FDA Approves Entresto for Pediatric Heart Failure

FDA批准Entesto用于治疗儿童心脏衰竭

2019-10-09 14:33:36 drugs

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East Hanover, N.J., Oct. 1, 2019 – Novartis announced today that the U.S. Food and Drug Administration has approved Entresto for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged 1 year and older. Entresto reduces NT-proBNP and is expected to improve cardiovascular outcomes.1 The approval was based on an analysis at 12 weeks from the 52-week PANORAMA-HF trial which demonstrated reductions in the cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients 1 to <18 years with heart failure due to systemic left ventricular systolic dysfunction with Entresto.1 Because Entresto improved outcomes and reduced NT-proBNP in adult patients in PARADIGM-HF, this effect on NT-proBNP was considered a reasonable basis to infer improved cardiovascular outcomes in pediatric patients.1,3 The reductions from baseline in NT-proBNP for Entresto (44%), and the active comparator enalapril (33%), were similar to or greater than those observed in adults, but the difference between treatment groups was not statistically significant.1 Safety and tolerability of Entresto in pediatric patients were consistent with that observed in adult patients.1,3 Children diagnosed with systolic HF face a poor prognosis.2 It has been estimated that half require a heart transplant before the age of five, and almost one-third die or require a transplant within 1 year.2 “Pediatric heart failure is extremely serious and carries a substantial burden. Given the significant unmet need for heart failure treatments that are proven safe and effective in pediatric patients, this approval and the availability of a new treatment option is great news for these children and their families,” said Andrea Baer, Executive Director at Mended Little Hearts. “The current clinical management of pediatric systolic heart failure includes the use of several medicines based mostly on data from adult studies, and there is limited data in children with heart failure in clinical trials. PANORAMA-HF is ongoing to secure 52-week follow-up data for the full study population. We remain committed to trial completion to generate further evidence on how Entresto impacts the clinical course of pediatric HF and are grateful for the ongoing collaboration with the investigators, as well as the patients and their families,” said David Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis. Entresto has been approved in the U.S. since 2015 to reduce the risk of cardiovascular (CV) death or HF hospitalization in adult patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction (HFrEF). It is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.1 It is a first-choice treatment for HFrEF, which affects about 50 percent of all adult HF patients.3,4,5,6  HF is a chronic and progressive condition where the heart cannot pump enough blood to support the body’s need for blood and oxygen.7,8 Congenital malformations account for most of the HF burden in children, with cardiomyopathy (diseases of the heart muscle itself) serving as the other main cause.8 Pediatric systolic HF is caused by a structural and/or functional impairment of ventricular systole (when the heart