La Commission Européenne approuve Yervoy (ipilimumab) de Bristol-Myers Squibb pour le traitement du mélanome non résécable ou métastatique chez les patients pédiatriques âgés de 12 ans et plus

07/02/18

Yervoy est le premier et le seul agent immuno-oncologique à recevoir l’approbation de l’Union Européenne pour le traitement de cette population de patients

 

(Braine L’Alleud, le 7 février 2018) – Aujourd’hui, Bristol-Myers Squibb Company (NYSE : BMY) a annoncé que la Commission Européenne (CE) a étendu l’indication de Yervoy (ipilimumab) pour inclure le traitement du mélanome avancé (non résécable ou métastatique) chez les patients pédiatriques âgés de 12 ans et plus. L’approbation de la CE marque l’obtention de la première indication pédiatrique de Bristol-Myers Squibb pour un médicament immunooncologique au sein de l’Union Européenne (UE) et permet la commercialisation de Yervoy pour cette indication dans les 28 Etats Membres de la CE. 

« L’extension d’indication au sein de l’UE de Yervoy pour le traitement des patients pédiatriques atteints d’un mélanome non résécable ou métastatique est le résultat de l’engagement permanent de Bristol-Myers Squibb pour l’avancée des traitements destinés aux patients dont les besoins médicaux ne sont pas satisfaits », a déclaré le Dr Fouad Namouni, responsable du service de Développement oncologique de Bristol-Myers Squibb. « Cette approbation nous permet d’offrir une alternative aux jeunes patients dont les options thérapeutiques sont généralement limitées. »  

Yervoy a été évalué au cours de deux études cliniques menées chez des enfants et des adolescents : une étude de recherche de dose réalisée chez 33 patients âgés de 2 à 21 ans ayant des tumeurs solides réfractaires ou une récidive de tumeurs solides, et une étude à bras unique réalisée en ouvert chez 12 adolescents (âgés de 12 à 16 ans) atteints d’un mélanome malin de stade III ou IV non résécable, ayant fait ou non l’objet d’un traitement préalable. 

« Bien que le mélanome touche rarement les enfants, nous avons besoin de davantage de traitements efficaces pour cette population de patients », a déclaré le Dr Peter Mohr, médecin chef du service de Dermatologie à l’Elbe Klinikum de Buxtehude et responsable du Skin Cancer Center de Buxtehude. « Cette approbation de Yervoy dans l’UE permet d’élargir les options offertes aux médecins pour le traitement des patients pédiatriques atteints d’un mélanome avancé, en incluant la possibilité d’un traitement immuno-oncologique. »

En juillet 2017, la FDA américaine (Food and Drug Administration) a approuvé Yervoy pour le traitement des patients pédiatriques âgés de 12 ans et plus atteints d’un mélanome non résécable ou métastatique. 

À propos des études réalisées avec Yervoy chez des patients pédiatriques

Au cours de l’étude de mise au point de la dose menée chez des patients ayant des tumeurs solides réfractaires ou une récidive de tumeurs solides, l’âge moyen des patients était de 13 ans, 20 patients étant âgés de 12 ans ou plus. Yervoy a été administré à raison de 1, 3, 5 et 10 mg/kg par voie intraveineuse pendant 90 minutes, toutes les trois semaines pour les quatre premières doses puis toutes les 12 semaines jusqu’à la survenue d’une progression ou l’interruption du traitement. 

Au cours de l’étude à bras unique réalisée en ouvert chez des patients atteints d’un mélanome malin de stade III ou  IV non résécable, ayant fait ou non l’objet d’un traitement préalable, les patients ont reçu Yervoy à raison de 3 mg/kg (quatre patients) ou de 10 mg/kg (huit patients) par voie intraveineuse pendant 90 minutes, toutes les trois semaines pour quatre doses.

Parmi les 12 patients âgés de 12 ans et plus atteints d’un mélanome et traités par Yervoy au cours des deux études, deux patients ont présenté des réponses objectives, dont une réponse partielle qui s’est maintenue pendant plus d’un an. 

L’utilisation de Yervoy dans cette tranche d’âge est également soutenue par des données issues d’études adéquates et bien contrôlées réalisées chez des adultes et des données issues d’études de pharmacocinétique de population démontrant que l’exposition résultant de l’administration d’une dose de 3 mg/kg est comparable dans les populations adultes et pédiatriques. De plus, la biologie de la tumeur et l’évolution du mélanome avancé sont suffisamment similaires chez les patients adultes et pédiatriques âgés de 12 ans et plus pour permettre une extrapolation des données des adultes aux patients pédiatriques.

