Bristol-Myers Squibb - Bristol-Myers Squibb Reports Results for Phase 3 Trial of Yervoy® (Ipilimumab) in P...
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`Bristol-Myers Squibb Reports Results for Phase 3 Trial of Yervoy®
`(Ipilimumab) in Previously-Treated Castration-Resistant Prostate Cancer
`
`09/12/2013
`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
`
`PRINCETON, N.J.--(BUSINESS WIRE)--Sep. 12, 2013-- 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 Congressin an oral session on September
`28 (Abstract # 2850).
`
`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 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
`
`http://investor.bms.com/investors/news-and-events/press-releases/
`
`
`
`JANSSEN EXHIBIT 2078
`Mylan v. Janssen IPR2016-01332
`
`

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`Bristol-Myers Squibb - Bristol-Myers Squibb Reports Results for Phase 3 Trial of Yervoy® (Ipilimumab) in P...
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`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
`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
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`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.
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`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
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`Severe immune-mediated reactions involving any organ system
`
`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
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`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:
`
`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
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`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
`
`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:
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`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%)
`
`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 aboutBristol-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.
`
`Source: Bristol-Myers Squibb Company
`
`Bristol-Myers Squibb Company
`Media:
`, melanie.brunner@bms.com
`Melanie Brunner, 609-252-6338
`, sarah.koenig@bms.com
`Sarah Koenig, 609-252-4145
`or
`Investors:
`Ranya Dajani, 609-252-5330
`, ranya.dajani@bms.com
`, ryan.asay@bms.com
`Ryan Asay, 609-252-5020
`
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