Containing Campath Strategy BioCentury,

BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS AUGUST 27 , 2012 PAGE A7 OF 18
Strategy
Containing Campath
By Erin McCallister
Senior Writer
Sanofi and its Genzyme Corp. subsidiary are not com-
pletely withdrawing alemtuzumab from the market, but they are
making it harder for doctors to use the drug for its approved use,
chronic lymphocytic leukemia, and nearly impossible to use off
label for multiple sclerosis.
In its 1H12 earnings, Sanofi disclosed it would withdraw
alemtuzumab from the market for CLL. On Aug. 8, the European
Commission issued a decision to withdraw the marketing autho-
rization for MabCampath in Europe. Withdrawal in the U.S.,
where the drug is sold under the name Campath, will be effective
Sept. 4.
Going forward, Sanofi and Genzyme
will to provide Campath free of charge to
oncologists for CLL and a handful of off-
label indications through a patient access
program, which has already started in
Europe.
In a written statement, the pharma told
BioCentury it has decided “to focus on
bringing alemtuzumab forward for MS,”
and that restricting access will help pre-
vent off-label use of the drug in this indi-
cation.
In June, Genzyme and Sanofi submitted
applications to FDA and EMA to market
alemtuzumab for MS under the name
Lemtrada.
Oncologists contacted by BioCentury were disappointed by
the decision, but generally don’t believe it will negatively affect
patients as long as the access program isn’t too onerous.
Neurologists weren’t bothered by Genzyme’s decision and
believe blocking off-label use will prevent safety issues from
arising while the Lemtrada applications are under review.
Meanwhile, the move offers financial upside for holders of the
Genzyme CVR. Sanofi acquired the biotech in 2011 for about
$20.1 billion plus a $14 contingent value right, $12 of which is
tied to sales milestones for Lemtrada for MS.
Off-label use of Campath would be cheaper than Lemtrada,
which is likely to be priced competitively with other MS drugs.
Cancer OK
Alemtuzumab is a humanized mAb against CD52. The mAb
binds the target, which is present on the surface of B and T
lymphocytes, and causes the cells to undergo antibody-depen-
dent cell-mediated lysis and die.
For CLL, which is associated with an increase in B lympho-
cytes, alemtuzumab destroys the excess B cells.
In MS, alemtuzumab is believed to exert its therapeutic effects
by depleting T and B cells that may be responsible for cellular
damage.
In 2001, alemtuzumab was approved in the U.S. and Europe
to treat B cell CLL in patients previously treated with alkylating
agents and who have failed fludarabine therapy. Campath was
approved as a first-line treatment in the U.S. in 2007.
“I wasn’t surprised that they
took it off the market. It is
being relaunched in a
different context, a different
patient population and a
different dose.”
Steven Krieger, Mount Sinai
Medical Center
According to the National Cancer Institute (NCI), about
16,000 patients will be diagnosed with CLL in the U.S. this year.
However, the cancer drug is only used first line in the 10% of
patients with the 17p deletion, according to Brian Hill, an
oncologist in the department of hematologic oncology and blood
disorders at the Cleveland Clinic.
He said Campath is used so narrowly because of its safety
profile and its efficacy in this subgroup.
Campath’s label carries a boxed warning about the risk of
cytopenias, infusion reactions and infections. In the Phase III trial
in 147 treatment-naïve patients, 97% reported grade 3 or 4
lymphopenia and 42% reported grade 3 or 4 neutropenia.
Additionally, 55% of patients experienced CMV viremia, and
16% of patients had CMV infections. About
10% of patients experience grade 3 or 4
pyrexia and/or chills associated with infu-
sion of Campath.
According to Hill, standard of care
fludarabine typically produces only a 30%
response rate in CLL patients with the 17p
deletion.
In a subgroup of treatment-naïve pa-
tients with 17p deletions in the Phase III
trial, Campath resulted in median pro-
gression-free survival (PFS) of 10.7 vs. 2.2
months for control and response rates of
64% for Campath and 20% for control.
