Overall Survival and Safety Profile of YERVOY in Patients with Unresectable or Metastatic Melanoma

Transcription

1 FDA Apprves YERVOY (ipilimumab) fr the Treatment f Patients with Newly Diagnsed r Previusly-Treated Unresectable r Metastatic Melanma, the Deadliest Frm f Skin Cancer First and Only Apprved Therapy fr Unresectable r Metastatic Melanma t Demnstrate a Significant Imprvement in Overall Survival First FDA-Apprved Therapy fr Unresectable r Metastatic Melanma in Mre than a Decade First Apprved Cancer Immuntherapy fr Melanma t Target CTLA-4 and First FDA-Apprved Cmpund in the Cmpany s Rbust Immun-Onclgy Pipeline Risk Evaluatin and Mitigatin Strategy Develped with FDA t Supprt the Safe and Apprpriate Use f YERVOY and Help Infrm Patients and Prviders Abut Imprtant Safety Risks (Princetn, NJ, March 25, 2011) Bristl-Myers Squibb Cmpany (NYSE: BMY) tday annunced that the U.S. Fd and Drug Administratin (FDA) apprved YERVOY (ipilimumab) 3 mg/kg fr the treatment f patients with unresectable (inperable) r metastatic melanma. YERVOY is the first and nly therapy fr unresectable r metastatic melanma t demnstrate a significant imprvement in verall survival based n results frm a pivtal randmized, duble-blind Phase 3 study. Median verall survival was 10 mnths (95% CI: ) fr YERVOY, 6 mnths (95% CI: ) fr gp100 and 10 mnths (95% CI: ) fr YERVOY + gp100, with p-values f (nt adjusted fr multiple cmparisns) fr YERVOY and fr YERVOY + gp100 vs. gp100, respectively. As published in the New England Jurnal f Medicine, the Kaplan-Meier estimated survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the YERVOY arm vs. 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. YERVOY, which is a recmbinant, human mnclnal antibdy, is the first FDA-apprved cancer immuntherapy that blcks the cyttxic T- lymphcyte antigen-4 (CTLA-4). The full Prescribing Infrmatin fr YERVOY includes a bxed warning fr immune-mediated adverse reactins. YERVOY can result in severe and fatal immune-mediated adverse reactins due t T-cell activatin and prliferatin. These immune-mediated reactins may invlve any rgan system; hwever, the mst cmmn severe immune-mediated adverse reactins are enterclitis, hepatitis, dermatitis (including txic epidermal necrlysis), neurpathy, and endcrinpathy. The majrity f these immune-mediated reactins initially manifested during treatment; hwever, a minrity ccurred weeks t mnths after discntinuatin f YERVOY (ipilimumab). Permanently discntinue YERVOY and initiate systemic high-dse crticsterid therapy fr severe immune-mediated reactins. Patients shuld be assessed fr signs and symptms f enterclitis, dermatitis, neurpathy and endcrinpathy and clinical chemistries shuld be evaluated, including liver functin tests and thyrid functin tests, at baseline and befre each dse. Please see cmplete Imprtant Safety Infrmatin including Bxed WARNING regarding immune-mediated adverse reactins n pages 6-9.

