Europese Commissie keurt Yervoy (ipilimumab) van Bristol-Myers Squibb goed voor behandeling van pediatrische patiënten van 12 jaar of ouder met niet-reseceerbaar of gemetastaseerd melanoom

12/02/18

Yervoy is het eerste en enige immuno-oncologische middel dat binnen de Europese Unie goedkeuring krijgt voor deze patiëntenpopulatie

 

(Braine L’Alleud, 12 februari 2018) – Bristol-Myers Squibb Company (NYSE: BMY) kondigde vandaag aan dat de Europese Commissie (EC) de indicatie van Yervoy (ipilimumab) heeft uitgebreid, zodat het ook geïndiceerd is voor de behandeling van gevorderd (nietreseceerbaar of gemetastaseerd) melanoom bij pediatrische patiënten van 12 jaar of ouder. Dankzij deze Europese goedkeuring verkrijgt Bristol-Myers Squibb zijn eerste pediatrische indicatie voor een immuno-oncologisch geneesmiddel binnen de Europese Unie (EU) en kan Yervoy voor deze indicatie in de handel worden gebracht in de 28 lidstaten van de EU.

“De uitgebreide Europese indicatie van Yervoy voor pediatrische patiënten met nietreseceerbaar of gemetastaseerd melanoom is het resultaat van de niet-aflatende inspanningen van Bristol-Myers Squibb om de behandelingen voor patiënten met onbeantwoorde klinische behoeften te verbeteren,” aldus Fouad Namouni, M.D., hoofd van Oncology Development bij Bristol-Myers Squibb. “Dankzij deze goedkeuring kunnen we een alternatief bieden aan jonge patiënten voor wie de behandelingsopties lange tijd beperkt waren.”

Yervoy werd geëvalueerd bij kinderen en adolescenten in twee klinische onderzoeken: een dosisbepalend onderzoek met 33 deelnemers tussen 2 en 21 jaar oud met recidiverende of refractaire solide tumoren, en een open-label onderzoek met één onderzoeksarm waaraan 12 adolescenten (tussen 12 en 16 jaar) deelnamen met eerder behandeld of onbehandeld, niet- reseceerbaar maligne melanoom van stadium III of IV.

 “Hoewel melanoom zelden bij kinderen voorkomt, is er nood aan een meer doeltreffende therapeutische aanpak voor deze patiëntenpopulatie,” aldus Peter Mohr, M.D., hoofdgeneesheer van het Department of Dermatology van de Elbe Klinikum Buxtehude en hoofd van het Skin Cancer Center Buxtehude. “Dankzij de goedkeuring van Yervoy binnen de EU kunnen artsen pediatrische patiënten met gevorderd melanoom nu ook een immuno-oncologische behandeling aanbieden.”

In juli 2017 keurde de Amerikaanse Food and Drug Administration (FDA) Yervoy goed voor de behandeling van pediatrische patiënten van 12 jaar of ouder met niet-reseceerbaar of gemetastaseerd melanoom.

Over de onderzoeken met Yervoy bij pediatrische patiënten

In het dosisbepalend onderzoek bij patiënten met recidiverende of refractaire solide tumoren bedroeg de mediane leeftijd van de patiënten 13 jaar en waren twintig van de deelnemers 12 jaar of ouder. Yervoy werd intraveneus toegediend in doses van 1, 3, 5 en 10 mg/kg gedurende 90 minuten, om de drie weken voor de eerste vier doses en daarna om de twaalf weken totdat progressie optrad of de behandeling werd stopgezet.

In het open-label onderzoek met één onderzoeksarm bij eerder behandeld of onbehandeld, niet-reseceerbaar maligne melanoom van stadium III of IV kregen de patiënten Yervoy 3 mg/kg (vier patiënten) of 10 mg/kg (acht patiënten), intraveneus toegediend gedurende 90 minuten, om de drie weken voor vier doses. Bij twee van de twaalf melanoompatiënten van 12 jaar of ouder die in een van de twee onderzoeken met Yervoy werden behandeld, werd een objectieve respons gezien, waaronder één partiële respons die langer dan een jaar behouden bleef.

