Bristol-Myers Squibb GmbH & Co.KG aA

YERVOY? (ipilimumab) Approved for the Treatment of Previously-Treated Advanced Melanoma in the EU

Paris (ots/PRNewswire) -

        - First and Only Approved Therapy for Pre-treated Unresectable
          or Metastatic Melanoma to Demonstrate a Significant Improvement in
          Overall Survival
        - First EU-Approved Therapy for Pre-treated Unresectable or
          Metastatic Melanoma in More Than Two Decades 

Bristol-Myers Squibb today announced that the European Commission has approved YERVOY(TM) (ipilimumab) for the treatment of adult patients with previously-treated advanced melanoma.

YERVOY, an innovative immunotherapy, showed long-term survival in the treatment of patients with advanced melanoma in a randomised, double-blind Phase III study published in the New England Journal of Medicine in June 2010.[1] Based on the survival (Kaplan-Meier) curve, the 1 and 2-year estimated survival rates for patients treated with YERVOY were 46% and 24% respectively vs. 25% and 14% in the comparator arm with some patients alive at 3 and 4 years.

"With the approval of YERVOY physicians now have an important new option to offer to patients with metastatic melanoma. This is a chance of not just months but potentially 3 to 4 years of prolonged survival for some patients in the treatment of metastatic melanoma," comments Professor Alexander Eggermont, General Director, Institut Gustave Roussy, Paris, France. "There is hope that YERVOY's novel mode of action, together with the fact that the recommended complete course of treatment with YERVOY (3 mg/kg) includes 4 infusions over 3 months, could potentially change the way we treat patients with previously treated advanced melanoma. It is an example of what can be done through unleashing the power of one's own immune response."

Bristol-Myers Squibb will now work closely with local health authorities to expedite the availability of YERVOY across the European Union. Prior to approval, the Company provided ipilimumab to nearly 3,000 patients throughout Europe through Compassionate Use / Named Patient Programmes. The Company remains committed to helping ensure that appropriate patients who need YERVOY will receive it while the reimbursement process is finalised by the relevant authorities throughout Europe.

Ron Cooper, President Bristol-Myers Squibb Europe, stated:"With an average survival time on diagnosis of 6-9 months, patients with advanced melanoma have had little hope - until now. The European Union approval of YERVOY is a milestone for patients with advanced disease and is the first outcome of Bristol-Myers Squibb's commitment to immuno-oncology. Through the Bristol-Myers Squibb String of Pearls strategy, we began a collaboration with Medarex, acquired the company and developed YERVOY. We will continue this strategy to seek and establish collaborations with other leading innovators across the globe. Through these and other initiatives we work towards our single mission: to discover, develop and deliver innovative medicines that help patients prevail over serious diseases."

YERVOY represents a new treatment paradigm in the evolving discipline of immuno-oncology. It indirectly targets the tumour by stimulating the patient's immune system to recognise and destroy cancer cells.[2] YERVOY specifically blocks cytotoxic T lymphocyte antigen 4 (CTL4), which plays a role in suppressing the normal immune response. YERVOY blocks that suppression to allow the immune system to respond to melanoma cancer cells.

The types of adverse events (AEs) attributed to YERVOY are generally mechanism (immune)-based. YERVOY can result in severe and fatal immune-related adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and clinical chemistries should be evaluated, including liver function tests and thyroid function tests, at baseline and before each dose.

Adverse events associated with YERVOY are managed with protocol-specific guidelines, including the administration of systemic corticosteroids, dose interruption/discontinuation and/or other immunosuppressants.

About Advanced Melanoma

Melanoma is a form of skin cancer characterised by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin.[3] Advanced melanoma occurs when cancer spreads beyond the surface of the skin to other organs, such as the lymph nodes, lungs, brain or other areas of the body. Some cancer cells can actively evade surveillance by the immune system, allowing tumours to survive.

Melanoma is mostly curable when treated in its early stages.[4] However, metastatic melanoma is one of the most aggressive forms of cancer with 75% of people dying within one year.[5] Due to the very poor prognosis and lack of effective treatments for patients with stage III unresectable and stage IV metastatic melanoma, there remains a significant unmet medical need.

Unlike most other solid tumours, melanoma affects younger, middle aged people. The median age at diagnosis for melanoma is 57 and the median age at death is 67.[6]

About YERVOY (ipilimumab)

YERVOY, which is a recombinant, human monoclonal antibody, blocks the cytotoxic T- lymphocyte antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. YERVOY binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of YERVOY's effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumour immune responses.