2 2 Metastatic melanma is ne f the mst aggressive frms f cancer and despite the rising incidence, n new treatments have been apprved in mre than a decade, said Lambert Andretti, chief executive fficer, Bristl-Myers Squibb. Tday s apprval f YERVOY is an example f Bristl-Myers Squibb living its missin f develping and delivering innvative medicines that address the unmet needs f patients with serius diseases. It als represents a significant step frward in ur cmmitment t deliver and execute against ur differentiated and fcused BiPharma strategy. Fr the first time, nclgists have a treatment ptin fr patients with unresectable r metastatic melanma that has been prven in a randmized Phase 3 clinical trial t significantly extend the lives f patients, said Steven J. O Day, M.D., Chief f Research and Directr f the Melanma Prgram at The Angeles Clinic and Research Institute, Califrnia, and an investigatr f the pivtal trial. In fact, the Kaplan- Meier curve frm this study suggests a prlnged survival benefit fr sme patients. Median verall survival was 10 mnths (95% CI: ) fr YERVOY (ipilimumab), 6 mnths (95% CI: ) fr gp100 and 10 mnths (95% CI: ) fr YERVOY + gp100, with p-values f (nt adjusted fr multiple cmparisns) fr YERVOY and fr YERVOY + gp100 vs gp100, respectively. The FDA apprval f YERVOY is the culminatin f mre than 14 years f research and develpment by ur dedicated develpment teams and clinical trial investigatrs, said Ellitt Sigal, M.D., Ph.D., executive vice president, chief scientific fficer, and president, Research & Develpment, Bristl-Myers Squibb. YERVOY is the first FDA-apprved cmpund frm ur rbust immun-nclgy pipeline, which cmprises a variety f ther cmpunds with the ptential t harness the patient s immune system t fight cancer. The mechanism f actin f ipilimumab s effect in patients with melanma is indirect, pssibly thrugh T-cell mediated anti-tumr immune respnses. Bristl-Myers Squibb has agreed with the FDA t cnduct a pst-marketing study cmparing the safety and efficacy f the 3 mg/kg dse vs. an investigatinal 10 mg/kg dse in patients with unresectable r metastatic melanma. The cmpany expects t begin shipping YERVOY within weeks f tday s FDA apprval. Overall Survival and Safety Prfile f YERVOY in Patients with Unresectable r Metastatic Melanma YERVOY is the first and nly therapy t demnstrate a statistically significant verall survival benefit in patients with unresectable r metastatic melanma. The apprval is based n a Phase 3, randmized (3:1:1), duble-blind study that included 676 patients with unresectable r metastatic melanma wh were previusly treated with ne r mre f the fllwing: aldesleukin, dacarbazine, temzlmide, ftemustine, r carbplatin. As published in the New England Jurnal f Medicine, the Kaplan-Meier estimated survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the YERVOY arm vs. 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% reductin in the risk f death ver the

3 3 gp100 cntrl arm (HR = 0.66 [95% CI: ], P=0.0026). Patients treated with YERVOY (ipilimumab) plus gp100 had a 32% reductin in the risk f death ver the gp100 cntrl arm (HR = 0.68 [95% CI: ], P=0.0004). Median verall survival was 10 (95% CI: ), 10 (95% CI: ) and 6 (95% CI: ) mnths fr the YERVOY alne, YERVOY + gp100 arm and gp100 alne arms, respectively. The best verall respnse rate (BORR) as assessed by the investigatr was 10.9% (95% CI: 6.3, 17.4) in patients treated with YERVOY (ipilimumab) (n=15 f 137), 5.7% (95% CI: 3.7, 8.4) in the YERVOY + gp100 arm (n=23 f 403) and 1.5% (95% CI: 0.2, 5.2) in the gp100 arm (n=2 f 136). BORR is defined as the ttal number f patients with the best respnse f a cmplete respnse (CR) r a partial respnse (PR) divided by the ttal number f patients treated. The median duratin f respnse was 11.5 mnths in the YERVOY + gp100 arm and has nt been reached in the YERVOY r gp100 arm at the time f the analysis because mre than half f patients wh had a cnfirmed CR r PR remained free f any relapse. In patients wh received 3 mg/kg YERVOY alne (n=131), severe t fatal immune-mediated adverse reactins were reprted and included enterclitis (7%), endcrinpathy (4%, all f which had hyppituitarism), dermatitis (2%), hepatitis (1%), neurpathy (1%), nephritis (1%), and esinphilia (1%). In patients wh received 3 mg/kg f YERVOY + gp100 (n=380) severe t fatal immune-mediated adverse reactins were reprted and included enterclitis (7%), hepttxicity (2%), dermatitis (3%), endcrinpathy (1%, hyppituitarism, 1% adrenal insufficiency), pneumnitis (<1%), meningitis (<1%), pericarditis (<1%).The mst cmmn adverse reactins were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%) and clitis (8%) fr the YERVOY alne arm, diarrhea (37%), fatigue (34%), rash (25%), pruritus (21%), and clitis (5%) fr the YERVOY +gp100 arm, and fatigue (31%), diarrhea (20%), pruritus (11%), rash (8%), and clitis (2%) fr gp100 arm. YERVOY therapy was discntinued fr adverse reactins in 10% f patients. Please see cmplete Imprtant Safety Infrmatin including Bxed WARNING regarding immune-mediated adverse reactins n pages 6-9. Results frm this study were previusly published in the New England Jurnal f Medicine and presented during a plenary sessin at the 46th Annual Meeting f the American Sciety f Clinical Onclgy. YERVOY: Risk Evaluatin and Mitigatin Strategy Bristl-Myers Squibb is cmmitted t the safe and apprpriate use f ur medicines, said Annalisa Jenkins, senir vice president glbal medical, Bristl-Myers Squibb. As part f the U.S. apprval f YERVOY, we have cllabrated with the FDA n the develpment f a Risk Evaluatin and Mitigatin Strategy t help infrm patients and prviders abut imprtant safety risks assciated with YERVOY. The YERVOY Risk Evaluatin and Mitigatin Strategy (REMS) cnsists f a Cmmunicatin Plan t infrm ptential prescribers and supprtive healthcare prviders abut serius adverse reactins assciated with YERVOY. T supprt this cmmunicatin plan, Bristl-Myers Squibb has put in place a system that will enable

