Unsubstantiated whisperings about Biogen Idec and its controversial multiple sclerosis drug took an ugly turn to the truth on Thursday when Europeon regulators disclosed another new case of progressive multifocal leukoencephalopathy, a serious brain infection known as PML, in a relapsed MS patient receiving Tysabri (natalizumab) infusions. With 11 new cases in two months, Biogen is going to face some awkward questions that will challenge the credibility of the company — and its promising MS franchise:

What did they know?

How long have they known it (more PML cases)?

And, how safe are other drugs in the MS pipeline?

In response to an email I wrote to the FDA inquiring as to how many confirmed cases of PML were on file — and were more reports to be expected — spokeswoman Sandra Walsh would only say:

"Yes, there are 24 confirmed cases of PML (since Tysabri re-marketing in 2006). The FDA is still receiving and reviewing follow-up information on cases of PML so we cannot yet comment further.

We’ll keep you posted as we learn more."

The global press will likely scapegoat Biogen management, accusing officials of withholding clinical data on side effects culled from Tysabri-treated patients. Before criticizing chief executive Jim Mullen & Co., however, the American public needs to remember that all current and emerging biological therapies for immune-mediated diseases, such as rheumatoid arthritis, Crohn’s disease, and MS, are imperfectly understood at best. The actual mechanism by which most of these drugs work is often murky, and they can cause unknown side effects as well:

Increasing numbers of invasiv e fungal infections are being reported in patients who have autoimmune inflammatory diseases and are being treated with newer immunosuppressive drugs, such as the well-known tumor necrosis factor (TNF)-alpha antagonist Enbrel (Etanercept), the anti-CD52 antibody Campath (alemtuzumab), or the interleukin-2 receptor antibody Simulect (basiliximab). [Current Infectious Disease Reports, 2009 Nov; 11(6): 435-8]

Or, as Ralf Gold, a well-respected neurologist in residence at Ruhr-University, located in Bochum, Germany, pointed out in a paper published in the New England Journal of Medicine:

“new MS drugs unfortunately have new side effects that can sometimes be fatal. Currently Natalizumab is the focal point of interest throughout the world, but [that] other new drugs, such as Alemtuzumab or anti-CD20 antibodies may soon follow.”

Still, all stakeholders, especially MS patients, have the right to feel both betrayed and angry, as Biogen management appeared to be both evasive and equivocal when answering queries from biotech analysts on the October 20 third-quarter earnings call. For example, as up to 17 worldwide cases of PML had been reported prior to third-quarter end, Eun Yang, biotech analyst at Jeffries & Co, asked management about emerging data suggesting there was a link between duration of Tysabri therapy and increased risk of developing PML.

“When you look at the patients who have been on the treatment for 24-months or longer, PML rate runs around 1 in 800, which is higher than what is in the [prescribing] label,” said Yang. “So, my question to you is what do you think would be the critical threshold of a PML rate where physicians or regulatory agencies would become more cautious on Tysabri?”

“I don’t want to speculate what makes regulators want to do things,” responded chief operating officer Bob Hamm, “but I can assure you that our current thinking is that the risk of PML even in that third year beyond 24-months is within the currently implied risk in the label.”

The current rate of PML in patients who had received at least 24 infusions ranges from 0.4 to 1.3 per 1,000 - patients, according to an FDA Safety Alert Update posted on September 16.
Management also downplayed any safety advantage to “drug holidays” for long-term Tysabri users. Specifically, when asked to comment on the proportion of patients in Biogen’s database where providers implemented drug holidays, senior researcher Al Sandrock tersely replied: “From the data we have — we are seeing very, very isolated cases of that.”

As I referenced in an earlier BNET Pharma posting, about 13,400 patients receiving monthly infusions (or approximately 29 percent of all patients taking the drug) had been on Tysabri therapy for more than two years — paying, on average, $28,500 per year for 13 infusions. It’s easy to do the math, subtract number of infusions and units sold decline.

Short-term, in my opinion, physician and patient distrust could lead to Tysabri (once again) losing market share to Teva Pharmaceutical’s (non-interferon) immunomodulator Copaxone (glatiramer acetate), with harmless injection-site reactions the most annoying of reported adverse events. Data from a 15-year ongoing Copaxone prospective study demonstrating patients treated for 10 and 15 years with the drug had significant reduction in disease severity should stimulate growth in sales, too.

“To stumble twice against the same stone is a proverbial disgrace, ” said the great Roman statesman Marcus Cicero. Not that Jim Mullens need give a Richard Nixon-like Checkers speech: “My fellow Americans.” The goal of Biogen management, nonetheless, is the same as Nixon’s was 50 years ago — damage control with humility. Admit (without admitting liability) that PML is more prevalent than original surveillance data suggested and move forward, working with MS interest groups and the FDA and European regulators to strengthen distribution and monitoring programs at Tysabri infusion centers worldwide. Also, Mullens should remind providers that the drug’s demonstrated 67 percent reduction in the relapse rate tips the risk-benefit scale in Tysabri’s continued favor.

The importance to Biogen of retaining credibility cannot be understated, as the company is racing against European drugmakers Merck KGaA (cladribine) and Novartis AG (fingolimod) to introduce the first oral pill for MS to market. Biogen agreed back in July to pay up to $510 million to market Fampridine SR (sustained-release), an oral tablet owned by Acorda Therapeutics, outside the United States.

The FDA’s Peripheral and Central Nervous System Drugs (PCNSD) Advisory Committee voted 12 to 1 that clinical data on Fampridine-SR 10 mg twice daily, which will sold under the brand name Amaya, has demonstrated substantial evidence of effectiveness as a treatment to improve walking in MS patients. Most experts agree that the drug could likely be on pharmacy shelves in the U.S. by the second quarter of 2010.

Biogen Idec expects to file for approval by the European Medicines Agency (EMEA) in early 2010. However, an unknown here and abroad is whether the therapy will receive a boxed warning for seizure risk (side effect looks to be dose-related). Consequently, the key issue to early adoption by physicians of Fampridine SR will likely, once again, turn on credibility — do neurologists trust Biogen Idec?

Story in BNET