【转帖】FDA快速批准 布鲁替尼 ibrutinib

清歌一曲月如霜

【转帖】FDA快速批准 布鲁替尼 ibrutinib


FDA speedily approves Imbruvica, a treatment for rare lymphoma

洛杉矶时报

注: 这是华人潘博士(已回深圳)设计合成的新药

Less than five months after a pair of biotech companies submitted a candidate cancer drug to the Food & Drug Administration, the FDA has approved the drug ibrutinib as a "breakthrough therapy" for a rare and deadly form of the cancer, mantle cell lymphoma. The new medication, to be marketed under the commercial name Imbruvica, becomes a new option for patients who are diagnosed with this malignancy of the immune system's B-cells and who have received at least one prior therapy.

The medication is the first product developed by Sunnyvale, Calif., biotech firm Pharmacyclics, where its promise as a treatment for B-cell malignancies such as lymphoma became evident in 2009. Pharmacyclics partnered with Janssen Biotech Inc. to bring the new drug to the market.

Each year, some 2,900 Americans receive a diagnosis of mantle cell lymphoma. Existing treatments rarely halt this aggressive cancer's progression for more than five months. The FDAaccelerated its consideration of ibrutinib because mantle cell lymphoma is a life-threatening disease for which few effective treatment options are available.

"MCL is the worst of the worst," said Dr. John Byrd, a hematologist at the Ohio State UniversityComprehensive Cancer Center, who is leading a trial testing the ibrutinib's effectiveness in a more common but less aggressive form of lymphoma, chronic lymphatic leukemia (CLL), which is diagnosed in roughly 14,000 patients a year. A new drug that shows promise of achieving "very, very durable" results in some patients "is a blessing," said Byrd, who has served as an unpaid consultant to Pharmacyclics.

Trials of the drug's effectiveness in treatment of CLL have also been conducted at City of Hope in Duarte, where hematologist Dr. Leslie Popplewell said, "It's nice to have the more gentle therapy" of a daily pill available to patients whose principal option -- if they are healthy enough to withstand it -- has been a grueling regimen of intravenous chemotherapy with debilitating side effects.

City of Hope will soon open new clinical trials of ibrutinib for patients with untreated low-grade lymphomas, new diagnosed follicular lymphoma and refractory marginal zone lymphoma -- all less aggressive, more chronic forms of the disease.

"I don't think we've explored the full capabilities if ibrutinib," Popplewell said.

Because of its accelerated review, the drug's approval by the FDA was based not on hard outcomes such as patients' survival or symptom improvement, but on trial investigators' assessment of the "overall response rate" of patients taking the drug. In a multi-center clinical trial that did not assign any subjects to take a placebo medication for comparison, 65.8% of 111 patients with mantle cell lymphoma were deemed to have responded to the medication, with 17% of the total achieving a "complete response" and 49% achieving a "partial response."

The median duration of patients' responsiveness to the medication was 17.5 months.

Ibrutinib is expected to be considered next by the FDA as a treatment for chronic lymphatic leukemia, a disease for which second-line treatment has been able to hold off progression for a median of 14 months. Ohio State University's Byrd said that roughly three-quarters of the patients he is overseeing in the trial are still taking the medication and doing well at the 26-month mark.

For nearly half of research subjects who took a high dose of ibrutinib, bleeding events, including bruising, occurred, and they were serious in 5% of those who took it. Infections, renal toxicity and disturbances in blood chemistry all occurred in at least a quarter of subjects taking the medication.

[Corrected at 6:20 p.m., Nov. 13: An earlier version of this post referred to Dr. Leslie Popplewell as Dr. Leslie Popplewhite. Corrected at 4:55 p.m. Nov. 14: An earlier version of this post reported that three-quarters of patients with CLL on ibrutinib were doing well at the 26-week mark. They are doing well at the 26-month mark.]

生物探索

当地时间2013年11月13日，Ibrutinib的先期开发者Pharmacyclics公司在其网站主页宣布，美国食品药品管理局（USFDA）已批准Ibrutinib（商标名 IMBRUVICA）作为套细胞淋巴癌的单个治疗药物，适用于之前用其他手段治疗过的套细胞淋巴癌患者，标志着该药物正式进入市场化运营阶段。

Ibrutinib早先由Pharmacyclics公司单独开发。2011年，强生（JNJ）旗下子公司杨森制药（Jassen）通过先期支付1.5亿美元而获得与Pharma -cyclics公司合作开发的权利。这款药物于今年2月份已被FDA授予突破性治疗药物资格。杨森制药于7月份向FDA提交了这款药物的上市申请，该药物用于治疗两种B细胞恶性肿瘤，即作为二线治疗药物用于慢性淋巴细胞性白血病(CLL)/小淋巴细胞淋巴瘤(SLL)和套细胞淋巴癌(MCL)治疗。10月份，杨森制药再次宣布，已向欧洲药品管理局（EMA）提交了抗癌药物Ibrutinib的上市许可申请（MAA），寻求批准用于上述三种血液性肿瘤的治疗。

此次Ibrutinib用于治疗套细胞淋巴癌获得批准是在对111名之前经历过治疗的患者进行全面试验的基础上做出的。药物效用结果显示，Ibrutinib在上述111名被试中的总体应答率高达65.8%，完全应答率达到17%，另有49%的患者为部分应答。持续应答时间的中值为17.5个月。

美国每年大约有1.6万人被诊断为慢性淋巴细胞性白血病，目前该疾病的标准治疗通常是化疗。然而，好多慢性淋巴细胞性白血病老年患者无法容忍激进的治疗，而染色体17p缺失引起的恶性肿瘤患者通常对治疗没有响应。在临床试验中，Ibrutinib已证实有较高的总体响应和持续响应，不论染色体17p状态如何。因此，Ibrutinib的批准将为相关的患者带来福音。

早先有分析师已预测Ibrutinib所有适应症的年销售峰值将会达到大约5亿美元，其最大销售份额可能来自慢性淋巴细胞性白血病适应症，而目前该适应症正在进行三项期临床试验。Ibrutinib在治疗套细胞淋巴癌领域的首先批准相信会让处于III临床试验的其他几种适应症被批准的希望大增。

关于Ibrutinib

Ibrutinib是一种名为Bruton’s酪氨酸激酶（BTK）抑制剂的首创新药。BTK是细胞生理活动中的一个重要蛋白，参与介导调控B细胞成熟和生存的胞内信号通路。在恶性B细胞中，B细胞受体信号通路过度活跃，该信号通路即包括BTK。Ibrutinib能够与BTK形成强有力的共价键，从而抑制恶性B细胞中过度活跃的细胞生存信号的传输，从而达到抑制肿瘤生长和转移的效果。

参考链接

1. Pharmacyclics公司网站消息

2. 强生在美国提交“突破性治疗药物” Ibrutinib的上市申请