美国FDA在认定一个药物为非常重要、能治疗严重疾病的时候，会授予其优先审批资格，即会在6个月之内给予答复。
Opdivo (nivolumab)是一种新型PD-1免疫检查点单抗。公司针对该药物共开展超过35项临床研究，有超过7000名患者参与，适应症包括非小细胞肺癌、黑色素瘤、肾脏上皮肾细胞癌、头颈癌、胶质母细胞瘤和非霍奇金淋巴瘤。
该药物于2014年5月还被FDA授予“突破性疗法”认定，用于霍奇金淋巴瘤治疗。今年7月，日本厚生劳动省正式批准该药物在日本上市，用于不可切除的黑色素瘤。
今年7月，阿斯利康宣布耗资21亿美元收购西班牙Almirall公司的呼吸系统业务，尽管该笔收购尚未完成，但该业务中的一种慢性阻塞性肺病（COPD）复方药Duaklir Genuair，在审批方面已收到了欧盟CHMP建议批准的积极意见。CHMP已建议批准该药作为一种维持性支气管扩张剂，用于缓解COPD患者的症状。
Duaklir Genuair是由2种已上市的长效支气管扩张剂组成的固定剂量复方药物，其中，bromide（阿地溴铵）是一种新颖的长效毒蕈碱拮抗剂（LAMA），formoterol fumarate（富马酸福莫特罗）是一种长效β2受体激动剂（LABA）。
该笔收购将于2014年底完成。交易完成后，阿斯利康将拥有Almirall现有呼吸系统业务的开发和商业化权利，包括拥有来自Almirall现有合作伙伴关系的收入流及研发管线中实验性新颖疗法的权利。Almirall公司的呼吸系统专营权包括Eklira（aclidinium，阿地尼亚）、LAS40464（阿地尼亚+福莫特罗复方药，已在欧盟申请注册，在美国处于在研）、LAS100977（abediterol，一种每日一次的长效β2受体激动剂LABA，处于II期临床）、处于临床前开发（LAS191351，LAS194871）和I期临床（LAS190792）的M3拮抗剂β2受体激动剂（MABA）平台、多个临床前项目。
根据协议，Almirall旗下专注于创新专有设备研发的子公司Almirall Sofotec，也将转让给阿斯利康。
此次业务合并，将使阿斯利康立即获得市场收入，将有助于促进公司收入增长的恢复。Almirall公司新颖的呼吸资产及其设备能力，将进一步加强阿斯利康的呼吸系统产品组合，包括Symbicort和Pulmicort及在研的实验性药物。
而药物Eklira和LAS40464及专有的Genuair设备等资产，将使阿斯利康能够为患者提供横跨一系列分子和复方药物的干粉吸入器及计量吸入器设备的治疗选择。
阿斯利康首席执行官Pascal Soriot表示，与Almirall之间的战略交易，将为阿斯利康强大的呼吸系统专营权带来战略性及长期价值。呼吸系统专营权是我们的主要增长平台之一，此次交易将使公司即刻获得并不断增长的产品收入。通过结合自身的创新组合，并充分利用阿斯利康的全球科学和商业能力，我们将加强在哮喘和慢性阻塞性肺病（COPD）整个护理范畴的应对能力。我们非常欢迎Almirall的员工加入我们的队伍。
英文原文：Almirall's aclidinium bromide/formoterol fumarate recommended for approval in Europe to treat COPD
Positive CHMP opinion is an important step in making this new respiratory therapy available to treat Chronic Obstructive Pulmonary Disease (COPD)
Marketing authorisation in the European unio is expected before the end of the year
Aclidinium/Formoterol will be marketed in Europe under the trademarks Duaklir® Genuair® and Brimica® Genuair®
Barcelona, September, 25 2014. - Almirall S.A. (ALM) announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for the regulatory approval of Duaklir® Genuair® (aclidinium bromide/formoterol fumarate) in all EU member states as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).1
Aclidinium bromide/formoterol fumarate is a fixed dose combination of two approved long-acting bronchodilators. Aclidinium bromide is a novel anticholinergic or long acting muscarinic antagonist (LAMA). Formoterol fumarate is a long-acting beta-agonist (LABA).2
As part of its assessment, CHMP reviewed efficacy and safety data of aclidinium bromide/formoterol fumarate BID from more than 2,000 patients. The clinical program included 11 clinical studies conducted in 29 countries worldwide.2
"We are very pleased with the CHMP positive recommendation for aclidinium bromide/formoterol fumarate" said Thomas Eichholtz, Chief Scientific Officer at Almirall. "The Committee's positive opinion today marks a significant step forward in bringing this new treatment option to patients with COPD."