Het gebruik van Yervoy in deze leeftijdsgroep wordt ook ondersteund door bewijs afkomstig van adequate en goed gecontroleerde onderzoeken met Yervoy bij volwassenen en door populatie-farmacokinetische gegevens die aantonen dat blootstelling aan een dosis van 3 mg/kg in de pediatrische populatie en in de volwassen populatie vergelijkbaar is. Bovendien zijn de tumorbiologie en het verloop van gevorderd melanoom bij volwassenen en bij pediatrische patiënten van 12 jaar of ouder voldoende vergelijkbaar, zodat gegevens van volwassenen geëxtrapoleerd kunnen worden naar pediatrische patiënten.

De goedgekeurde dosis van Yervoy voor pediatrische patiënten met niet-reseceerbaar of gemetastaseerd melanoom is 3 mg/kg, intraveneus toegediend gedurende 90 minuten, om de drie weken voor vier doses.

Over Yervoy

Yervoy is een recombinant, humaan monoklonaal antilichaam dat zich aan het cytotoxische T-lymfocyt geassocieerd antigen-4 (CTLA-4) bindt. CTLA-4 is een negatieve regulator van de T-celactiviteit. Yervoy bindt zich aan CTLA-4 en blokkeert de interactie van  CTLA-4 met zijn liganden: CD80/CD86. Er werd aangetoond dat blokkade van CTLA-4 de activatie en proliferatie van T-cellen, waaronder de activatie en proliferatie van  tumorinfiltrerende effector-T-cellen, verhoogt. Remming van de signaaltransductie via CTLA-4 kan ook de werking van suppressor-T-cellen verminderen, wat kan bijdragen tot een algemene toename van de T-celrespons, waaronder de anti-tumor immuunrespons. Op 25 maart 2011 keurde de Amerikaanse Food and Drug Administration (FDA) Yervoy 3 mg/kg goed als monotherapie voor patiënten met niet-reseceerbaar of gemetastaseerd melanoom. Yervoy is in meer dan 50 landen goedgekeurd voor de behandeling van niet-reseceerbaar of gemetastaseerd melanoom. Er is een breed ontwikkelingsprogramma voor Yervoy aan de gang dat betrekking heeft op meerdere tumortypes.

Indicaties en belangrijke veiligheidsinformatie voor YERVOY® (ipilimumab) 

Indicaties

YERVOY® (ipilimumab) is geïndiceerd voor de behandeling van niet-reseceerbaar of gemetastaseerd melanoom bij volwassenen en pediatrische patiënten (12 jaar of ouder).

YERVOY® (ipilimumab) is geïndiceerd voor de adjuvante behandeling van melanoompatiënten met metastasen in de regionale lymfeknopen van meer dan 1 mm die complete resectie, waaronder volledige lymfadenectomie, hebben ondergaan.

Bristol-Myers Squibb & Immuno-Oncology: Vooruitgang in oncologisch onderzoek

Bij Bristol-Myers Squibb staan patiënten centraal in alles wat wij doen. Onze visie op de toekomst van de kankerzorg richt zich op het onderzoek en de ontwikkeling van transformationele Immuno-Oncologische (I-O) therapieën voor moeilijk te behandelen kankers om de uitkomsten voor deze patiënten mogelijks te kunnen verbeteren.

We zijn de leiders in wetenschappelijk inzicht in I-O dankzij onze uitgebreide portefeuille aan onderzoeks- en goedgekeurde geneesmiddelen. Ons gedifferentieerd programma voor klinische ontwikkeling onderzoekt brede patiëntenpopulaties met meer dan 50 types kanker met 14 moleculen in klinische onderzoeksfases, die ontworpen werden om verschillende banen van het immuunstelsel in het vizier te nemen. Onze diepgaande expertise en vernieuwende ontwerpen van onze klinische studies helpen ons om vooruitgang te boeken op vlak van I-O/I-O, IO/chemotherapie, I-O/gerichte therapieën en I-O/radiotherapie bij meerdere tumoren en om spoedig de volgende stroom behandelingen aan te reiken. Wij blijven ook baanbrekend onderzoek verrichten voor een beter begrip van de rol van immunologische biomarkers en hoe de tumorbiologie van patiënten kan worden aangewend als leidraad voor behandelingsbeslissingen doorheen hun traject.

