Elan, according to Biogen CEO James Mullen.

There are now 28 confirmed cases of patients with progressive multifocal leukoencephalopathy (PML) as of the last count in mid-December. That’s one more case than I counted in a detailed summary of PML risk that we published on November 19. Mullen made his remarks in front of a group of investors today at a Goldman Sachs conference titled “Healthcare CEOs Unscripted: A View From the Top.”

Mullen talked about the hit drug’s difficult history with PML as part of a wide-ranging and candid conversation with Goldman analyst May-Kin Ho in New York. These were the first public remarks Mullen, 51, has made since the Cambridge, MA-based company (NASDAQ: BIIB) announced this week he is stepping down in June as CEO, after a decade at the helm. He offered his thoughts on how to mitigate the risk for multiple sclerosis patients, his reflections on what worked and what didn’t in the 2003 merger with San Diego-based Idec Pharmaceuticals, and how the industry needs to change its ways to keep innovation alive. Here are the highlights that I picked up from the webcast.

On how Biogen Idec plans to keep doctors, patients, and investors informed about PML risk:

Biogen Idec says it plans to offer monthly updates to physicians about the latest statistics on PML cases, and infection rates. It will also staff a hotline for physicians who want to gather detailed, updated information and context from the company’s medical staff. The company plans to lay out the numbers in a more detailed fashion, with rates on incidence of infection, numbers showing how long certain groups of patients have been on the drug, combined with data on how many total patients are receiving treatment. “That’s the best way for people to visualize what’s going on,” Mullen says.

“The whole communications strategy around that has been challenging,” Mullen said. “We’ve gotten lots of feedback. Pretty much whatever we’ve done, someone won’t like it.”

On why he’s leaving the company in June:

Mullen noted that the Tysabri risk-management situation has stabilized during the past year. A new patent that lasts until 2026 has extended the lifespan of pegylated interferon beta (Avonex) which may help it fend off cheaper “follow-on” biologic competitors. And the product pipeline looks encouraging as well, he said.

“There are a lot of good prospects out there for Tysabri, and there aren’t, if you will, a lot of huge, thorny issues to be wrestled to the ground here in the short term. It’s a good time for a transition.”

From a personal perspective, he added: “If you’re going to have a mid-life crisis, you can do one of two or three things, right? Sports cars I’m too big for. Mistresses are not approved at home. Maybe a career change is what’s in order. I decided to go with Number 3. I think it’s a good time, for, you know, a transition. We’ve also got a new chairman with Bill Young. We’ve got some new board members. We’ll have a few more new board members. It’s a good time for people to sort of re-think about the strategy and get some fresh views.”

On his plans after June:

“A lot of people don’t think I take advice very well, but one of the pieces of advice I got from a lot of people was—finish what you’re doing, clear your head, take some time, and consider the different options on what you plan to do. That’s what I intend to do.”

On the status of competing MS drugs:

“Anybody else’s delay is our good news.” Given the well-known PML risk with natalizumab, Merck KGaA’s cladribine, and Novartis’ FTY-720, those companies will have to deal with more regulatory scrutiny, Mullen said. “The safety scrutiny has gone up and up and up. In the U.S., everyone is going to have to have a REMS [risk evaluation and mitigation strategy]. It might be modest, or it might be as restrictive or tight as Tysabri’s.”

“Certainly an oral product will [find] a lot of interest in the marketplace. On the other hand, that product also has some fairly significant safety issues and it’s going to have a REMS program. I think the established safety and efficacy profile of the ABCRs [Avonex, Betaseron, Copaxone, & Rebif, the standard treatments] is such that they are the first-line therapies, and it will be true for some period of time.”

On how to mitigate the risk of PML by testing for biomarkers to gauge a patient’s vulnerability:

“We have done, since 2005, a tremendous amount of work to look at anything and everything to mitigate the risk around this product. Certainly the JCV antibody test, we think, is the most solid diagnostic we have seen. The data as we developed it have tipped over some of the widely held beliefs that essentially everybody here was going to be JCV antibody positive, because we’ve all been exposed to JC virus [the virus that crosses into the brain and causes PML]. It looks like it’s more like half of us. We also have serum samples from patients with PML, and they were all JCV positive. So it’s a solid assay.

