`
`http://news.bms.com/press-release/rd-news/bristol-myers-squibb-reports-...
`
`Bristol-Myers Squibb Reports Results for Phase 3 Trial of
`Yervoy® (Ipilimumab) in Previously-Treated Castration-
`Resistant Prostate Cancer
`Primary endpoint of overall survival did not reach statistical significance
`in this advanced patient population (p=0.053); however, anti-tumor
`activity was observed in other efficacy endpoints, including
`progression-free survival
`
`Drug-related adverse events were mostly immune-related, consistent
`with those observed previously with Yervoy
`
`Phase 3 trial (Study 095) assessing overall survival of Yervoy in
`patients with less advanced castration-resistant prostate cancer who
`have received no prior cytotoxic treatment is ongoing
`
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`Category: R&D News
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`Thursday, September 12, 2013 4:01 am EDT
`
`PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb
`Company (NYSE:BMY) today reported results from the Phase 3
`randomized, double-blind clinical trial (Study 043) comparing
`Yervoy 10 mg/kg (ipilimumab) (n=399) to placebo (n=400)
`following radiation in patients with advanced metastatic
`castration-resistant prostate cancer (mCRPC) who have
`received prior treatment with docetaxel. The study’s primary
`endpoint of overall survival (OS) did not reach statistical
`significance (HR = 0.85; 95% CI = 0.72-1.00; p = 0.053).
`However, anti-tumor activity was observed across some
`efficacy endpoints, including progression free-survival. These
`data will be presented at the 2013 European Cancer Congress
`in an oral session on September 28 (Abstract # 2850).
`
`"These results
`offer important
`insights for
`ongoing and
`future studies of
`Yervoy in
`prostate cancer,
`including a
`second large trial
`of Yervoy in
`patients with less
`advanced
`disease."
`
`Treatment-related adverse events were common, with most
`being immune-related (irAEs), and were managed using standard Yervoy management
`protocols. Grade ≥3 irAEs in the Yervoy and placebo arms, respectively, were
`gastrointestinal (GI; 18% vs. 1%), liver (5% vs. 1%), endocrine (2% vs. 1%), and
`dermatologic (1% vs. 0%). The incidence of drug-related death was 1%.
`
`“While we are disappointed that the primary endpoint of overall survival was not met,
`we remain encouraged that results in this advanced population support the potential
`role of immunotherapies for prostate cancer. We are committed to continuing our
`development of Yervoy in prostate cancer,” said Brian Daniels, senior vice president,
`Global Development and Medical Affairs, Bristol-Myers Squibb. “Immuno-oncology is a
`rapidly evolving treatment modality and findings from this study provide important
`scientific insights that can be applied to current and future studies of Yervoy as well as
`our broad pipeline of immunotherapies in development.”
`
`Yervoy 3 mg/kg monotherapy is currently approved in more than 40 countries for the
`treatment of patients with unresectable or metastatic melanoma.
`
`“Although the study did not meet its primary endpoint, clinical activity was observed in
`this Phase 3 trial with a suggestion of greater activity in those with less advanced
`castration-resistant prostate cancer,” said W.R. Gerritsen, MD, Radboud University
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`002008
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`AVENTIS EXHIBIT 2008
`Mylan v. Aventis, IPR2016-00712
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`Bristol-Myers Squibb Reports Results for Phase 3 Trial of Yervoy® (Ipi...
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`http://news.bms.com/press-release/rd-news/bristol-myers-squibb-reports-...
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`Nijmegen Medical Centre, Nijmegen, Netherlands. “These results offer important
`insights for ongoing and future studies of Yervoy in prostate cancer, including a second
`large trial of Yervoy in patients with less advanced disease.”
`
`The Phase 3 program for Yervoy includes Study 095, an ongoing Phase 3 randomized
`double-blind trial comparing the efficacy of Yervoy 10 mg/kg versus placebo in patients
`with mCRPC who have not received prior cytotoxic treatment. Yervoy is also being
`studied in Phase 3 trials in adjuvant melanoma and non-small cell lung cancer.