In the EU, the European Commission generally follows the recommendations of the CHMP (EMA) and delivers its final decision within three months after the CHMP recommendation. The decision will be applicable to all 28 EU member states plus Iceland and Norway. Aclidinium bromide/formoterol fumarate will be marketed in Europe by Almirall under the trade name Duaklir®Genuair® and Brimica® Genuair®.
Almirall's respiratory franchise is complemented by aclidinium bromide, a long-acting inhaled muscarinic receptor antagonist (LAMA) for COPD. Aclidinium bromide was approved by the EMA and by the US Food and Drug Administration (FDA) in 2012 and is available in in 24 countries marketed under the trade names Eklira® Genuair®, Bretaris® Genuair®, Tudorza™ Pressair™ and Tudorza™ Genuair™. Further compounds in development include abediterol, a novel long acting beta-2 adrenergic agonist (LABA) for asthma and COPD, two novel dual action long-acting muscarinic antagonist beta-2 agonist MABA compounds plus PAN-JAK and PI3Kδ inhibitors.
美国FDA于今年4月加速批准Zykadia (ceritinib)，用于治疗克唑替尼耐药的ALK+的转移性非小细胞肺癌。
在公司此次进行的临床I期试验中，共有246位非小细胞肺癌患者参与。结果显示，应答率达到61.8%以及无进展生存时间达到9个月
之前从未接受过克唑替尼治疗的患者中的应答率达到72.3%以及无进展生存时间达到18.4个月。之前接受过克唑替尼治疗的患者的应答率达到56.4%以及无进展生存时间达到6.9个月。
Novartis International AG / Patients lived average of 18 months without cancer progressing when taking Novartis' Zykadia(TM) as their first ALK inhibitor for ALK+ NSCLC . Processed and transmitted by NASDAQ OMX Corporate Solutions. The issuer is solely responsible for the content of this announcement.
The digital press release with multimedia content can be accessed here:
basel, September 27, 2014- Novartis today announced new data showing patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) lived an average of more than 18 months without their cancer progressing when taking Zykadia(TM) (ceritinib) as their first ALK inhibitor. Overall, data from the pivotal study confirmed ceritinib continues to demonstrate efficacy in ALK+ NSCLC patients regardless of whether or not they received previous treatment with an ALK inhibitor[1]. In addition, patients who entered the study with brain metastases experienced similar results following treatment with ceritinib[2].
These data are being presented at the European Society for Medical oncology (ESMO) 2014 Congress in Madrid.
"These findings are very exciting because until now, most ALK+ NSCLC patients experience disease progression within less than a year of treatment with an ALK inhibitor," said lead investigator Enriqueta Felip, MD, PhD, Vall d'Hebron University. "This is the longest median progression-free survival data we've seen in this broad patient population and it is even more striking when you consider that most of them have received up to three rounds of chemotherapy before taking ceritinib as their first ALK inhibitor."
Among the combined study population of 246 NSCLC patients, including patients who had received previous treatment with an ALK inhibitor as well as those receiving one for the first time, ceritinib achieved an overall response rate (ORR) of 61.8% and a media progression-free survival (PFS) of 9.0 months. In the subset of 83 patients who had not received prior treatment with an ALK inhibitor, ceritinib achieved an ORR of 72.3% and a median PFS of 18.4 months. Among the subset of 163 patients who were previously treated with the commonly prescribed ALK inhibitor crizotinib, the ORR was 56.4% and the median PFS was 6.9 months[1].