According to Howard Ozer, chief of
hematology/oncology and interim director of the University of
Illinois Cancer Center, Campath also is used in heavily
refractory patients.
“Patients who are completely refractory to other treatments
can benefit from Campath and doctors like having the drug
available as an option. Loss of the drug would not be a good
thing,” he said.
According to Genzyme spokesperson Bo Piela, the company
started informing U.S. doctors of the impending withdrawal of
Campath and the patient access plan in July and European
doctors earlier this month.
He said physicians in the U.S. and Europe will be able to
request Campath/MabCampath on a per patient basis.
Physicians will need to complete a product request form
indicating basic patient information, the intended use, the
number of vials requested and agree to the terms and conditions
of the program.
“If the request falls outside of predefined criteria, physicians
may also be asked to complete a medical review form to
document the clinical rationale for the intended treatment,” Piela
said.
He added the program also will make the drug available for
certain off-label malignancies for which conventional therapies
have failed, are unsuitable or unavailable.
The drug will also be provided for hematopoietic stem cell
transplant conditioning and solid organ transplant at institutions
that have documented protocols.
Alemtuzumab will be available for MS patients only within the
See next page

BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS AUGUST 27 , 2012 PAGE A8 OF 18
Strategy,
from previous page
clinical trial setting, Piela said.
While doctors said they were assuaged
by Sanofi and Genzyme’s plan to provide
the drug under the patient access pro-
grams, some physicians are concerned
that the additional work could deter use of
Campath.
“Restricted access is always concern-
ing and the addition of more paperwork can create a lag time,”
said Javier Pinilla-Ibarz, a hematologic oncologist at H. Lee
Moffitt Cancer Center & Research Institute. Nevertheless,
he said, “I don’t think lag times will prevent its use among the
majority of clinicians.”
Matthew Davids, an instructor and attending physician in the
lymphoma group at Dana-Farber Cancer Center, noted that
larger research institutes have more experience in dealing with
special access programs like the one Sanofi and Genzyme are
proposing and may be more immune to any potential obstacles.
Nonetheless, he also believes most doctors will still use the
drug.
“I don’t think the paperwork burden will be huge. It is an
important drug for those patients in which it works, so motiva-
tion is on the clinician’s side to get patients the drug,” Davids
said.
However, Thomas Elter, a physician in the department of
Hematology and Oncology at the University of Cologne,
hasn’t yet used MabCampath since the program started in
Europe.
Elter said Genzyme told him it should take no more than two
weeks to receive the drug, although Piela told BioCentury it
should take no more five days from when a request is submitted
to when the drug is shipped to the physician.
In any case, Elter estimated it takes physicians about 30
minutes to fill out the paperwork, which is too long for him.
“Before, it took just seconds between when I would prescribe
the drug and could have access to it. But now it will take just a
half hour to fill out the paper work. I don’t have a half an hour,
so to save my time I will look for an alternative,” he said.
According to Elter, other options could include enrolling CLL
patients with the 17p deletion in a clinical trial.
Piela said that Genzyme is “hoping to implement online forms
in the future.”
On Friday, the Arzneimittelkommission der deutschen
Arzteschaft (AkdA) released a statement calling Genzyme
and Sanofi’s decision purely commercial and said the volun-
tary withdrawal unnecessarily complicates cancer treatment.
AkdA is the Drug Commission of the
Bundesarztekammer, the German
Medical Association.
Off label, off limits
While most MS doctors contacted by
BioCentury haven’t used Campath off la-
bel, they believe the decision to withdraw
was a good one and could prevent poten-
tial safety issues from arising while the
drug is under review.
Steven Krieger, assistant professor of See next page
neurology at Mount Sinai Medical Cen-
ter, wasn’t surprised by Genzyme’s deci-
sion.
“I wasn’t surprised that they took it off
the market. It is being relaunched in a
different context, a different patient popu-
lation and a different dose,” he said.
