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

Paris (ots/PRNewswire) -

- European Commission approves NULOJIX(R) (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(R) (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(R) (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(R) (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 http://www.ema.europa.eu/docs/en_GB/document_librar
y/Summary_of_opinion_Init
ial_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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