4 4 the cmpany t deliver these educatinal materials t the apprpriate healthcare prfessinal at the time f prduct rder. Mre infrmatin and dwnladable safety educatin materials will be available at YERVOY Was Studied in a Pivtal Phase 3 Clinical Trial f Patients with Unresectable r Metastatic Melanma The apprval is based n a Phase 3, duble-blind study that randmized 676 patients with unresectable r metastatic melanma wh were previusly treated with ne r mre f the fllwing: aldesleukin, dacarbazine, temzlmide, ftemustine, r carbplatin. Patients were randmized in a 3:1:1 rati t receive either YERVOY (ipilimumab) (3mg/kg) in cmbinatin with the investigatinal peptide vaccine gp100 (n=403), YERVOY alne (3mg/kg; n=137), r gp100 alne (n=136). The primary endpint f the pivtal Phase 3 study was verall survival in the YERVOY plus gp100 arm vs. the gp100 arm. Secndary efficacy endpints included verall survival in the YERVOY plus gp100 arm vs. the YERVOY arm, verall survival in the YERVOY arm vs. the gp100 arm, BORR at week 24 and duratin f respnse. Patients received YERVOY (3mg/kg) as an intravenus infusin administered ver 90 minutes every 3 weeks fr fur dses. Assessment f tumr respnse t YERVOY was cnducted at weeks 12 and 24, and every 3 mnths thereafter. Patients with evidence f bjective tumr respnse at 12 r 24 weeks had assessment fr cnfirmatin f durability f respnse at 16 r 28 weeks, respectively. Between 57% and 64% f patients treated in each study arm received all fur planned dses. YERVOY was studied in patients with a typically pr prgnsis, including thse with brain metastases, elevated LDH, and visceral disease (M1c). In the study, 71% had M1c stage, 12% had a histry f previusly-treated brain metastasis, 98% had ECOG perfrmance status f 0 and 1, 23% had received aldeskeukin and 38% had elevated LDH level. Additinally, 29% f patients were 65 years r lder with a median age f 57 years. The median duratin f fllw-up was 8.9 mnths. Please see cmplete Imprtant Safety Infrmatin including Bxed WARNING regarding immune-mediated adverse reactins n pages 6-9. YERVOY: Mechanism f Actin Cyttxic T-lymphcyte antigen-4 (CTLA-4) is a negative regulatr f T-cell activatin. Ipilimumab binds t CTLA-4 and blcks the interactin f CTLA-4 with its ligands, CD80/CD86. Blckade f CTLA-4 has been shwn t augment T-cell activatin and prliferatin. The mechanism f actin f ipilimumab s effect in patients with melanma is indirect, pssibly thrugh T-cell mediated anti-tumr immune respnses.