contracts to pump blood out) and is characterized by significant morbidity and mortality, frequent hospitalization and poor quality of life.8,9  PANORAMA-HF is a two-part study. Part 1 is an open-label dose determination study. Part 2 is a randomized, double-blind, 52-week study comparing Entresto to the active comparator enalapril in patients aged 1 month to <18 years old with HF (NYHA/Ross Class II-IV) due to systemic left ventricular systolic dysfunction (LVEF <40% or fractional shortening ≤20%).9 It is the largest prospective pediatric HF trial conducted to date and employs the use of a global rank primary endpoint, based on clinical events encompassing death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores) and patient-reported HF symptoms.9 The trial is ongoing and is being conducted in approximately 39 countries and 129 clinical sites across North America, Europe, Asia and Latin America.9 Each of 360 planned participants will be followed for 52 weeks after his or her respective enrollment.9 The trial is expected to be completed in 2021. FDA approval of Entresto for the treatment of symptomatic HF with systemic left ventricular systolic dysfunction in children aged 1 year and older was based on an analysis in 110 patients evaluating the reduction from baseline to 12 weeks in NT-proBNP.1 The analysis included 90 patients aged 6 to 18 years old and 20 patients aged 1 to 6 years old.1  Entresto (sacubitril/valsartan) is a prescription medicine used to reduce the risk of cardiovascular death and heart failure hospitalization in people with certain types of long-lasting (chronic) heart failure (HFrEF).1 Entresto is usually used with other heart failure therapies, in place of an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin II receptor blocker (ARB) therapy.1 Entresto is a twice-a-day prescription medicine that works by enhancing the beneficial neurohormonal systems (natriuretic peptide system) while simultaneously inhibiting the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS).1,10 Most other heart failure medicines only block the harmful effects of the overactive RAAS. Entresto contains the neprilysin inhibitor sacubitril and the ARB valsartan.1 Entresto film-coated tablets are available in three dosage strengths: 24/26 mg, 49/51 mg and 97/103 mg (sacubitril/valsartan).1 These doses are referred to as 50 mg, 100 mg and 200 mg in the clinical trial literature including The New England Journal of Medicine publication of the results of PARADIGM-HF.3  An oral solution also may be compounded.1 In adult patients, the target maintenance dose of Entresto is 97/103 mg twice daily as tolerated by the patient.1 In pediatric patients, the target maintenance dose is dependent on body weight.1  IMPORTANT SAFETY INFORMATIONEntresto can harm or cause death to an unborn baby. Patients should talk to their doctor about other ways to treat heart failure if they plan to become pregnant. If a patient gets pregnant while taking Entresto, she should tell her doctor right away. Patients are not to take Entresto if they are allergic to sacubitril or valsartan or any of the ingredients in Entresto; have had an allergic reaction including swelling of the face, lips, tongue, throat or trouble breathing while taking a type of medicine