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突破性抗癌药venetoclax获欧盟受理上市许可

2016-06-27 04:22:35 作者：新特药房来源：互联网浏览次数：1 文字大小：【大】【中】【小】

简介： 2016年2月26日，欧洲药品管理局（EMA）授予突破性抗癌药venetoclax治疗急性髓性白血病（AML）的孤儿药地位。之前，EMA已授予venetoclax治疗慢性淋巴细胞白血病（CLL）的孤儿药地位。而就在上个月，EMA已受 ...

关键字：venetoclax商品名venclex tacll者有17p缺失突破性治疗加速批准优先审评孤儿药物

2016年2月26日，欧洲药品管理局（EMA）授予突破性抗癌药venetoclax治疗急性髓性白血病（AML）的孤儿药地位。
之前，EMA已授予venetoclax治疗慢性淋巴细胞白血病（CLL）的孤儿药地位。而就在上个月，EMA已受理venetoclax单药治疗携带17p删除突变或TP53突变的慢性淋巴细胞白血病（CLL）的上市许可申请（MAA）。
在美国监管方面，FDA最近也授予venetoclax治疗AML的突破性药物资格和孤儿药地位，这也标志着venetoclax收获的FDA第3个突破性药物资格。2015年4月，FDA授予venetoclax单药治疗携带17p删除突变（del 17p）的复发性/难治性慢性淋巴细胞白血病（R/R CLL）的突破性药物资格。今年1月，FDA授予venetoclax联合罗氏抗癌药美罗华（Rituxan，通用名：rituximab，利妥昔单抗）治疗复发性/难治性慢性淋巴细胞白血病（R/R CLL）的突破性药物资格。另外，今年1月，FDA也授予venetoclax单药治疗既往已接受至少一种疗法的CLL（包括del 17p CLL）的新药申请（NDA）优先审查资格，这也意味着venetoclax很有可能在今年夏天就能获批在美国上市。
急性髓性白血病（AML）是一种进展迅速的血液和骨髓恶性肿瘤，也是成人群体中最常见的一种急性白血病类型。在欧洲，AML的年发病率大约为1/33000-1/25000。
venetoclax是一种口服的B细胞淋巴瘤因子-2（BCL-2）抑制剂，BCL-2在细胞凋亡（程序性细胞死亡）中发挥重要作用，可阻止一些细胞（包括淋巴细胞）的凋亡，并且在某些类型癌症中过度表达，与耐药性的形成相关。venetoclax旨在选择性抑制BCL-2的功能，恢复细胞的通讯系统，让癌细胞自我毁灭，达到治疗肿瘤的目的。
venetoclax由艾伯维与罗氏合作开发。目前，双方正在开展一个大型临床项目，调查venetoclax单药及组合疗法治疗多种类型血癌，包括CLL、NHL、弥漫性大B细胞淋巴癌（DLBCL）、急性髓性白血病（AML）和多发性骨髓瘤（MM）。
venetoclax的成功对艾伯维尤其关键，该公司在去年3月以210亿美元从强生手中成功抢婚Pharmacyclics公司，顺利获得一款“钱”途无量且与自身肿瘤学管线完美互补的突破性抗癌药Imbruvica在美国市场的销售权。
截至目前，Imbruvica在美国已收获4个适应症，在2015年度为艾伯维带来了近10亿美元收入，该药将奠定艾伯维在高速增长的肿瘤治疗市场中的强大存在。业界预计Imbruvica的年销售峰值将突破50亿美元。艾伯维认为，venetoclax联合Imbruvica将创造血液肿瘤临床治疗的一个一流组合疗法。
IMPORTANT SAFETY INFORMATION
•VENCLEXTA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy
•This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial
Important Safety Information
Contraindication
•Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated
Tumor Lysis Syndrome
•Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden treated with VENCLEXTA
•VENCLEXTA poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase
•Patients should be assessed for TLS risk, including evaluation of tumor burden and comorbidities, and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Reduced renal function (CrCl <80 mL/min) further increases the risk. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases
•Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors and P-gp inhibitors may increase the risk of TLS at initiation and during the ramp-up phase, and may require dose adjustment due to increases in VENCLEXTA exposure
Neutropenia
•Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with VENCLEXTA. Monitor complete blood counts throughout treatment. Interrupt dosing or reduce dose for severe neutropenia
Immunization
•Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery
Embryo-Fetal Toxicity
•VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment
Adverse Reactions
•Serious adverse reactions were reported in 43.8% of patients. The most frequent serious adverse reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia, anemia, and TLS
•The most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue
Drug Interactions
•For patients who have completed the ramp-up phase and are on a steady daily dose of VENCLEXTA, reduce the dose by at least 75% when used concomitantly with strong CYP3A inhibitors
•Avoid concomitant use of moderate CYP3A inhibitors or P-gp inhibitors. If an inhibitor must be used, reduce the VENCLEXTA dose by at least 50%
•Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A
•Avoid concomitant use of strong or moderate CYP3A inducers
•Avoid concomitant use of narrow therapeutic index P-gp substrates. If these substrates must be used, they should be taken at least 6 hours before VENCLEXTA
•Monitor international normalized ratio (INR) closely in patients receiving warfarin
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New Drugs Online Report for venetoclax
Information
Generic Name: venetoclax
Trade Name: Venclexta
Synonym: GDC-0199, ABT-199, RG7601
Entry Type: New molecular entity
Development and Regulatory status
UK: Pre-registration (Filed)
EU: Pre-registration (Filed)
US: Approved (Licensed)
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
Apr 16: Approved in US [13]