5 5 Abut the YERVOY Filing YERVOY (ipilimumab) was granted rphan drug status in 2004, which is a designatin given t drugs that treat rare diseases. In 2006, YERVOY received a fast track designatin. The FDA s fast track prcess is designed t facilitate the develpment, and expedite the review, f drugs t treat serius diseases and fill an unmet medical need. The purpse is t get imprtant new drugs t the patient earlier. In August f 2010, YERVOY received a pririty review designatin, which is given t drugs that ffer majr advances in treatment, r prvide a treatment where n adequate therapy exists. Metastatic Melanma is the Deadliest Frm f Skin Cancer Melanma is a frm f skin cancer characterized by the uncntrlled grwth f pigment-prducing cells (melancytes) lcated in the skin. Metastatic melanma is the deadliest frm f the disease, and ccurs when cancer spreads beynd the surface f the skin t ther rgans, such as the lymph ndes, lungs, brain r ther areas f the bdy. Sme cancer cells can actively evade surveillance by the immune system, allwing tumrs t survive. Melanma is mstly curable when treated in its early stages. Hwever, in its late stages, the average survival rate is just 6 mnths with a 1-year mrtality rate f 75%, making it ne f the mst aggressive frms f cancer. These rates are based n a meta-analysis f 42 Phase 2 trials f mre than 2,100 previusly-treated and treatment-naïve patients with Stage IV metastatic melanma cnducted by multiple cperative grups frm Metastatic melanma is a devastating disease and treating it has been a significant challenge, said Tim Turnham, executive directr f the Melanma Research Fundatin. The incidence f melanma has been increasing fr at least 30 years. The median age at diagnsis fr melanma is 57 and the median age at death is 67. Abut Bristl-Myers Squibb s Patient Access Prgrams Bristl-Myers Squibb is cmmitted t supprting patient access t YERVOY and has put in place a number f prgrams t help patients and prviders. Destinatin Access, which is the Bristl-Myers Squibb Reimbursement Supprt Prgram, is a cmprehensive service that supprts patient access by prviding benefits investigatin supprt, prir authrizatin assistance, appeals assistance and patient assistance. Mre infrmatin abut ur patient assistance prgram can be btained by calling In additin t Destinatin Access, Bristl-Myers Squibb has develped the YERVOY C-Pay Prgram t help eligible, cmmercially insured patients wh have been prescribed YERVOY fr unresectable r metastatic melanma with their c-pay r c-insurance csts fr this drug. Additinal infrmatin abut this prgram will be available at

6 6 Imprtant Safety Infrmatin WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactins due t T-cell activatin and prliferatin. These immune-mediated reactins may invlve any rgan system; hwever, the mst cmmn severe immune-mediated adverse reactins are enterclitis, hepatitis, dermatitis (including txic epidermal necrlysis), neurpathy, and endcrinpathy. The majrity f these immune-mediated reactins initially manifested during treatment; hwever, a minrity ccurred weeks t mnths after discntinuatin f YERVOY. Assess patients fr signs and symptms f enterclitis, dermatitis, neurpathy and endcrinpathy and evaluate clinical chemistries including liver functin tests (LFTs) and thyrid functin tests at baseline and befre each dse. Permanently discntinue YERVOY and initiate systemic high-dse crticsterid therapy fr severe immune-mediated reactins. Recmmended Dse Mdificatins Withhld dse fr mderate immune-mediated adverse reactins until return t baseline, imprvement t mild severity, r cmplete reslutin, and patient is receiving <7.5 mg prednisne r equivalent per day. Permanently discntinue YERVOY fr any f the fllwing: Persistent mderate adverse reactins r inability t reduce crticsterid dse t 7.5 mg prednisne r equivalent per day. Failure t cmplete full treatment curse within 16 weeks frm administratin f first dse. Severe r life-threatening adverse reactins. Immune-mediated Enterclitis: In the pivtal Phase 3 study in YERVOY-treated patients, severe, life-threatening r fatal (diarrhea f 7 stls abve baseline, fever, ileus, peritneal signs; Grade 3-5) immune-mediated enterclitis ccurred in 34 (7%) and mderate (diarrhea with up t 6 stls abve baseline, abdminal pain, mucus r bld in stl; Grade 2) enterclitis ccurred in 28 (5%) patients. Acrss all YERVOY-treated patients (n=511), 5 (1%) develped intestinal perfratin, 4 (0.8%) died as a result f cmplicatins, and 26 (5%) were hspitalized fr severe enterclitis. Mnitr patients fr signs and symptms f enterclitis (such as diarrhea, abdminal pain, mucus r bld in stl, with r withut fever) and f bwel perfratin (such as peritneal signs and ileus).