In 124 patients who entered the trial with brain metastases, those treated with ceritinib achieved an ORR of 55.6%[2]. Of note, ceritinib also demonstrated activity in the brain, known as intracranial responses, suggesting that ceritinib may be an effective therapy for brain metastases, one of the most common and difficult-to-treat sites of disease progression for patients with ALK+ NSCLC. Specifically, ceritinib shrank brain metastases in about one-third of the 29 patients who entered the study with measurable brain lesions[2].
No unexpected side effects were observed and the most common adverse events, occurring in more than half of patients, were diarrhea, nausea and vomiting[1].
"These findings in patients being treated with an ALK inhibitor for the first time reinforce the impressive ceritinib data that were already seen in patients who had stopped responding to an ALK inhibitor," said Alessandro Riva, MD, Global Head, Novartis oncolog Development and Medical Affairs. "We are committed to bringing this treatment to ALK+ NSCLC patients around the world who are in need of effective options."
Approximately 2-7% of patients with NSCLC harbor the ALK gene rearrangement, which causes cancer growth[3]. These patients are candidates for treatment with a targeted ALK inhibitor. Patients with ALK+ NSCLC are often younger than the average NSCLC patient and in many cases have never smoked[4].
The study presented at ESMO 2014 served as the basis for the US Food and Drug Administration (FDA) approval of Zykadia in April 2014, which followed the FDA's Breakthrough Therapy designation. Additional ongoing regulatory reviews for Zykadia are currently underway in the European unio and several countries within North America, South America, Central America and Asia.
about the study and ceritinib clinical trial program
The 246 patients with ALK+ NSCLC in this Phase I single-arm study received ceritinib 750 mg daily and were observed over time for a median duration of 11.1 months. Of these, 166 (67%) had received at least two prior treatment regimens and 163 (66%) had been previously treated with an ALK inhibitor. Findings from the study showed that patients treated with ceritinib achieved an ORR of 61.8% [95% CI, 55.4-67.9%] and a median PFS of 9.0 months [95% CI, 6.9-11.0 months] based on investigator assessment. The median duration of response was 9.7 months [95% CI, 8.3-11.4 months][1].
In the subset of 83 patients who had not received prior treatment with an ALK inhibitor, the ORR was 72.3% [95% CI, 61.4-81.6%] and the median PFS was 18.4 months [95% CI, 11.1-NE (not estimable) months]. Among the subset of 163 patients receiving 750 mg of ceritinib daily and who were previously treated with the commonly prescribed ALK inhibitor crizotinib, the ORR was 56.4% [95% CI, 48.5-64.2%] and the median PFS was 6.9 months [95% CI, 5.6-8.7 months][1].
In the 124 patients who started the study with brain metastases, ceritinib achieved an ORR, including partial responses (PR) and complete responses (CR), of 55.6% [95% CI, 46.5-64.6%]. Confirmed responses (PR/CR) were seen in 51.0% of patients [50 of 98 patients; 95% CI, 40.7-61.3%] with brain metastases who had received previous ALK inhibitor therapy, while 73.1% of patients [19 of 26 patients; 95% CI, 52.2-88.4%] with brain metastases who were not previously treated with an ALK inhibitor achieved confirmed responses following treatment with ceritinib. The median PFS was 6.9 months [95% CI, 4.9-8.4 months] among patients with brain metastases who were previously treated with an ALK inhibitor and 9.7 months [95% CI, 4.6-NE months] in those with brain metastases who were receiving ALK inhibitor therapy for the first time[2].
Seventy-four out of the 124 ALK+ NSCLC patients with brain metastases had MRI scans available for evaluation, of whom 29 were identified as having measurable brain lesions at baseline according to standard clinical criteria (RECIST v1.1). Ceritinib achieved confirmed responses in the brain in 34.5% of those patients with measurable brain lesions [10 of 29 patients, 95% CI, 17.9-54.3%][2].