“But then there’s chatter about what does it mean for JCV antibody positive patients? You really have to put yourself in the shoes of those patients. Right now, Tysabri is a third or fourth line product. The 48,000 patients who are on it have failed one or more therapies. They aren’t doing well. Their options are being exhausted rapidly. When they look at being JCV antibody positive or negative, the question is, ‘How am I doing on the product?’ If I’m doing well on the product, they’ll be left on the product, and probably monitoring will increase. The more we can learn about other risk factors will be helpful. For those who are negative, it opens up the question of whether we should treat patients who are negative, at least some of them, more aggressively, and earlier. So that’s a potential opening to go there. Everything else we learn over time to further parse the risk is all to their benefit.”

On what worked, and what didn’t, in Biogen’s 2003 merger with San Diego-based Idec Pharmaceuticals:

“Now you’re really taking us back to ancient history. Here’s what went as expected. The combination of the two companies really allowed us to fundamentally re-allocate capital in a different way than either one was doing. They had a lot of the oncology infrastructure. We had the international footprint. We brought better manufacturing capabilities. They brought much better process sciences. Developing the processes to go into manufacturing. That has had a terrific payoff. Those two things came together seamlessly. It allowed us to compete much better, and more broadly, on business development. We’ve done a lot of small and mid-sized deals. Half of the pipeline today comes out of business development.

“In terms of things that exceeded expectations from the original models we had? Rituxan is much bigger. By being in RA [rheumatoid arthritis, as well as non-Hodgkin's lymphoma], the whole CD20 area turns out to be more important. As does the durability and size of the Avonex business and the MS franchise, which turned out to be better.

“But some of the products that were in the pipeline at that point that we thought would be important products, frankly, they haven’t. Amevive basically got wiped out by the anti-TNFs [what's that]. Raptiva is gone from the market, it has a little problem with that three-letter word we don’t like to say—PML. That’s gone from the market, Amevive is still on the market, but disappointing. Zevalin never really lived up to what we hoped would be its commercial potential. And some of the late-stage pipeline candidates evaporated, as tends to happen in this business.

“From an integration of people standpoint, it always takes a little longer, but right now, it works pretty well. The R&D being bi-coastal works very seamlessly and smoothly. Most oncology is done on the West Coast, most of the immunology is done on the East Coast, but some is on the West Coast, and pretty much all of the neurology is on the East Coast. Then there’s a lot of shared infrastructure, and that works pretty well.”

On the biggest surprises of his 20-year career in biotechnology:

“What surprises me is that it’s very hard to pick out which technologies and products will turn into the blockbusters. I remember the conversations going in the early ’90s, happening in our place, when people said, ‘This monoclonal antibody stuff, it’s not going to turn into any products.’ It’s not quite right. And we are one of the biggest beneficiaries of that. Gene therapy was going to be huge. Then it was RNAi. And all sorts of other stuff.

“It’s always been difficult to pick the technologies and platforms that will turn into products because it always sounds a lot easier than it is and more logical than the biology turns out to be. That’s one. The second is that regulatory success by no means [translates into commercial success]. You really have to think carefully about all your products. Just getting over the regulatory hurdle, and getting the whole organization to understand that getting over the regulatory hurdle is not sufficient.

“How intractable the whole R&D productivity issue has been for the industry. I’ve been around 30 years in the industry, and every three or four years along comes some new thing that’s going to somehow improve our hit rate or drop the costs. Well, none of that has happened. The regulatory hurdles go up, the trial sizes go up, the timelines get longer, things get more expensive, and the hit rates don’t go up, they go down.

“If I want to be futuristic, I would ask how we’re going to change the paradigm. We’re still living in a paradigm of placebo-controlled trials that were put in place in the 60s, 70s and 80s. It won’t work any longer over the next 30 or 40 years. Frankly, a lot of basic problems got solved. This idea that you’re going to do comparative effectiveness studies—they sound great as headlines, and they play well with the public, but when you run the statistics, they don’t work at all.

“So I think there’s got to be really new thinking in the industry. It’s going to take a while, and it will need to take hold with the regulators. The whole Critical Path Initiative at the FDA has always been disappointingly underfunded, and do not [have] enough intellectual horsepower, but the industry has to rally around it and help come up with some new paradigms, and move the regulators to a point where the paradigms are meaningful and put into place. This whole equation is heading to a place where innovation is really going to be crimped.”

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