Edward Fox, a neurologist at Central
Texas Neurology Consultants and a
PI in the Phase II trials for alemtuzumab for
MS, believes that once the Phase III results
are published in scientific journals, off-label use could have been
expected to increase.
“I think once data is published that spells out how alemtuzumab
can be given in MS, the chance of off-label use goes up
dramatically. The concern is that the company and FDA have not
instituted any sort of risk management system,” he said.
Krieger agreed.
“I think now that the Phase III trials and data are public and
as publications come out detailing the data, there will surely be
an interest. But with the drug under FDA review that is not the
best time to experiment with it,” he said.
Krieger added: “This is the time to expectantly wait to see
what FDA rules and if they approve it, how the drug should be
monitored and how to achieve the best benefit to risk profile.”
Genzyme would not disclose whether the company has
submitted or FDA has requested a REMS for Lemtrada. The
company submitted its sBLA in June.
Even if data are published, Til Menge, a neurologist at
University Hospital Dusseldorf, believes doctors will re-
main hesitant to use alemtuzumab off label because of the mAb’s
safety.
“Given the known safety profile of alemtuzumab, I think MS
doctors will be reluctant to use it off label,” he said.
In the Phase III CARES-MS trial of 840 patients with relapsing-
remitting MS (RRMS) who relapsed while receiving beta inter-
feron or Copaxone glatiramer acetate, about 16% of Lemtrada
patients developed an autoimmune thyroid-related adverse event
and about 1% developed immune thrombocytopenia.
The rates of immune AEs were not reported for the active
control arm of Rebif interferon beta-1a.
Teva Pharmaceutical Industries Ltd. markets Copaxone.
Merck Serono S.A., a division of Merck KGaA, markets Rebif
with Pfizer Inc.
Covering the CVR
Campath is distributed in a 1-mL vial of 30 mg/mL. The
recommended dose for CLL is 30 mg/day three times per week
for 12 weeks.
According to Genzyme, the annual
treatment cost for Campath is about
$60,000 per patient. Assuming one 12-
week course per year, the per dose price
of Campath is about $1,666.67.
In the Phase III trials for Lemtrada, the
mAb was dosed at 12 mg per day on the
first five days of the trial. The patients
were dosed again a year later with 12 mg
per day for three days for a total of 8
doses.
MS doctors using Campath off label
“Given the known safety
profile of alemtuzumab,
I think MS doctors will be
reluctant to use it off label.”
Til Menge, University Hospital
Dusseldorf
“It is an important drug for
those patients in which it
works, so motivation is on
the clinician’s side to get
patients the drug.”
Matthew Davids,
Dana-Farber Cancer Center

BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS AUGUST 27 , 2012 PAGE A9 OF 18
according to the Lemtrada dosing schedule would only use 96 mg
of the CLL drug over two years for a total treatment cost of
$6,666.68.
The off-label cost of Campath for MS is considerably lower
than other MS drugs.
For example, the average wholesale cost of Tysabri natalizumab
is $4,576.37 for a 15-mL vial of 20 mg/mL. With a recommended
dose of 300 mg every four weeks, the annual cost of Tysabri is
about $59,375.81.
Biogen Idec Inc. and Elan Corp. plc market Tysabri.
If Genzyme and Sanofi plan to price Lemtrada competitively
with other MS drugs, doctors could use Campath off label at a
lower cost, which would be bad news for holders of the Genzyme
CVRs.
In 2011, Sanofi acquired Genzyme for about $20.1 billion
plus the $14 CVR, $13 of which is tied to milestones for Lemtrada
for MS (see BioCentury, Feb. 21, 2011).
The first CVR milestone for Lemtrada is $1 for FDA approval.
The next $2 Lemtrada milestone will trigger if net sales over four
quarters exceed $400 million.
Strategy,
from previous page
The next $10 includes payments of $3 if net sales of Lemtrada
total $1.8 billion over four quarters, $4 for sales of $2.3 billion
over four quarters and $3 for sales of $2.8 billion.
