First-in-class Biologic Agent for Kidney Transplant Rejection Approved in Europe

PARIS, June 20, 2011 -

• European Commission approves NULOJIX^®
  (belatacept), in combination with corticosteroids and a
  mycophenolic acid and an interleukin-2 receptor antagonist at
  induction, for prophylaxis of graft rejection in adult patients
  receiving a kidney transplant
• First new mode of action for prevention of graft rejection
  in kidney transplantation in a decade
• Similar rates of graft and patient survival with better
  preservation of renal function seen at one year and maintained
  through three years vs. cyclosporine
• Overall safety profile of belatacept comparable to
  cyclosporine; higher rates of post-transplant lymphoma especially
  in EBV seronegative patients

Bristol-Myers Squibb today announced that the European
Commission has granted Marketing Authorization for
NULOJIX^® (belatacept), a new biologic agent for the
prophylaxis of graft rejection in adult patients receiving a kidney
transplant.

Belatacept is the first molecule with a new mechanism of action
approved in a decade in kidney transplantation. By acting
selectively on the immune system to prevent graft rejection,
belatacept helps safeguard renal function, which is increasingly
recognized as a key predictor of long term outcomes in kidney
transplant recipients, impacting both patient and graft
survival.^[1,2,3]

“One of the key challenges in kidney transplantation has been
achieving improvements in renal function that are sustained in the
long term,” said Professor Josep Grinyó of the University Hospital
of Bellvitge, Spain. “We observe progressive renal function decline
in our patients, which may cause additional co-morbidities and
result in graft failure. With belatacept’s positive impact on renal
function, this approval represents a promising new option for adult
kidney transplant patients.”

Approximately 18,000 kidney transplants were performed in the
European Union in 2009.^[4] As of 31 December 2009,
however, more than 50,000 people across the 27 countries were still
in need of a kidney transplant.^[4] Preserving renal
function after transplantation can help avoid a return to dialysis
and the need for another transplant.

“As the first new biologic therapy approved for the prevention
of graft rejection in kidney transplantation in a decade, Nulojix
gives kidney transplant recipients a new innovative treatment
option,” said Ron Cooper, President, Europe, Bristol-Myers Squibb.
“What we see today with Nulojix is that it helps preserve kidney
function after transplantation and we know that this is critical
for patients to keep their graft healthier for longer.”

Belatacept, in combination with corticosteroids and a
mycophenolic acid (MPA), is indicated for the prophylaxis of graft
rejection in adults receiving a renal transplant. It is recommended
to add an interleukin (IL)-2 receptor antagonist for induction
therapy to this belatacept-based regimen.^[5] Belatacept
is contraindicated in transplant recipients who are Epstein-Barr
virus (EBV) seronegative or serostatus unknown.

The Marketing Authorization for belatacept follows the positive
opinion by the Committee for Human Medicinal Products, which
considered that there is a favorable benefit to risk balance for
belatacept on the basis of quality, safety and efficacy data
submitted.^[6] The two pivotal Phase III clinical trials
(BENEFIT and BENEFIT-EXT^[7,8])have been extended to
seven years in duration and will, upon completion, provide the
largest set of controlled long term data of a transplant
immunosuppressive regimen to date.

Following approval from the European Commission, belatacept is
expected to become commercially available in the European Community
in the coming months.

About the belatacept pivotal
trials

BENEFIT study shows superior and sustained renal function
with belatacept vs. cyclosporine (CsA)^[7]

The BENEFIT study enrolled 666 de novo recipients of
renal transplants from living or standard criteria deceased donors
(SCD). The study compared two dosing regimens of belatacept with
cyclosporine: More Intensive (MI) and Less Intensive (LI). The MI
regimen included higher and more frequent dosing during the first
six months post-transplantation. The approved dosing regimen is
10mg/kg during the initial phase (a total of six infusions over the
first 12 weeks from the day of transplantation) and 5mg/kg every
four weeks thereafter for maintenance, and is consistent with the
LI regimen utilized in the clinical trials.

At three years, patient and graft survival were similar between
belatacept-treated patients at the approved dose (92% of 226)
compared to cyclosporine-treated patients (88.7% of 221).

Higher rates and grade of acute rejection were observed in the
belatacept arms, although this did not increase the rate of graft
loss in the Intent-To-Treat (ITT) population.

Renal function for belatacept-treated patients was superior
after one year and this benefit was sustained over three years,
with mean calculated Glomerular Filtration Rate (GFR) being 21
mL/min higher by three years for patients receiving belatacept-LI
than for patients receiving cyclosporine.