Discontinuation of treatment due to adverse events occurred in 9.8% of ALK+ NSCLC patients in the study[1].
Among 255 patients treated with ceritinib at a dose of 750 mg once daily, including 246 patients with NSCLC and nine patients with other types of cancer, 156 (61.2%) required at least one dose reduction. The most frequent adverse events (incidence >50%) among 255 patients were diarrhea (86.7%), nausea (82.7%) and vomiting (61.6%). Most adverse events were of low grade and treated with dose interruption and/or dose reductions[1].
This study is part of the ongoing Novartis clinical trial program in this patient population. Several major studies evaluating treatment with ceritinib are being conducted in more than 300 study centers across more than 30 countries. Two Phase II single-arm clinical trials in previously treated and treatment-naïve ALK+ NSCLC patients, (www.clinicaltrials.gov identifiers NCT01685060 and NCT01685138), are fully enrolled and ongoing. In addition, two Phase III clinical trials comparing ceritinib with chemotherapy in treatment-naïve and in previously-treated patients, (www.clinicaltrials.gov identifiers NCT01828099 and NCT01828112), are ongoing and actively recruiting patients worldwide[5],[6],[7],[8].
about Zykadia
Zykadia (ceritinib) is indicated in the US for the treatment of patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Zykadia is an FDA-approved prescription medicine that is currently available through a number of specialty pharmacies in the US. Outside of the US, Zykadia (ceritinib) is an investigational agent and has not been approved by regulatory authorities.
Zykadia important Safety Information
Zykadia may cause serious side effects, such as:
Zykadia causes stomach and intestinal problems in most people, including diarrhea, nausea, vomiting, and stomach-area pain. These problems can sometimes be severe. Patients should follow their doctor's instructions about taking medicines to help these symptoms, and should call their doctor for advice if symptoms are severe or do not go away.
Zykadia may cause liver injury. Patients should have blood tests at least every month while taking Zykadia, and should talk to their doctor right away if they experience any of the following symptoms: tiredness (fatigue), itchy skin, yellow skin and eyes, nausea or vomiting, decreased appetite, pain on the right side of the stomach, urine turns dark or brown, bleeding or bruising more easily than normal.
Zykadia may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those symptoms from lung cancer. Patients should tell their doctor right away about any new or worsening symptoms, including trouble breathing or shortness of breath, fever, cough, with or without mucous, or chest pain.
Zykadia may cause very slow, very fast, or abnormal heartbeats. Doctors should check their patient's heart during treatment with Zykadia. Patients should tell their doctor right away if they feel new chest pain or discomfort, dizziness or lightheadedness, faint, or have abnormal heartbeats, or if they start to take or have any changes in heart or blood pressure medicines.
People who have diabetes or glucose intolerance, or who take a corticosteroid medicine have an increased risk of high blood sugar with Zykadia. Patients should follow their doctor's instructions about blood sugar monitoring and call their doctor right away with any symptoms of high blood sugar, including increased thirst, increased hunger, headaches, trouble thinking or concentrating, urinating often, blurred vision, tiredness, or breath that smells like fruit.
Before patients take Zykadia, they should tell their doctor about all medical conditions, including liver problems; diabetes or high blood sugar; heart problems, including a condition called long QT syndrome; are pregnant, think they may be pregnant, or plan to become pregnant; are breastfeeding or plan to breastfeed.
Zykadia may harm unborn babies. Women who are able to become pregnant must use an effective method of birth control during treatment with Zykadia and for at least 2 weeks after stopping Zykadia. It is not known if Zykadia passes into breast milk. Patients and their doctor should decide whether to take Zykadia or breastfeed, but should not do both.
Patients should tell their doctor about medicines they take, including prescription medicines, over-the-counter medicines, vitamins and herbal supplements.
The most common side effects of Zykadia include diarrhea, nausea, vomiting, abdominal pain, tiredness (fatigue), decreased appetite and constipation.
Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Zykadia. For more information, patients should ask their doctor or pharmacist.