7 7 In symptmatic patients, rule ut infectius etilgies and cnsider endscpic evaluatin fr persistent r severe symptms. Immune-mediated Hepatitis: In the pivtal Phase 3 study in YERVOY-treated patients, severe, life-threatening, r fatal hepattxicity (AST r ALT elevatins >5X the upper limit f nrmal (ULN) r ttal bilirubin elevatins >3X the ULN; Grade 3 5) ccurred in 8 (2%), with fatal hepatic failure in 0.2% and hspitalizatin in 0.4%. 13 (2.5%) additinal YERVOY-treated patients experienced mderate hepattxicity manifested by LFT abnrmalities (AST r ALT elevatins >2.5X but 5X the ULN r ttal bilirubin elevatin >1.5X but 3X the ULN; Grade 2). Mnitr LFTs (hepatic transaminase and bilirubin levels) and assess patients fr signs and symptms f hepattxicity befre each dse f YERVOY. In patients with hepattxicity, rule ut infectius r malignant causes and increase frequency f LFT mnitring until reslutin. Immune-mediated Dermatitis: In the pivtal Phase 3 study in YERVOY-treated patients, severe, life-threatening r fatal immunemediated dermatitis (e.g., Stevens-Jhnsn syndrme, txic epidermal necrlysis, r rash cmplicated by full thickness dermal ulceratin, r necrtic, bullus, r hemrrhagic manifestatins; Grade 3 5) ccurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result f txic epidermal necrlysis. 1 additinal patient required hspitalizatin fr severe dermatitis. There were 63 (12%) YERVOY-treated patients with mderate (Grade 2) dermatitis. Mnitr patients fr signs and symptms f dermatitis such as rash and pruritus. Unless an alternate etilgy has been identified, signs r symptms f dermatitis shuld be cnsidered immune-mediated. Immune-mediated Neurpathies: In the pivtal Phase 3 study in YERVOY-treated patients, 1 case f fatal Guillain-Barré syndrme and 1 case f severe (Grade 3) peripheral mtr neurpathy were reprted. Acrss the clinical develpment prgram f YERVOY, myasthenia gravis and additinal cases f Guillain-Barré syndrme have been reprted.

8 8 Mnitr fr symptms f mtr r sensry neurpathy such as unilateral r bilateral weakness, sensry alteratins, r paresthesia. Immune-Mediated Endcrinpathies: In the pivtal Phase 3 study in YERVOY- treated patients, severe t life-threatening immune-mediated endcrinpathies (requiring hspitalizatin, urgent medical interventin, r interfering with activities f daily living; Grade 3-4) ccurred in 9 (1.8%). All 9 patients had hyppituitarism and sme had additinal cncmitant endcrinpathies such as adrenal insufficiency, hypgnadism, and hypthyridism. 6 f the 9 patients were hspitalized fr severe endcrinpathies. Mderate endcrinpathy (requiring hrmne replacement r medical interventin; Grade 2) ccurred in 12 (2.3%) YERVOY-treated patients and cnsisted f hypthyridism, adrenal insufficiency, hyppituitarism, and 1 case each f hyperthyridism and Cushing s syndrme. Median time t nset f mderate t severe immune-mediated endcrinpathy was 11 weeks and ranged up t 19.3 weeks after the initiatin f YERVOY. Mnitr patients fr clinical signs and symptms f hypphysitis, adrenal insufficiency (including adrenal crisis), and hyper- r hypthyridism. Patients may present with fatigue, headache, mental status changes, abdminal pain, unusual bwel habits, and hyptensin, r nnspecific symptms which may resemble ther causes such as brain metastasis r underlying disease. Unless an alternate etilgy has been identified, signs r symptms f endcrinpathies shuld be cnsidered immune-mediated. Mnitr thyrid functin tests and clinical chemistries at the start f treatment, befre each dse, and as clinically indicated based n symptms. In a limited number f patients, hypphysitis was diagnsed by imaging studies thrugh enlargement f the pituitary gland. Other Immune-mediated Adverse Reactins, Including Ocular Manifestatins: In the pivtal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactins seen in <1% were: nephritis, pneumnitis, meningitis, pericarditis, uveitis, iritis, and hemlytic anemia. Acrss the clinical develpment prgram fr YERVOY, immune-mediated adverse reactins als reprted with <1% incidence were: mycarditis, angipathy, tempral arteritis, vasculitis, plymyalgia