Largest trial in extended criteria donors (BENEFIT-EXT)
demonstrates benefits of belatacept across donor
types^[8]

With 543 de novo recipients of renal transplants from
extended criteria donors (ECD), the BENEFIT-EXT study is the
largest study conducted to date in patients receiving ECD kidneys.
ECD organs are suboptimal organs but represent a viable alternative
to remaining on the waiting
list.^[9]

The dosing regimens of belatacept and cyclosporine were the same
as in the BENEFIT trial. As demonstrated in BENEFIT, BENEFIT-EXT
showed that patient and graft survival were similar between
belatacept-treated patients at the approved dose (LI) (82% of 175)
compared to cyclosporine-treated patients (80% of 184) at Year 3.
Acute rejection rates were comparable in the belatacept and
cyclosporine arms. In addition, belatacept-treated patients showed
less decline in renal function over time, with mean calculated GFR
being 11 mL/min higher by three years for patients receiving
belatacept-LI than in patients receiving cyclosporine.

Pooled data define the safety profile of
belatacept^[10]

The safety of belatacept was evaluated based on pooled data from
three belatacept trials (one Phase II study and two Phase III
studies). In these trials, 401 patients received the approved LI
regimen of belatacept, 403 patients received the more intensive
(MI) regimen and 405 patients received cyclosporine. The pooled
data show that the incidence of death and discontinuation due to
adverse events was lower with belatacept compared with
cyclosporine. Overall rates of adverse events were similar between
belatacept-treated patients receiving the approved LI dose and
those patients receiving cyclosporine.

Post-transplant lymphoproliferative disorder (PTLD) was observed
in the belatacept clinical trials. The frequency of PTLD was higher
in the belatacept-LI dosing regimen (1.3%, 6/472) than in the
cyclosporine group (0.6%, 3/476). The frequency was highest in the
belatacept MI group (1.7%, 8/477), which is not approved for use.
Nine of the 14 cases of PTLD in belatacept-treated patients were
located in the central nervous system. Of the six PTLD cases with
the LI regimen, three involved the central nervous system and were
fatal. The risk for PTLD was increased for belatacept-treated
patients who were seronegative for the Epstein-Barr virus (EBV).
Belatacept is therefore contraindicated for patients who are
EBV-negative or serostatus unknown.

The incidence of all malignancies was stable over time in each
study. A Risk Management Plan will be implemented as part of the
pharmacovigilance programme to monitor for infections and
malignancies.

The most common serious adverse reactions (>= 2%) reported
with belatacept cumulative up to Year 3 were urinary tract
infection, CMV infection, pyrexia, increased blood creatinine,
pyelonephritis, diarrhea, gastroenteritis, graft dysfunction,
leukopenia, pneumonia, basal cell carcinoma, anemia and
dehydration.

About NULOJIX^® (belatacept)

NULOJIX is the first approved costimulation blocker for
maintenance immunosuppression in kidney transplantation. NULOJIX, a
soluble fusion protein, is a selective T-cell costimulation blocker
that binds to CD80 and CD86 on antigen-presenting cells.  As a
result, NULOJIX blocks CD28 mediated costimulation of T cells. In
vitro, belatacept inhibits T lymphocyte proliferation and the
production of the cytokines interleukin-2, interferon-g,
interleukin-4, and TNF-a. Activated T cells are the predominant
mediators of immunologic rejection.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail against serious diseases. Around the
world, our medicines are helping millions of patients in their
fight against such diseases as cancer, heart disease, HIV/AIDS,
psychiatric disorders, rheumatoid arthritis, chronic hepatitis B
virus infection and diabetes.

Bristol-Myers Squibb Forward-Looking
Statement

This press release contains “forward-looking statements” as the
term is defined in the Private Securities Litigation Reform Act of
1995 regarding product development. Such forward-looking statements
are based on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that NULOJIX^® (belatacept) will become a
commercially successful product. Forward-looking statements in this
press release should be evaluated together with the many
uncertainties that affect Bristol-Myers Squibb’s business,
particularly those identified in the cautionary factors discussion
in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year
ended December 31, 2009, in our Quarterly Reports on Form 10-Q and
our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or
otherwise.

References

  1. Hariharan S et al. Kidney Int 2002;62:311-8.
  2. Lenihan CR et al. Ren Fail 2008;30:345-52.
  3. Salvadori M et al. Transplantation
2006;81(2):202-6.
  4. Council of Europe. International Figures on Donation and
Transplantation –– 2009: Transplant Newsletter
2010;15:1––76.
  5. Belatacept European SmPC.
  6. European Medicines Agency. Summary of opinion
EMA/CHMP/273603/2011. 14 April 2011.available on href="www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_Initial_authorisation/human/002098/WC500105253.pdf">
www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_Initial_authorisation/human/002098/WC500105253.pdf  

  7. Vincenti F et al. ATC 2011; Abstract 227.
  8. Medina Pestana J et al. ATC 2011; Abstract 1088.
  9. Ojo AO et al. J Am Soc Nephrol 2001;12:589––97.
  10. Larsen C. et al. ATC 2011; Abstract 228.

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