12/04/2016 09:28:55
Jan 16: Breakthrough Therapy Designation granted in 2015 was to single agent venetoclax for treatment of CLL in previously treated (relapsed/refractory) patients with the 17p deletion genetic mutation [12].
21/01/2016 10:29:07
Jan 16: US FDA grants Breakthrough Therapy Designation to venetoclax in combination with rituximab, in treatment of relapsed/refractory patients with CLL [11].
21/01/2016 10:27:46
Jan 16. Granted priority review in US [10].
19/01/2016 11:44:33
Oct 15: AbbVie reported regulatory submission to the EMA for venetoclax in the treatment of relapsed or refractory CLL, in pts with 17p deletion [8].
17/12/2015 10:36:24
Aug 15: AbbVie plans to file in the EU & US in 2015 on the back of promising PII data [6].
14/08/2015 10:35:10
May 15: FDA grant Breakthrough Therapy Designation [5].
08/05/2015 09:13:08
Mar 14: EU & US filings planned for 2016 [3].
23/06/2014 10:45:40
Trial or other data
May 16: Results of PII (NCT01889186) trial, published online in the Lancet Oncology. This single arm study (n=107) found that at 12.1 months median follow-up 79.4% patients achieved an overall response with venetoclax monotherapy. Neutropenia (40%), infection (20%) and anaemia (18%) were the most common adverse events [14].
13/05/2016 15:28:36
Dec 15: Genentech and AbbVie presented PII data (from the open label, multicentre M13-982 study, NCT01889186) in more detail in which venetoclax monotherapy achieved primary efficacy endpoints with 79.4% of pts (n=107) with relapsed or refractory CLL and a 17p deletion showing an overall response rate. Partial response was reported in 69.2% of pts. Independently assessed complete or partial response (at 12 months) was achieved in 10.3%, complete response or complete response with incomplete marrow recovery was reported in 7.5% and nodular partial response was reported in 2.8% of pts. Of the pts treated with Venetoclax, 84.7% sustained response for ~12 months, with 94.4% of these having MRD-negative responses (MRD negative means no cancer could be detected). Eighteen pts who took venetoclax achieved MRD-negativity and 10 of these 18 pts also had bone marrow assessments of which 6 were MRD-negative. Twelve months progression-free survival and overall survival rates were 72% and 86.7%, respectively [7-9].
17/12/2015 10:33:35
Aug 15: PII data announced showing the primary endpoint of achieving overall response rates in patients with CLL with 17p deletion was met. Also, the safety profile was similar to previous studies and no unexpected safety signals were reported. Full data is to be unveiled at a medical conference in the near future and will form the basis of applications to the health authorities around the globe [6].
14/08/2015 10:36:30
Q1 14: First pt enrolled in PIII MURANO as planned [4].
16/03/2015 10:42:28
Jun 14: PIII NCT02005471 = MURANO. First pt expected to be enrolled Q1 14 [3].
23/06/2014 11:09:12
Jun 14: At the interim point of a PIb study, ABT-199/GDC-0199 combined with rituximab registered an 84% overall response rate among patients with CLL. Nine of 25 evaluable patients in the study achieved either a complete response or complete response with incomplete blood count recovery, while close to half--12 patients--achieved a partial response. Among the complete responders, 75% (6 patients) were identified as minimal residual disease negative, indicating the detection of zero leukaemic cells [2].
09/06/2014 12:50:00
Roche arecollaborating with AbbVie on development.
10/12/2013 10:22:42
NCT02005471 is a multicentre, PIII, open-label, randomized study in r370 elapsed/refractory patients with CLL of GDC-0199 (ABT-199) + rituximab vs bendamustine + rituximab. Patients randomized to GDC-0199+R will be given GDC-0199 daily (oral, target dose 400 mg) until disease progression or 2 years since treatment start, whichever comes first. and will receive 6 cycles of IV rituximab. Patients randomized to B+R will receive 6 cycles of treatment. Anticipated time on study is up to 5 years. The primary outcome is PFS. The study starts Dec 13 and is due to complete Aug 20 [1].
10/12/2013 10:15:28
References
Available only to registered users