9 9 rheumatica, cnjunctivitis, blepharitis, episcleritis, scleritis, leukcytclastic vasculitis, erythema multifrme, psriasis, pancreatitis, arthritis, and autimmune thyriditis. Pregnancy & Nursing: YERVOY is classified as pregnancy categry C. There are n adequate and well-cntrlled studies f YERVOY in pregnant wmen. Use YERVOY during pregnancy nly if the ptential benefit justifies the ptential risk t the fetus. Human IgG1 is knwn t crss the placental barrier and YERVOY is an IgG1; therefre, YERVOY has the ptential t be transmitted frm the mther t the develping fetus. It is nt knwn whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because f the ptential fr serius adverse reactins in nursing infants frm YERVOY, a decisin shuld be made whether t discntinue nursing r t discntinue YERVOY. Cmmn Adverse Reactins: The mst cmmn adverse reactins ( 5%) in patients wh received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and clitis (8%). Please see full Prescribing Infrmatin, including Bxed Warnings regarding Immune-related side effects at r Immun-Onclgy at Bristl-Myers Squibb Immun-nclgy, which fcuses n the scientific ptential f harnessing the unique prperties f the immune system t fight cancer, is a key area f fcus at Bristl-Myers Squibb. A variety f cmpunds and immuntherapeutic appraches are being explred fr patients with different types f cancer. The substantial ptential f the immune system s intrinsic ability t fight cancer is fundamental t the immun-nclgy research at Bristl-Myers Squibb and its nging cmmitment t shaping and advancing cancer care. The mechanism f actin f ipilimumab s effect in patients with melanma is indirect, pssibly thrugh T-cell mediated anti-tumr immune respnses. Abut Bristl-Myers Squibb Bristl-Myers Squibb is a glbal bipharmaceutical cmpany whse missin is t discver, develp and deliver innvative medicines that help patients prevail ver serius diseases. Fr mre infrmatin abut Bristl-Myers Squibb, visit r fllw us n Twitter at This press release cntains "frward-lking statements" as that term is defined in the Private Securities Litigatin Refrm Act f 1995 regarding prduct develpment. Such frward-lking statements are based n current expectatins and invlve inherent risks and uncertainties, including factrs that culd delay, divert r

10 10 change any f them, and culd cause actual utcmes and results t differ materially frm current expectatins. N frward-lking statement can be guaranteed. Amng ther risks, there can be n guarantee that ipilimumab will becme a cmmercially successful prduct. Frward-lking statements in this press release shuld be evaluated tgether with the many uncertainties that affect Bristl-Myers Squibb's business, particularly thse identified in the cautinary factrs discussin in Bristl-Myers Squibb's Annual Reprt n Frm 10-K fr the year ended December 31, 2010, in ur Quarterly Reprts n Frm 10-Q and ur Current Reprts n Frm 8-K. Bristl-Myers Squibb undertakes n bligatin t publicly update any frward-lking statement, whether as a result f new infrmatin, future events r therwise. # # # Media: Sarah Kenig, , sarah.kenig@bms.cm Investrs: Jhn Elicker, , jhn.elicker@bms.cm