COMPANIES AND INSTITUTIONS MENTIONED
Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.
Bundesarztekammer, Berlin, Germany
Central Texas Neurology Consultants, Round Rock, Texas
Cleveland Clinic, Cleveland, Ohio
Dana-Farber Cancer Center, Boston, Mass.
Elan Corp. plc (NYSE:ELN), Dublin, Ireland
Genzyme Corp., Cambridge, Mass.
H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla.
Merck KGaA (Xetra:MRK), Darmstadt, Germany
Mount Sinai Medical Center, New York, N.Y.
National Cancer Institute (NCI), Bethesda, Md.
Pfizer Inc. (NYSE:PFE), New York, N.Y.
Sanofi (Euronext:SAN; NYSE:SNY), Paris, France
Teva Pharmaceutical Industries Ltd. (NYSE:TEVA), Petah Tikva,
Israel
University Hospital Dusseldorf, Dusseldorf, Germany
University of Cologne, Cologne, Germany
University of Illinois Cancer Center, Chicago, Ill.
Featured links this week
Links to the following documents reside online on the BioCentury on
BioBusiness page of www.biocentury.com.
Antibiotics
NICE guidance on use of antibiotics to prevent and treat early
onset neonatal infection.
CalPERS
California Public Employees’ Retirement System (CalPERS) five-
year strategic plan for meeting the retirement and health benefits
needs of its members.
Devices
Registration for the Aug. 30 FDA workshop to discuss
postapproval studies for class III devices regulated under PMA
regulations (see BioCentury Extra, Monday, Aug. 20).
IOM
Institute of Medicine summary of a June workshop to discuss
implementation of the Cures Acceleration Network (CAN), a
program that will allow NIH to fund R&D at biopharma
companies.
JOBS Act
SEC FAQ on research provisions in Title I of the Jumpstart Our
Businesses Startups (JOBS) Act.
NIH
NIH policy to give extra scrutiny to grant applications from
researchers who already receive $1 million or more per year
under active NIH awards (see BioCentury Extra, Wednesday,
Aug. 22).
Stem cells
U.S. Court of Appeals for the District of Columbia Circuit ruling
that upheld a lower court’s 2011 dismissal of a suit claiming NIH
violated a law prohibiting federal funds for research in which a
human embryo is destroyed (see BioCentury Extra, Friday, Aug. 24).
Venture tax
European Commission public consultation seeking evidence of
direct tax problems that arise when venture capital is invested
across borders and possible solutions; comments are due Nov. 5.
Product documentation
— Avastin: NICE final guidance recommending against Avastin
bevacizumab in combination with capecitabine for first-line
treatment of metastatic breast cancer; from the Genentech Inc.
unit of Roche (SIX:ROG; OTCQX:RHHBY).
— Alimta: CHMP revised EPAR updating SPC to include anaphy-
lactic shock as an adverse reaction for Alimta pemetrexed to
treat pleural mesothelioma and non-small cell lung cancer
(NSCLC); from Eli Lilly and Co. (NYSE:LLY).
— Humira: Briefing documents for the Aug. 28 meeting of the
Gastrointestinal Drugs Advisory Committee to discuss an sBLA
for Humira adalimumab to treat moderately to severely active
ulcerative colitis in adults who failed conventional therapies;
from Abbott Laboratories (NYSE:ABT) and Eisai Co. Ltd.
(Tokyo:4523; Osaka:4523) (see BioCentury Extra, Friday, Aug. 24).
— Xgeva: NICE final appraisal determination (FAD) recom-
mending the use of Xgeva denosumab to prevent skeletal-related
events (SREs) in patients with bone metastases from breast
cancer and from solid tumors other than breast and prostate
cancer for whom zoledronic acid would be indicated; and against
use in patients with hormone-refractory prostate cancer (HRPC);
from Amgen Inc. (NASDAQ:AMGN).
‘It’s the BioCentury’TM