La dose approuvée de Yervoy chez les patients pédiatriques atteints d’un mélanome non résécable ou métastatique est de 3 mg/kg, à administrer par voie intraveineuse sur une durée de 90 minutes, toutes les trois semaines pour atteindre un total de quatre doses. 

À propos de Yervoy

Yervoy est un anticorps monoclonal humain recombinant, qui se lie à l'antigène 4 des lymphocytes T cytotoxiques (CTLA-4). Le CTLA-4 est un régulateur négatif de l’activité des cellules T. Yervoy se lie au CTLA-4 et bloque ainsi l’interaction du CTLA-4 avec ses ligands, CD80/CD86. On a constaté que le blocage du CTLA-4 augmente l’activation et la prolifération des cellules T, y compris l’activation et la prolifération des lymphocytes T effecteurs infiltrant la tumeur. L’inhibition des signaux liés au CTLA-4 peut également réduire la fonction des lymphocytes T régulateurs, ce qui peut contribuer à une augmentation générale de la réponse des cellules T, notamment la réponse immunitaire anti-tumorale. Le 25 mars 2011, la FDA américaine a approuvé l’utilisation de Yervoy en monothérapie à la dose de 3 mg/kg pour le traitement des patients atteints d’un mélanome non résécable ou métastatique. Yervoy est approuvé dans plus de 50 pays pour le traitement du mélanome non résécable ou métastatique. Un large programme de développement est actuellement en place pour l’utilisation de Yervoy dans le cadre du traitement de plusieurs types de tumeur. 

Indications et informations de sécurité importantes concernant  YERVOY® (ipilimumab) 

Indications

YERVOY® (ipilimumab) est indiqué pour le traitement du mélanome non résécable ou métastatique chez les patients adultes et pédiatriques (âgés de 12 ans et plus).

YERVOY® (ipilimumab) est indiqué pour le traitement adjuvant des patients atteints d’un mélanome s'accompagnant de métastases de plus de 1 mm dans les ganglions lymphatiques régionaux et qui ont subi une résection complète, incluant une lymphadénectomie totale.  

Bristol-Myers Squibb & l’immuno-oncologie: la recherche en oncologie évolue

Chez Bristol-Myers Squibb, le patient est au cœur de toutes nos actions. Nous concentrons tous nos efforts en matière de traitements anticancéreux sur la recherche et le développement de médicaments transformationnels en immuno-oncologie (I-O) qui pourraient potentiellement améliorer les résultats chez les patients atteints de cancers difficiles à traiter.

Nous sommes à la pointe des connaissances scientifiques en immuno-oncologie grâce à notre vaste portefeuille de produits d’investigation et de médicaments approuvés. Notre programme de développement clinique diversifié étudie de larges populations de patients pour plus de 50 types de cancer, avec 14 produits au stade de développement clinique, conçus pour cibler différentes voies du système immunitaire. Notre expertise solide et nos concepts d’essais cliniques innovants nous permettent de progresser en I-O/IO, IO/chimiothérapie, I-O/thérapies ciblées et IO/radiothérapie pour de nombreux types de tumeurs et de fournir à court terme et de manière urgente, une nouvelle vague de traitements. Nous continuons également à mener des recherches pionnières afin de mieux comprendre le rôle des biomarqueurs immunitaires et la façon dont la biologie des tumeurs des patients peut être utilisée pour guider les décisions thérapeutiques tout au long de leur trajet.

Nous sommes conscients que pour que l’immuno-oncologie tienne ses promesses pour les nombreux patients qui peuvent bénéficier de ces traitements, nous devons non seulement être innovants mais également agir en étroite collaboration avec les meilleurs experts dans ce domaine. Nos partenariats avec le monde universitaire, les gouvernements, les groupes de sensibilisation et les entreprises de biotechnologie soutiennent notre objectif commun d'offrir de nouvelles options thérapeutiques pour faire avancer les normes en matière de pratique clinique.

A propos de Bristol-Myers Squibb Belgique

Bristol-Myers Squibb Belgique est une filiale indirecte appartenant en propriété exclusive à la Société Bristol-Myers Squibb, une société biopharmaceutique d’envergure mondiale dont la mission est de découvrir, de mettre au point et de fournir des médicaments novateurs ayant pour but d'aider les patients à combattre des maladies graves. Pour de plus amples renseignements, visitez le site www.bms.be ou suivez-nous sur LinkedIn, Twitter, YouTube en Facebook.

Contacts presse

Ketchum
Samantha Lomonaco
Samantha.Lomonaco@ketchum.com
+32 (0)488/790.589

Bristol-Myers Squibb
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Sabine.deBeuf@bms.com
Public Affairs Lead, Benelux
+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.