Patients should take Zykadia exactly as their health care provider tells them. Patients should not change their dose or stop taking Zykadia unless their health care provider advises them to. Zykadia should be taken once a day on an empty stomach. Patients should not eat for 2 hours before and 2 hours after taking Zykadia. If a dose of Zykadia is missed, they should take it as soon as they remember. If their next dose is due within the next 12 hours, they should skip the missed dose and take the next dose at their regular time. Patients should not drink grapefruit juice or eat grapefruit during treatment with Zykadia, as it may make the amount of Zykadia in their blood increase to a harmful level.
Please see full Prescribing Information for Zykadia.
Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "underway," "being presented," "may," "committed," "Breakthrough Therapy," "ongoing," "being conducted," "contingent," "investigational," or similar terms, or by express or implied discussions regarding potential additional marketing authorizations for Zykadia, potential new indications or labeling for Zykadia, or regarding potential future revenues from Zykadia. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management 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 Zykadia will be approved for sale in any market wher it has been submitted, or that it will be submitted or approved for sale in any additional markets, or at any particular time. Neither can there be any guarantee that Zykadia will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Zykadia will be commercially successful in the future. In particular, management's expectations regarding Zykadia could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, 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 updat any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
about Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 135,000 full-time-equivalent associates and sell products in more than 150 countries around the world. For more information, please visit http://www.novartis.com.
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References
[1] Felip E, et al. Efficacy and Safety of Ceritinib in Patients (pts) with Advanced Anaplastic Lymphoma Kinase (ALK)-rearranged (ALK+) Non-small Cell Lung Cancer (NSCLC): An updat of ASCEND-1. Abstract #1295P. European Society of Clinical oncology (ESMO) 2014 Congress, Madrid, Spain.
[2] Shaw A, et al. evaluation of Ceritinib-treated Patients (pts) with Anaplastic Lymphoma Kinase rearranged (ALK+) Non-small Cell Lung Cancer (NSCLC) and Brain metastases in the ASCEND-1 study. Abstract #1293P. European Society of Clinical oncology (ESMO) 2014 Congress, Madrid, Spain.
[3] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in oncology (NCCN Guidelines): Non-Small Cell Lung Cancer. NCCN 2014 3:1-148.
[4] Shaw A, et al. Targeting Anaplastic Lymphoma Kinase in Lung Cancer. Clin Cancer Res 2011;17:2081-2086.
[5] ClinicalTrials.gov. LDK378 in Adult Patients With ALK-activated NSCLC Previously Treated With Chemotherapy and Crizotinib. Available at: http://clinicaltrials.gov/ct2/sh ... e+II%22&rank=1. Accessed August 2014.
[6] ClinicalTrials.gov. LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-Small Cell Lung Cancer. Available at: http://clinicaltrials.gov/ct2/sh ... e+II%22&rank=2. Accessed August 2014.
[7] ClinicalTrials.gov. LDK378 Versus Chemotherapy in Previously Untreated Patients With ALK Rearranged Non-Small Cell Lung Cancer. Available at: http://clinicaltrials.gov/ct2/sh ... e+III%22&rank=1 Accessed August 2014.
[8] ClinicalTrials.gov. LDK378 Versus Chemotherapy in ALK Rearranged (ALK Positive) Patients Previously Treated With Chemotherapy (Platinum Doublet) and Crizotinib. Available at: http://clinicaltrials.gov/ct2/sh ... e+III%22&rank=2 Accessed August 2014.
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公司此次进行的是双盲、随机、安慰剂对照临床III期研究，共有410位患者参与。试验结果显示，接受依维莫司治疗患者的总体生存率达到44个月，略高于安慰剂的37.68月。
依维莫司最早于2009年在美国食品药品监督管理局（FDA）获批，主要适应症包括HER-阴性乳腺癌、晚期肾癌以及肾血管平滑肌脂肪瘤。
Novartis today presented final results on overall survival (OS) from a Phase III trial of Afinitor® (everolimus) tablets plus best supportive care (BSC) compared to placebo plus BSC in patients with well-differentiated advanced and progressive pancreatic neuroendocrine tumors (pNET)1. Overall survival was a secondary endpoint of the trial1. The findings were presented at the European Society for Medical oncology (ESMO) Congress, September 26-30, 2014 in Madrid, Spain, and are to be submitted to health authorities for inclusion in the Afinitor prescribing information.