`
`Study 043 Results
`
`In the intent-to-treat population, the median OS was 11.2 months for Yervoy and 10
`months for placebo and the hazard ratio was 0.85 (95% CI = 0.72-1.00; p = 0.053).
`The one- and two-year survival rates for Yervoy versus placebo were 47% versus
`40%, and 26% versus 15%, respectively.
`
`Median progression-free survival favored Yervoy over placebo (HR=0.70; 95% CI =
`0.61-0.82) as did prostate-specific antigen (PSA) response rates, as evidenced by
`declines of ≥50% in evaluable patients (13.1% vs. 5.3%, respectively). Pre-specified
`subset analyses suggest that Yervoy may be more active in patients with indicators for
`less advanced disease.
`
`Treatment-related adverse events were common and most were immune-related.
`Grade ≥3 irAEs in the Yervoy and placebo arms, respectively, were gastrointestinal
`(GI; 18% vs. 1%), liver (5% vs. 1%), endocrine (2% vs. 1%), and dermatologic (1%
`vs. 0%). Most were managed using standard Yervoy management protocols, including
`the administration of systemic corticosteroids, dose interruption/discontinuation and/or
`other immunosuppressants. Incidences of drug-related death and GI perforation, per
`investigator assessment, were 1% and 0.5%, respectively.
`
`About Study 043
`
`CA-184-043 is a randomized, double-blind, Phase 3 study comparing Yervoy to placebo
`following radiotherapy in patients with CRPC who have received prior treatment with
`docetaxel. Patients received bone-directed radiation therapy after being randomly
`assigned 1:1 to receive Yervoy 10 mg/kg (n=399) or placebo (n=400) every three
`weeks for a total of four doses. Eligible patients received maintenance treatment every
`three months.
`
`Patient baseline characteristics were indicative of advanced disease. Forty-eight
`percent had baseline pain of ≥4, based on the Brief Pain Inventory (BPI), a
`questionnaire used by clinicians to assess and measure pain.
`
`About Prostate Cancer
`
`Prostate cancer is the second most frequently diagnosed cancer and the sixth most
`deadly cancer in men. In the United States, it is estimated that more than 238,000
`men will be diagnosed with prostate cancer and more than 29,700 will die from the
`disease in 2013. Most of these deaths will be caused by metastatic castration-resistant
`prostate cancer, which occurs when the cancer becomes resistant to standard
`hormonal treatment and spreads from the prostate to other organs in the body. New
`treatment options have recently become available for patients with mCPRC, yet the
`disease remains largely incurable.
`
`About Yervoy
`
`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
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`proliferation. The mechanism of action of Yervoy’s effect in patients with melanoma is
`indirect through T-cell mediated anti-tumor immune responses. On March 25, 2011,
`the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or
`metastatic melanoma. Yervoy is now approved in more than 40 countries.
`YERVOY® (ipilimumab) INDICATIONS & IMPORTANT SAFETY INFORMATION
`
`YERVOY is indicated for the treatment of unresectable or metastatic melanoma.
`
`Important Safety Information
`
`WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
`
`YERVOY can result in severe and fatal immune-mediated 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.
`
`Assess patients for signs and symptoms of enterocolitis, dermatitis,
`neuropathy, and endocrinopathy and evaluate clinical chemistries including
`liver function tests (LFTs) and thyroid function tests at baseline and before
`each dose.
`
`Permanently discontinue YERVOY and initiate systemic high-dose
`corticosteroid therapy for severe immune-mediated reactions.
`
`Recommended Dose Modifications
`
`Withhold dose for any moderate immune-mediated adverse reactions or for
`symptomatic endocrinopathy until return to baseline, improvement to mild severity, or
`complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per
`day.