called an ACE inhibitor or ARB; or take an ACE inhibitor medicine. Patients are not to take Entresto for at least 36 hours before or after they take an ACE inhibitor medicine. Patients should talk with their doctor or pharmacist before taking Entresto if they are not sure if they take an ACE inhibitor medicine. Patients are not to take Entresto if they have diabetes and take a medicine that contains aliskiren. Before they take Entresto, patients should tell their doctor about all of their medical conditions, including if they have kidney or liver problems; or a history of hereditary angioedema; are pregnant or plan to become pregnant; are breastfeeding or plan to breastfeed. Patients should either take Entresto or breastfeed. They should not do both. Patients should tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. They should especially tell their doctor if they take potassium supplements or a salt substitute; nonsteroidal anti-inflammatory drugs (NSAIDs); lithium; or other medicines for high blood pressure or heart problems such as an ACE inhibitor, ARB, or aliskiren. Entresto may cause serious side effects including serious allergic reactions causing swelling of the face, lips, tongue, and throat (angioedema) that may cause trouble breathing and death. Patients are to get emergency medical help right away if they have symptoms of angioedema or trouble breathing. Patients are not to take Entresto again if they have had angioedema while taking Entresto. People who are black or who have had angioedema may have a higher risk of having angioedema if they take Entresto. Entresto may cause low blood pressure (hypotension). Patients are to call their doctor if they become dizzy or lightheaded, or they develop extreme fatigue. Entresto may cause kidney problems or an increased amount of potassium in the blood. The most common side effects in adults were low blood pressure, high potassium, cough, dizziness, and kidney problems. The side effects in pediatric patients were consistent with those observed in adults.  Please see full Prescribing Information, including Boxed WARNING available at http://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf Patients are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Novartis is committed to providing patients with affordable access and resources through Entresto Central. For more information, please call 1-888-ENTRESTO or visit www.entresto.com. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. References Posted: October 2019 Entresto (sacubitril and valsartan) FDA Approval History
诺华(Novartis)公司今天宣布,美国食品药品监督管理局(Food and Drug Administration)已批准 Entesto 用于治疗1岁及以上儿童的系统性左室收缩功能障碍的症状性心力衰竭。Entesto 降低 NT-proBNP ,有望改善心血管疾病的预后。1 这一批准是基于对52周 PANTORAMA-HF 试验12周后的一项分析,该试验显示,儿童患者的心脏生物标志物 N-端前 B 型钠尿肽( NT-proBNP )在1至18岁之间由于 Entesto 系统左室收缩功能障碍而心力衰竭。1由于 Entesto 改善了 PARADIGM-HF 成人患者的预后,降低了 NT-proBNP ,这一对 NT-proBNP 的影响被认为是推断儿科患者心血管改善结果的合理依据。1,3 Entesto (44%)的 NT-proBNP 基线水平和比较国 enalapulli (33%)的下降幅度与成人相似或更大,但治疗组之间的差异在统计学上并不显著。儿童患者 Entesto 的安全性和耐受性与成人患者观察到的一致。1,3 确诊为收缩期 HF 的儿童预后不佳。据估计,有一半人在五岁之前需要心脏移植,近三分之一人死亡或需要在一年内进行移植。2 “小儿心衰竭是非常严重的,并有很大的负担。“考虑到儿童患者对心脏衰竭治疗的巨大需求并未得到满足,这一批准和新的治疗方案的提供对这些儿童及其家庭来说是个好消息,” Mended Little Hearts 执行董事 Andrea Baer 说。 “目前儿科收缩性心力衰竭的临床管理包括使用几种主要基于成人研究数据的药物,临床试验中心衰儿童的数据有限。