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

PARIS, June 20, 2011 /PRNewswire/ --

• 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 http://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.