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.”
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?
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