PANDORAMA-HF 正在为整个研究人群提供52周的随访数据。我们仍然致力于完成试验,以产生更多的证据,说明 Entroto 如何影响儿科 HF 的临床过程,并感谢正在进行的合作,调查人员,以及病人和他们的家庭,”大卫·索格尔,医学博士(M.D.)博士,心血管,肾脏和代谢药物开发全球负责人诺华(Novartis)。 Entesto 自2015年起在美国获得批准,用于降低成人慢性心力衰竭( NYHA II-IV 级)和减少射血分数( HFrEF )的心血管( CV )死亡或心衰住院治疗风险。它通常与其他心脏衰竭治疗联合使用,代替 ACE 抑制剂或其他 ARB 。这是 HFrEF 的首选治疗方法,影响了大约50%的成年 HF 患者。3,4,5,6 心衰是一种慢性进行性疾病,心脏不能泵出足够的血液来支持身体对血液和氧气的需求。7,8先天性畸形是儿童心衰负担的主要原因,而心肌病(心肌本身的疾病)是另一个主要原因。8儿童收缩期 HF 是由心室收缩的结构和/或功能损害(当心脏收缩时泵血)引起的,其特征是明显的发病率和死亡率,频繁住院治疗和生活质量差。8,9 PANTORAMA-HF 是一个两部分的研究。第一部分是开放标签剂量测定研究。第二部分是一项随机、双盲、52周的研究,将 Entesto 与1个月龄小于18岁的 HF 患者( NYHA / Ross II-IV )由于左室收缩功能障碍( LVEF <40%或分数缩短≤20%)比较。9这是迄今进行的最大的前瞻性儿科 HF 试验,根据包括死亡、启动机械生命支持、列出紧急心脏移植名单、恶化 HF测量功能能力( NYHA / Ross 评分)和病人报告的 HF 症状。9试验正在进行中,在北美、欧洲、亚洲和拉丁美洲的大约39个国家和129个临床地点进行。9.在360名计划参加者中,每名都将在其各自注册后52周内得到遵守。9审判预计将于2021年完成。 FDA 批准 Entesto 用于治疗1岁及以上儿童的系统性左室收缩功能障碍症状性 HF ,是基于对110例 NT-proBNP 基线至12周的评估。1分析包括90例6~18岁患者和20例1~6岁患者。1 Entroto ( saubitil / valsartan )是一种处方药,用于降低某些类型长期(慢性)心力衰竭( HFrEF )患者的心血管死亡和心衰住院治疗风险。1 Entroto 通常用于其他心力衰竭治疗,代替血管紧张素转换酶( ACE )抑制剂或其他血管紧张素 II 受体阻滞剂( ARB )治疗。1 Entroto 是一种每天两次的处方药,通过增强有益的神经激素系统(钠尿肽系统),同时抑制过度活跃的肾素-血管紧张素-醛固酮系统( RAAS )的有害作用。1,10大多数其他心力衰竭药物只能阻断过度活动 RAAS 的有害作用。Entesto 含有尼泊尔嗪抑制剂塞考昔和缬沙坦。1片 Entroto 薄膜包衣片有三种剂型:24/26mg 、49/51mg 和97/103 mg ( saubitil / valsartan )。1这些剂量在临床试验文献中被称为50mg 、100mg 和200mg ,包括新英格兰医学杂志发表的 PARADIGM-HF 结果。3口服液也可以混合.在成人患者中, Entesto 的目标维持剂量为97/103毫克,是患者每日耐受剂量的两倍。1儿科患者的目标维持剂量取决于体重。1 重要安全信息入境人员可能伤害或导致未出生婴儿死亡。如果病人打算怀孕,应该和医生谈谈治疗心力衰竭的其他方法。如果病人在服用 Entesto 时怀孕,她应该马上告诉医生。 患者不服用 Entroto ,如果他们是过敏的 saubittil 或缬沙坦或任何成分 Entroto ;有过敏反应,包括肿胀的脸,嘴唇,舌头,喉咙或呼吸困难,而采取一种药物称为 ACE 抑制剂或 ARB ;或采取 ACE 抑制剂药物。患者在服用 ACE 抑制剂药物之前或之后至少36小时不服用 Entesto 。如果病人不确定是否服用 ACE 抑制剂药物,他们应该在服用 Entesto 前与医生或药剂师交谈。如果患者患有糖尿病,并服用含有阿利西汀的药物,他们不会服用 Entesto 。 在他们服用 Entesto 之前,病人应该告诉他们的医生所有的医疗状况,包括是否有肾脏或肝脏问题;或有遗传性血管水肿的历史;怀孕或计划怀孕;母乳喂养或计划母乳喂养。患者应采取熵或母乳喂养。他们不应该同时这样做。 病人应该告诉医生他们服用的所有药物,包括处方和非处方药,维生素和草药补充剂。他们应该特别告诉他们的医生,如果他们服用钾补充剂或盐的替代品;非甾体抗炎药( NSAIDs );锂;或其他治疗高血压或心脏病的药物,如 ACE 抑制剂, ARB ,或阿利西卡伦。 熵可能引起严重的副作用,包括严重的过敏反应,导致面部、嘴唇、舌头和喉咙肿胀(血管水肿),可能导致呼吸困难和死亡。如果患者有血管水肿或呼吸困难的症状,他们将立即获得紧急医疗帮助。如果患者在服用 Entesto 时出现血管性水肿,则不再服用 Entesto 。患有血管性水肿的黑人如果服用 Entesto ,患血管性水肿的风险可能更高。熵可能导致低血压.如果病人头晕或头昏眼花,或出现极度疲劳,他们会打电话给医生。熵可能导致肾脏问题或血液中钾含量增加。 成年人最常见的副作用是低血压、高钾、咳嗽、头晕和肾脏问题。 儿科患者的副作用与成人观察到的一致。 请参阅完整的压榨信息,包括 BoxedWARNING ,网址为 http://www.pharma.us.novatos.com/products/pi/pdf/entsto 。pdf 鼓励患者向 FDA 报告处方药的副作用。访问 www.fda.gov / medwatch ,或拨打1-800-FDA-1088。 诺华(Novartis)致力于通过 Entesto Central 为患者提供负担得起的服务和资源。有关详细信息,请致电1-888-ENTRESTO 或访问:\160; www.entsto.com 。 免责声明 本新闻稿载有美国1995年《私人证券诉讼改革法案》含义内的前瞻性陈述。前瞻性陈述通常可以用“潜在”、“可以”、“将”、“计划”、“预期”、“预期”、“展望”、“相信”、“承诺”、“调查”、“管道”、“启动”或类似术语来标识,或者通过有关潜在营销批准的明示或暗示讨论来标识。本新闻稿中描述的调查或批准产品的新适应症或标签,或关于此类产品的潜在未来收入。你不应过分依赖这些陈述。该等前瞻性陈述乃基于我们目前对未来事件的信念及预期,并受重大已知及未知风险及不明朗因素影响。如果这些风险或不确定因素中的一个或多个发生,或基础假设证明不正确,实际结果可能与前瞻性陈述中的结果有重大差异。不能保证在本新闻稿中描述的调查或批准的产品将提交或批准销售,或在任何市场,或在任何特定时间的任何其他指示或标签。也不能保证此类产品在未来在商业上取得成功。特别是,我们对这类产品的预期可能会受到研究和开发固有的不确定性的影响,其中包括临床试验结果和对现有临床数据的额外分析;监管行动或延迟或一般的政府监管;全球卫生保健成本控制趋势,包括政府、支付者和一般公共定价和偿还压力,以及提高定价透明度的要求;我们获得或保持专有知识产权保护的能力;医生和患者的特殊处方偏好;一般政治和经济条件;安全质量或制造问题;潜在或实际的数据安全和数据隐私泄露,或我们信息技术系统的中断,以及诺华(Novartis)公司当前提交给美国证券交易委员会的20-F 表格中提到的其他风险和因素。诺华(Novartis)公司在本新闻稿中提供截至本日期的信息,并不承担任何义务更新本新闻稿中的任何前瞻性声明,因为新信息、未来事件或其他原因。 参考文献 张贴日期:2019年10月 FDA 批准历史

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