`
`Permanently discontinue YERVOY for any of the following:
`
`Persistent moderate adverse reactions or inability to reduce corticosteroid dose
`to 7.5 mg prednisone or equivalent per day
`
`Failure to complete full treatment course within 16 weeks from administration of
`first dose
`
`Severe or life-threatening adverse reactions, including any of the following
`Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in
`stool frequency (≥7 over baseline), stool incontinence, need for
`intravenous hydration for >24 hours, gastrointestinal hemorrhage, and
`gastrointestinal perforation
`
`AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 ×
`the ULN
`
`Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
`complicated by full-thickness dermal ulceration or necrotic, bullous, or
`hemorrhagic manifestations
`
`Severe motor or sensory neuropathy, Guillain-Barré syndrome, or
`myasthenia gravis
`
`Severe immune-mediated reactions involving any organ system
`
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`Immune-mediated ocular disease which is unresponsive to topical
`immunosuppressive therapy
`
`Immune-mediated Enterocolitis:
`
`In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening
`or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs;
`Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate
`(diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in
`stool; Grade 2) enterocolitis occurred in 28 (5%) patients
`
`Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal
`perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were
`hospitalized for severe enterocolitis
`
`Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or
`life-threatening immune-mediated enterocolitis following inadequate response to
`corticosteroids
`
`Monitor patients for signs and symptoms of enterocolitis (such as diarrhea,
`abdominal pain, mucus or blood in stool, with or without fever) and of bowel
`perforation (such as peritoneal signs and ileus). In symptomatic patients, rule
`out infectious etiologies and consider endoscopic evaluation for persistent or
`severe symptoms
`
`Permanently discontinue YERVOY in patients with severe enterocolitis and
`initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent).
`Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over
`at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in
`recurrence or worsening symptoms of enterocolitis in some patients
`
`Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment
`and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day
`prednisone or equivalent)
`
`Immune-mediated Hepatitis:
`
`In the pivotal Phase 3 study in YERVOY-treated patients, severe,
`life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or
`total bilirubin elevations >3x the ULN; Grade 3–5) occurred in 8 (2%) patients,
`with fatal hepatic failure in 0.2% and hospitalization in 0.4%
`
`13 (2.5%) additional YERVOY-treated patients experienced moderate
`hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x
`but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2)
`
`Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for
`signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients
`with hepatotoxicity, rule out infectious or malignant causes and increase
`frequency of LFT monitoring until resolution
`
`Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and
`administer systemic corticosteroids (1-2 mg/kg/day of prednisone or
`equivalent). When LFTs show sustained improvement or return to baseline,
`initiate corticosteroid tapering and continue over 1 month. Across the clinical
`development program for YERVOY, mycophenolate treatment has been
`administered in patients with persistent severe hepatitis despite high-dose
`corticosteroids
`
`Withhold YERVOY in patients with Grade 2 hepatotoxicity
`
`Immune-mediated Dermatitis:
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`In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening
`or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic
`epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or
`necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13
`(2.5%) patients
`1 (0.2%) patient died as a result of toxic epidermal necrolysis
`
`1 additional patient required hospitalization for severe dermatitis
`
`There were 63 (12%) YERVOY-treated patients with moderate (Grade 2)
`dermatitis
`
`Monitor patients for signs and symptoms of dermatitis such as rash and
`pruritus. Unless an alternate etiology has been identified, signs or symptoms of
`dermatitis should be considered immune-mediated
`
`Permanently discontinue YERVOY in patients with severe, life-threatening, or
`fatal immune-mediated dermatitis (Grade 3-5). Administer systemic
`corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is
`controlled, corticosteroid tapering should occur over a period of at least 1
`month. Withhold YERVOY in patients with moderate to severe signs and
`symptoms
`
`Treat mild to moderate dermatitis (e.g., localized rash and pruritus)
`symptomatically. Administer topical or systemic corticosteroids if there is no
`improvement within 1 week
`
`Immune-mediated Neuropathies:
`
`In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal
`Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor
`neuropathy were reported
`
`Across the clinical development program of YERVOY, myasthenia gravis and
`additional cases of Guillain-Barré syndrome have been reported
`
`Monitor for symptoms of motor or sensory neuropathy such as unilateral or
`bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue
`YERVOY in patients with severe neuropathy (interfering with daily activities)
`such as Guillain-Barré–like syndromes
`
`Institute medical intervention as appropriate for management of severe
`neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of
`prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients
`with moderate neuropathy (not interfering with daily activities)
`
`Immune-mediated Endocrinopathies:
`
`In the pivotal Phase 3 study in YERVOY- treated patients, severe to
`life-threatening immune-mediated endocrinopathies (requiring hospitalization,
`urgent medical intervention, or interfering with activities of daily living; Grade
`3-4) occurred in 9 (1.8%) patients
`All 9 patients had hypopituitarism, and some had additional concomitant
`endocrinopathies such as adrenal insufficiency, hypogonadism, and
`hypothyroidism.