On 25th March 2011, the US Food and Drug Administration (FDA) approved YERVOY 3 mg/kg for the treatment of patients with unresectable (inoperable) or metastatic melanoma in the US.

About the Reference Data - MDX010-020 Study: Improved Survival with Ipilimumab in Patients with Pre-Treated Metastatic Melanoma

The approval is based on a Phase 3, double-blind study that randomized 676 patients with unresectable or metastatic melanoma who were previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin.Patients were randomized in a 3:1:1 ratio to receive either YERVOY (ipilimumab) (3mg/kg) in combination with the investigational peptide vaccine gp100 (n=403), YERVOY alone (3mg/kg; n=137), or gp100 alone (n=136).

The primary endpoint of the pivotal Phase 3 study was overall survival in the YERVOY plus gp100 arm vs. the gp100 arm. Secondary efficacy endpoints included overall survival in the YERVOY plus gp100 arm vs. the YERVOY arm, overall survival in the YERVOY arm vs. the gp100 arm, Best Overall Response Rate ("BORR") at week 24 and duration of response.

Patients received YERVOY (3mg/kg) as an intravenous infusion administered over 90 minutes every 3 weeks for four doses. Assessment of tumor response to YERVOY was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively. Between 57% and 64% of patients treated in each study arm received all four planned doses.

YERVOY was studied in patients with a typically poor prognosis, including those with brain metastases, elevated LDH, and visceral disease (M1c). In the study, 71% had M1c stage, 12% had a history of previously-treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldeskeukin and 38% had elevated LDH level. Additionally, 29% of patients were 65 years or older with a median age of 57 years.The median duration of follow-up was 8.9 months.

Kaplan-Meier estimated survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the YERVOY armvs. 25% (95% CI: 18.1, 32.9) in the gp100 arm. The estimated survival rate at 2 years was 24% (95% CI: 16.0, 31.5) in the YERVOY arm vs. 14%[2] (95% CI: 8.0, 20.0) in the gp100 arm. Patients treated with YERVOY had a 34% reduction in the risk of death over the gp100 control arm (HR = 0.66 [95% CI: 0.51-0.87], P=0.0026). Patients treated with YERVOY (ipilimumab) plus gp100 had a 32% reduction in the risk of death over the gp100 control arm (HR = 0.68 [95% CI: 0.55-0.85], P=0.0004). Median overall survival was 10 (95% CI: 8.0-13.8), 10 (95% CI: 8.5-11.5) and 6 (95% CI: 5.5-8.7) months for the YERVOY alone, YERVOY + gp100 arm and gp100 alone arms, respectively.

In patients who received 3 mg/kg YERVOY alone (n=131), severe to fatal immune-related adverse reactions were reported and included enterocolitis (7%), endocrinopathy (4%, all of which had hypopituitarism), dermatitis (2%), hepatitis (1%), neuropathy (1%), nephritis (1%), and eosinophilia (1%).In patients who received 3 mg/kg of YERVOY + gp100 (n=380) severe to fatal immune-related adverse reactions were reported and included enterocolitis (7%), hepototoxicity (2%), dermatitis (3%), endocrinopathy (1%, hypopituitarism, 1% adrenal insufficiency), pneumonitis (<1%), meningitis (<1%), pericarditis (<1%).The most common adverse reactions were fatigue (41%), diarrhoea (32%), pruritus (31%), rash (29%) and colitis (8%) for the YERVOY alone arm, diarrhoea (37%), fatigue (34%), rash (25%), pruritus (21%), and colitis (5%) for the YERVOY +gp100 arm, and fatigue (31%), diarrhoea (20%), pruritus (11%), rash (8%), and colitis (2%) for gp100 arm. YERVOY therapy was discontinued for adverse reactions in 10% of patients.

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 over serious diseases.

This press release contains "forward-looking statements" as that 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 the product described in this release will become commercially successful. 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, 2010, 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.

1. Hodi FS et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 2010;363(8):711-23.

2. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune related adverse events. Oncologist 2007;12:864-72.

3. Skin Cancer Foundation. What is melanoma? Available at http://www.skincancer.org/Melanoma. Accessed July 2011.

4. American Cancer Society. Melanoma skin cancer. Can melanoma be found early? Available at http://www.cancer.org/cancer/skincancer-mel anoma/detailedguide/melanoma-skin -cancer-detection. Accessed July 2011.

5. Korn E et al. Meta-analysis of phase 2 cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase 2 trials. J Clin Oncol 2008;26:527-534.

6. Markovic SN et al. Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc. 2007;82:364-380.

Contact:

Media Contact: Elzbieta Zawislak,
+33-615-523-580,elzbieta.zawislak@bms.com



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