Results from the RADIANT-3 trial showed a median OS of 44.02 months (95% confidence interval [CI]: 35.61, 51.75) in the everolimus treatment arm and 37.68 months (95% CI: 29.14, 45.77) in the placebo arm1. The 6.34 month difference between the two arms was not statistically significant (Hazard Ratio [HR] 0.94; 95% CI: 0.73, 1.20; p=0.300)1. A high crossover of patients from placebo to everolimus (85%) likely contributed to the long median OS in the placebo arm of 37.68 months and may have confounded the ability to detect a difference in the OS results1.
"The median overall survival of 44 months for everolimus is unprecedented in controlled clinical trials for advanced progressive pancreatic neuroendocrine tumors," said James Yao*, MD, lead investigator, The University of Texas MD Anderson Cancer Center, Houston, Texas. "The results affirm the importance of targeting key pathways involved in tumor growth, such as the mTOR pathway in advanced pNET."
The safety profile was consistent with that observed for everolimus in advanced pancreatic NET and no unexpected or new safety concerns were identified at the time of this analysis, indicating that longer term treatment with everolimus continues to provide a positive benefit-risk ratio for patients1. The most commonly reported (>40%) adverse events (AEs) for everolimus compared to placebo during the core phase of the study were stomatitis (53.9% vs. 13.3%), rash (52.5% vs. 15.8%), diarrhea (48.0% vs. 23.6%) and fatigue (44.6% vs. 26.6%)1. The most common (≥40%) AEs reported with everolimus during this follow-up phase were stomatitis (46.7%), diarrhea (43.6%) and rash (40.0%)1.
Pancreatic NET originates from the islet cells of the pancreas and can grow aggressively2. It is uncommon and distinct from what is generally referred to as pancreatic cancer or pancreatic exocrine cancer5. The majority of patients with pNET have advanced disease at the time of diagnosis, meaning the cancer has spread to other parts of the body and has become more difficult to treat2,3.
"Novartis has more than 25 years of helping to advance NET care and this study, part of the largest global clinical program in NET, emphasizes our commitment to helping fulfill unmet needs for patients living with this disease," said Alessandro Riva, MD, Global Head, Novartis oncology Development and Medical Affairs. "We are pleased to see that Afinitor provided more than 3.5 years of overall survival in patients with progressive, well-differentiated pNET, an advanced and aggressive cancer."
The presentation at ESMO 2014 is an analysis of the mature OS results. Results from the primary analysis, which focused on the progression-free survival (PFS) endpoint in which Afinitor more than doubled median PFS vs. placebo, were previously published in the New England Journal of Medicine (NEJM; February 2011).
about the study
RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study1. The core phase of the trial examined the efficacy and safety of everolimus plus BSC versus placebo plus BSC in 410 patients with advanced, low- or intermediate-grade pancreatic NET, also known as islet cell tumors1. Patients who met the study entry criteria were randomized 1:1 to receive either everolimus 10 mg once-daily (n=207) or daily placebo (n=203) orally, both in conjunction with BSC1. The primary endpoint was PFS, and the key secondary endpoints were OS and the safety and tolerability of everolimus1.
Patients on placebo whose disease progressed during the core phase were allowed to cross over to open-label everolimus. In addition, when all patients were unblinded at the end of the core phase, those initially assigned to placebo were offered to switch to open-label everolimus and those in the everolimus arm could transition to open-label everolimus1. During the open-label phase patients continued with treatment until disease progression was documented by the investigator1. At this point, patients discontinued the study drug and entered the follow-up period to be monitored monthly for survival information1. All patients initially randomized to placebo were included in the placebo arm results, even if they crossed over to everolimus therapy after progression or unblinding1. In total, 85% of patients in the placebo arm crossed over to everolimus during the course of the study1.