`
`6 of the 9 patients were hospitalized for severe endocrinopathies
`
`Moderate endocrinopathy (requiring hormone replacement or medical
`intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and
`consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case
`each of hyperthyroidism and Cushing’s syndrome
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`Median time to onset of moderate to severe immune-mediated endocrinopathy
`was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY
`
`Monitor patients for clinical signs and symptoms of hypophysitis, adrenal
`insufficiency (including adrenal crisis), and hyper- or hypothyroidism
`Patients may present with fatigue, headache, mental status changes,
`abdominal pain, unusual bowel habits, and hypotension, or nonspecific
`symptoms which may resemble other causes such as brain metastasis or
`underlying disease. Unless an alternate etiology has been identified, signs
`or symptoms should be considered immune-mediated
`
`Monitor thyroid function tests and clinical chemistries at the start of
`treatment, before each dose, and as clinically indicated based on
`symptoms. In a limited number of patients, hypophysitis was diagnosed
`by imaging studies through enlargement of the pituitary gland
`
`Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2
`mg/kg/day of prednisone or equivalent) and initiate appropriate hormone
`replacement therapy. Long-term hormone replacement therapy may be
`necessary
`
`Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:
`
`In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant
`immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis,
`meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
`
`Across the clinical development program for YERVOY, immune-mediated adverse
`reactions also reported with <1% incidence were: myocarditis, angiopathy,
`temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis,
`episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis,
`pancreatitis, arthritis, and autoimmune thyroiditis
`
`Permanently discontinue YERVOY for clinically significant or severe immune-
`mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of
`prednisone or equivalent) for severe immune-mediated adverse reactions
`
`Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently
`discontinue YERVOY for immune-mediated ocular disease unresponsive to local
`immunosuppressive therapy
`
`Pregnancy & Nursing:
`
`YERVOY is classified as pregnancy category C. There are no adequate and
`well-controlled studies of YERVOY in pregnant women. Use YERVOY during
`pregnancy only if the potential benefit justifies the potential risk to the fetus
`
`Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1;
`therefore, YERVOY has the potential to be transmitted from the mother to the
`developing fetus
`
`It is not known whether YERVOY is secreted in human milk. Because many
`drugs are secreted in human milk and because of the potential for serious
`adverse reactions in nursing infants from YERVOY, a decision should be made
`whether to discontinue nursing or to discontinue YERVOY
`
`Common Adverse Reactions:
`
`The most common adverse reactions (≥5%) in patients who received YERVOY at
`3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and
`colitis (8%)
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`Please see full Prescribing Information, including Boxed WARNING regarding
`immune-mediated adverse reactions available at www.bms.com.
`
`YERVOY is a registered trademark of Bristol-Myers Squibb Company.
`
`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. For more information about Bristol-Myers Squibb, visit
`www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.
`
`Bristol-Myers Squibb Forward-Looking Statement
`
`This press release contains "forward-looking statements" as that term is defined in the
`Private Securities Litigation Reform Act of 1995 regarding the research, development
`and commercialization of pharmaceutical products. 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 investigational uses of Yervoy described in this release will lead to additional
`approved indications. 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,
`2012, 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.
`
`Contact:
`Bristol-Myers Squibb Company
`Media:
`Melanie Brunner, 609-252-6338, melanie.brunner@bms.com
`Sarah Koenig, 609-252-4145, sarah.koenig@bms.com
`or
`Investors:
`Ranya Dajani, 609-252-5330, ranya.dajani@bms.com
`Ryan Asay, 609-252-5020, ryan.asay@bms.com
`
`Business Wire NewsHQ℠
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