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诺华抗癌药Jakavi关键III期显著改善真性红细胞增多症疾病控制

  1. Jakavi
  2. JAK激酶抑制剂
  3. ruxilitinib
  4. 真性红细胞增多症
  5. 诺华

来源:生物谷 2014-06-05 09:16

诺华抗癌药Jakavi关键III期显著改善真性红细胞增多症(PV)患者疾病控制,如果获批,该药将成为用于PV治疗的首个JAK1/2抑制剂。

2014年6月4日讯 /生物谷BIOON/ --诺华(Novartis)6月3日公布了抗癌药物Jakavi(ruxilitinib)关键性III期RESPONSE研究的积极数据。RESPONSE是一项全球性、随机、开放标签研究,在全球109个位点开展。试验中,222例对羟基脲有抗性或不耐受的真性红细胞增多症(polycythemia vera,PV)患者,随机接受ruxolitinib(10mg,每日2次)或最佳疗法(即研究人员选择的单药疗法或仅仅观察)。在整个研究中,剂量会随着需要进行调整。主要终点是无需放血而血细胞比容得到控制的患者比例,以及32周时脾脏体积从基线缩小35%或更多(通过成像评估)。除安全性外,关键次要终点包括持久反应和完全的血液系统缓解。

研究结果表明,该研究达到了维持红细胞压积(红细胞体积)受控而无需放血(phlebotomy,从身体中出去一些血液的一种程序,以减少红细胞浓度)的主要终点,同时降低了对羟基脲有抵抗或不耐受真性红细胞增多症患者脾脏大小。Jakavi治疗组有70%的患者实现了血细胞比容控制或脾脏体积缩小,而最佳支持疗法治疗组为20%。研究中ruxolitinib的安全性与以往研究一致。

目前,诺华正在向全球的监管机构提交Jakavi治疗PV的监管申请文件。如果获批,Jakavi将成为首个用于PV患者治疗的JAK 1/2抑制剂。

真性红细胞增多症(polycythemia vera,PV)是一种慢性、无法治愈的血液癌症,该病与血细胞生产过剩相关,导致血液增稠,血液凝块风险增加。这些血凝块可导致严重心血管并发症,如中风和心脏病发作,从而增加病发率和死亡率。红细胞增多症患者,常有脾脏肿大及额外衰弱的症状。许多患者经常规治疗后会变得不耐受或抵抗,这与病情恶化的风险升高有关。

关于Jakavi:

Jakavi(ruxolitinib)是一种口服JAK1和JAK2酪氨酸激酶抑制剂,于2012年8月获欧盟批准,用于治疗中级或高危骨髓纤维化,包括原发性骨髓纤维化,真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化。目前,Jakavi已获全球50多个国家批准,包括欧盟、加拿大和一些亚洲、拉丁美洲和南美洲国家。

诺华从Incyte公司授权获得ruxolitinib在美国以外的开发和商业化权利。欧盟委员会和FDA均已授予ruxolitinib治疗骨髓纤维化的孤儿药地位。目前,Incyte已经在美国以商品名Jakafi销售,用于中级或高危骨髓纤维化的治疗。

英文原文:Pivotal Phase III data show polycythemia vera patients on Novartis drug Jakavi® achieved significant improvement in disease control

77% of patients on Jakavi® (ruxolitinib) vs 20% on best available therapy achieved hematocrit control or spleen reduction, key treatment goals in PV[1]

Nearly half of ruxolitinib-treated patients had a 50% or more reduction in debilitating PV symptoms compared to 5% on best available therapy[1]

Global regulatory filings are underway based on these data; if approved, ruxolitinib will be the first JAK 1/2 inhibitor available for PV patients

Basel, June 3, 2014 - Novartis today announced results from the first-ever pivotal Phase III study evaluating a JAK 1/2 inhibitor for the treatment of polycythemia vera (PV). Jakavi® (ruxolitinib) significantly improved hematocrit control without the need for phlebotomy (a procedure to remove blood from the body to reduce the concentration of red blood cells[2]) and reduced spleen size in patients with PV who are resistant to or intolerant of hydroxyurea[1]. Findings are being presented at the 50th Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois.

PV is a chronic, incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as stroke and heart attack[2]. Currently, there are limited treatments for polycythemia vera and a high unmet need exists for new therapies that provide effective disease control[3].

"Patients with polycythemia vera may not have their disease controlled with existing therapies, increasing their risk for cardiovascular complications," said Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center, Houston, Texas and lead study author. "In the RESPONSE trial, patients treated with ruxolitinib showed better disease control, including controlled hematocrit levels without the need for phlebotomy, reduced spleen size and improved symptom management compared to current therapies."