Wij weten dat, om de belofte van I-O waar te maken voor de vele patiënten die bij deze behandelingen baat kunnen hebben, niet enkel innovatie van onze kant vereist is, maar ook een nauwe samenwerking met topexperten uit het veld. Onze samenwerking met universiteiten, overheden, pleitbezorgers en biotechnologiebedrijven ondersteunt onze gezamenlijke doelstelling om nieuwe behandelingsmogelijkheden aan te bieden en zo de standaarden voor de klinische praktijk vooruit te helpen.

Over Bristol-Myers Squibb 

Bristol-Myers Squibb België is een indirecte dochteronderneming volledig in handen van de Bristol-Myers Squibb Company, een biofarmaceutische onderneming op wereldniveau met als missie: het ontdekken, ontwikkelen en leveren van innovatieve geneesmiddelen, teneinde patiënten te helpen in de strijd tegen ernstige ziekten. Voor meer informatie, bezoek de website www.bms.be of volg ons op LinkedIn, Twitter, YouTube en Facebook.

Perscontact:
Ketchum
Jeremy Bossu
Jeremy.bossu@ketchum.com
+32 (0)2 550 00 66

BMS
Sabine de Beuf
Public Affairs Lead, Benelux
Sabine.deBeuf@bms.com
+32 (0)475 26 50 55

Important Safety Information

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions. 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), adrenocorticotropic hormone (ACTH) level, 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

Endocrine: Withhold YERVOY for symptomatic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment.

All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Immune-mediated Enterocolitis

Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY. 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. 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). 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. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within

3-5 days or recurring after symptom improvement. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). 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 (8%) of the 62 patients with moderate, severe, or life-threatening immunemediated enterocolitis following inadequate response to corticosteroids. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications.

Immune-mediated Hepatitis

Immune-mediated hepatitis, including fatal cases, can occur with YERVOY. 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. Withhold YERVOY in patients with Grade 2 hepatotoxicity. Permanently discontinue YERVOY in patients with Grade 3-4 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. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8 YERVOY- treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2). In a dosefinding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune- mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3-4 hepatitis showed evidence of toxic or autoimmune hepatitis.

Immune-mediated Dermatitis

Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. 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. 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. Withhold YERVOY in patients with moderate to severe signs and symptoms. 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. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immunemediated 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 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate Grade 2 dermatitis.

Immune-mediated Neuropathies

Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barre-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in Trial 1, 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. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

Immune-mediated Endocrinopathies

Immune-mediated endocrinopathies, including life-threatening cases, can occur with 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 clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests 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 and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in Trial 1, severe to life-threatening immunemediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing's syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies occurred in 93 patients (20%). Of the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with 1 or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3-4 immune-mediated endocrinopathy was 2.2 months (range: 2 days-8 months). Twenty-seven (69.2%) of the 39 patients were hospitalized for immune-mediated endocrinopathies. Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with 1 or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immunemediated endocrinopathy was 2.1 months (range: 9 days-19.3 months).

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations

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. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic steroids to reduce the risk of permanent vision loss. In Trial 1, the following clinically significant immunemediated adverse reactions were seen in <1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. In Trial 2, the following clinically significant immune- mediated adverse reactions were seen in <1% of YERVOY-treated patients unless specified: eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis and fatal myocarditis. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immunemediated adverse reactions were also reported with <1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica , conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis , autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.

Embryo-fetal Toxicity

Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with a YERVOYcontaining regimen and for 3 months after the last dose of YERVOY.

Lactation

It is not known whether YERVOY is secreted in human milk. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

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%). The most common adverse reactions (≥5%) in patients who received YERVOY at 10 mg/kg were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%).

Please see U.S. Full Prescribing Information for YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions.

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 Yervoy will receive regulatory approval for additional 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, 2016 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.

IOBE18NP00346-01