In the double-blind phase, serious adverse events (SAEs) were reported more often in the everolimus arm than in the placebo arm (41.2% vs. 25.6%)4. The most commonly reported SAEs (>2% incidence) in the everolimus arm were pyrexia (3.9%), pneumonitis (3.4%), anemia (3.4%), abdominal pain (2.9%), dyspnea (2.9%), diarrhea (2.5%), pulmonary embolism (2.5%), asthenia (2.5%) and dehydration (2.5%)4. The frequency of AEs leading to study drug discontinuation during the double-blind period was higher for the everolimus treatment group (21.1%) compared to the placebo group (5.9%)4. In the open-label period, 23.6% of patients discontinued treatment due to AEs4.
At the time of the final OS analysis there were 126 (60.9%) deaths in the everolimus arm and 130 (64.0%) deaths in the placebo arm1. While no statistically significant difference was evident in terms of OS, the median OS favored the everolimus arm, with a clinically meaningful improvement of 6.34 months over placebo, and supports the concept of starting treatment with everolimus early, once progression is detected1. The OS benefit is consistent with the statistically significant gain of 6.44 months in PFS (HR 0.35; 95% CI: 0.27-0.45; p<0.001) observed in the primary analysis1,6.
about Afinitor® (everolimus) tablets
Afinitor® (everolimus) is approved in more than 85 countries including the United States and European unio for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin. It is also approved in more than 100 countries, including the United States and throughout the European unio, for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy.
Afinitor (everolimus) is approved in the European unio for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI). In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2-) breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.
Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.
Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywher else in the world.
important Safety Information about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.
The most common adverse drug reactions (incidence ≥10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, absence of menstrual periods, infections (including upper respiratory tract infection, sore throat and runny nose, sinusitis, and pneumonia), nausea, decreased appetite, low level of red blood cells, high levels of cholesterol, abnormal taste, acne, irregular menstrual periods, inflammation of lung tissue, high level of blood sugar, weight loss, itching, swelling of extremities or other parts of the body, nose bleeds, and headache. The most common Grade 3-4 adverse drug reactions (incidence ≥2 percent) are mouth ulcers, absence of menstrual periods, low level of red blood cells, infections (including pneumonia), high level of blood sugar, feeling tired or weak, low white blood cells, inflammation of lung tissue, diarrhea, and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.
Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "to be submitted," "indicating," "continues," "commitment," "concept," "has not yet," "will," or similar terms, or by express or implied discussions regarding potential new marketing approvals, indications or labeling for everolimus, or regarding potential future revenues from everolimus. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management 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 everolimus will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that everolimus will be commercially successful in the future. In particular, management's expectations regarding everolimus could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, 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 updat any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
about Novartis
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets innovative medicines aimed at improving patients' lives. We offer a broad range of medicines for cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, neurological disease, organ transplantation, psychiatric disease, respiratory disease and skin conditions. The company's mission is to improve people's lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 135,000 full-time-equivalent associates and sell products in more than 150 countries around the world. For more information, please visit http://www.novartis.com.
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* Dr. Yao has served as a consultant and has received research funding from Novartis
References
1. Oberg K, Yao J, Lam D H, et al. A randomized double-blind Phase III study of RAD001 10 milligrams per day (mg/d) plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced pancreatic neuroendocrine tumor (NET). Presented at the European Society for Medical oncology (ESMO) Congress, September 26-30, 2014, Madrid, Spain (abstract #1132O).
2. National Library of Medicine and the National Institutes of Health. Pancreatic islet cell tumor. Available at http://www.nlm.nih.gov/medlineplus/ency/article/000393.htm. Accessed July 2014.
3. Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc. 19: 1727-1733, 2008.
4. Novartis data on file.
5. American Cancer Society Detailed Guides. Pancreatic Cancer. Available at http://www.cancer.org/Cancer/Pan ... -pancreatic-cancer. Accessed July 2014.
6. Yao J et al. J Clin Oncol 2008;26:3063-72.
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