At week 32 of the study, 77% of patients randomized to ruxolitinib achieved one or both components of the composite endpoint of hematocrit control (volume percentage of red blood cells in whole blood[2]) or spleen size reductionin comparison with 20% of patients randomized to best available therapy[1]. A significantly greater proportion of patients achieved the composite primary endpoint when treated with ruxolitinib compared to best available therapy (21% compared to 1%, respectively; p< .0001), and 91% of these patients treated with ruxolitinib maintained their response at week 48[1].

"New treatments for polycythemia vera are greatly needed, as this is a disease that causes debilitating daily symptoms, which are as severe as symptoms associated with myelofibrosis, and also puts patients at risk for serious cardiovascular complications, such as stroke and heart attack," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "These findings reinforce ruxolitinib's significant clinical benefit and potential to become an important new treatment option for polycythemia vera patients who are no longer responding to or are intolerant of prior therapy."

In the study, a 50% or more improvement in PV-related symptoms was seen in 49% of ruxolitinib-treated patients compared to 5% of patients treated with best available therapy[1]. Patients treated with ruxolitinib also experienced a reduction in night sweats and itchiness (approximately 99% and 95%, respectively)[4]. In addition, a greater proportion of patients on the ruxolitinib treatment arm achieved complete hematologic response as defined by the modified 2009 European LeukemiaNet (ELN) criteria, a key secondary endpoint, when compared to the best available therapy arm (24% compared to 9%, respectively; p=.003)[1].

Ruxolitinib was well tolerated and adverse events (AEs) were consistent with those previously seen in ruxolitinib studies in PV and myelofibrosis[1],[5],[6]. Within the first 32 weeks of treatment, Grade 3 or 4 hematologic AEs in the ruxolitinib treatment arm were anemia (1.8%) and thrombocytopenia (5.5%), and fewer patients treated with ruxolitinib experienced thromboembolic events when compared to those who received best available therapy (1 patient compared to 6 patients, respectively)[1]. The most common non-hematologic AEs were headache, diarrhea and fatigue, which were mainly Grade 1 or 2[1]. Additionally, 3.6% of patients randomized to the ruxolitinib treatment arm discontinued treatment due to AEs compared to 1.8% on the best available therapy arm[4].

Data from the RESPONSE trial will support worldwide regulatory submissions planned this year. The data will also be presented at the upcoming 19th Congress of the European Hematology Association in Milan, Italy.

Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis, a debilitating and life-threatening blood cancer.

Study Design
RESPONSE is a global, randomized, open-label study conducted at 109 sites. 222 patients with PV resistant to or intolerant of hydroxyurea were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice-daily) or best available therapy, which was defined as investigator selected monotherapy or observation only. Ruxolitinib dose was adjusted as needed throughout the study[1].

The primary endpoint of the study was the proportion of patients whose hematocrit was controlled without phlebotomy from week 8 through 32 and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at 32 weeks. In addition, efficacy was further assessed using two key secondary endpoints: durable primary response and complete hematological remission. Other endpoints include safety, symptom improvement (as measured by the MPN-SAF 14-item total symptom score) and quality of life[1].

About Polycythemia Vera
PV is a chronic, incurable blood cancer associated with an overproduction of blood cells in the bone marrow[2] that affects roughly one to three people per 100,000 globally[7]. It is typically characterized by an elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots[2]. This can cause serious cardiovascular complications, such as stroke and heart attack[2], resulting in increased morbidity and mortality[8]. Phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, is commonly used to maintain a normal hematocrit level[2].

Additionally, patients with PV often have enlarged spleen and numerous debilitating symptoms that significantly affect their daily life[2]. A proportion of patients become intolerant or resistant to currently available therapies. In fact, approximately 25% of PV patients become resistant to or intolerant of hydroxyurea treatment, which results in inadequate disease control and an increased risk of progression[9],[10].

About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases and was approved by the European Commission in August 2012 for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. Jakavi is approved in more than 60 countries, including the European Union, Canada and some countries in Asia, Latin and South America. Additional worldwide regulatory filings are underway.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Both the European Commission and the U.S. Food and Drug Administration (FDA) granted ruxolitinib orphan drug status for myelofibrosis. Jakavi is marketed in the United States by Incyte Corporation under the name Jakafi® for the treatment of patients with intermediate or high-risk myelofibrosis.

The recommended starting dose for Jakavi in patients with myelofibrosis is 15 mg twice daily for patients with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously[11].

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside the approved indication.

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