EMA Review of Panobinostat (Farydak) for the Treatment of Adult Patients with Relapsed and/or Refractory Multiple Myeloma.
EMA Review of Panobinostat (Farydak) for the Treatment of Adult Patients with Relapsed and/or Refractory Multiple Myeloma.
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DOI：
10.1634/theoncologist.2017-0301
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Pignatti F
中科院分区：
文献类型：
--
作者：
Tzogani K;van Hennik P;Walsh I;De Graeff P;Folin A;Sjöberg J;Salmonson T;Bergh J;Laane E;Ludwig H;Gisselbrecht C;Pignatti F
本文总结了导致欧盟监管批准的帕比司他的科学审查。2015年8月28日，帕比司他联合硼替佐米和地塞米松获得了在欧盟有效的上市许可，用于治疗至少接受过两种既往治疗方案（包括硼替佐米和免疫调节剂（IMiD））的复发性和/或难治性多发性骨髓瘤成人患者。帕比司他是一种口服可利用的组蛋白脱乙酰酶（HDAC）抑制剂，其在纳摩尔浓度下抑制HDAC蛋白的酶活性。HDAC蛋白催化乙酰基从组蛋白和一些非组蛋白的赖氨酸残基的去除。HDAC活性的抑制导致组蛋白乙酰化增加，这是一种表观遗传改变，导致染色质松弛，从而导致转录激活。帕比司他的推荐起始剂量为20 mg，以周期性方式口服长达48周。在一项随机、双盲、安慰剂对照、多中心III期研究（PANORAMA I）中，在768例既往接受过1 - 3线治疗的复发性或复发性难治性多发性骨髓瘤患者中研究了帕比司他联合硼替佐米和地塞米松的使用。在接受过至少两种既往治疗方案（包括硼替佐米和IMiD）的患者亚组中，无进展生存期差异为7.8个月，有利于实验组（帕比司他+硼替佐米+地塞米松为12.5个月，安慰剂+硼替佐米+地塞米松为4.7个月;风险比= 0.47，95%置信区间0.31-0.72;对数秩p值= .0003）。帕比司他组和安慰剂组疑似与研究药物相关的3-4级不良事件的发生率分别为76.9%和51.2%。帕比司他最常见的副作用（3-4级）包括腹泻（18.9%）、疲乏（14.7%）、恶心（4.5%）、呕吐（5.5%）、血小板减少（43.6%）、贫血（7.9%）、中性粒细胞减少（16.5%）和淋巴细胞减少（8.1%）。本文总结了导致欧盟监管批准的申请的科学审查。完整的科学评估报告和产品信息（包括产品特性概要）可在欧洲药品管理局网站（http：//www.example.com）上获得www.ema.europa.eu/ema/index.jsp? curl=pages/includes/medicines/medicines_landing_page.jsp&mid=）。法替佐米在欧盟获批与硼替佐米和地塞米松联合治疗复发性和/或难治性多发性骨髓瘤成人患者，这些患者既往接受过至少两种治疗方案，包括硼替佐米和免疫调节剂（IMiD）。与硼替佐米和地塞米松相比，在硼替佐米和地塞米松的基础上添加帕比司他导致无进展生存期出现具有临床意义和统计学显著性的改善，并且认为具有新作用机制的额外治疗选择是有价值的。尽管与帕比司他组合相关的毒性是显著的，但在帕比司他的上市许可时，认为其是可接受的，并且应由临床医生和患者决定帕比司他组合是否是优选的治疗选择。
This article summarizes the scientific review of panobinostat that led to regulatory approval in the European Union. On August 28, 2015, a marketing authorization valid through the European Union was issued for panobinostat, in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD). Panobinostat is an orally available histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDAC proteins at nanomolar concentrations. HDAC proteins catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. The recommended starting dose of panobinostat is 20 mg, taken orally in a cyclical manner for up to 48 weeks. The use of panobinostat in combination with bortezomib and dexamethasone was studied in a randomized, double‐blind, placebo‐controlled, multicenter phase III study (PANORAMA I) in 768 patients with relapsed or relapsed and refractory multiple myeloma who had received one to three prior lines of therapies. In the subgroup of patients who have received at least two prior regimens including bortezomib and an IMiD, there was a difference of 7.8 months in the progression‐free survival in favor of the experimental arm (12.5 months for panobinostat + bortezomib + dexamethasone vs. 4.7 months for placebo + bortezomib + dexamethasone; hazard ratio = 0.47, 95% confidence interal 0.31–0.72; log‐rank p value = .0003). The incidence of grade 3–4 adverse events suspected to be related to study drug was 76.9% vs. 51.2%, for the panobinostat and the placebo group, respectively. The most common side effects (grade 3–4) associated with panobinostat included diarrhea (18.9%), fatigue (14.7%), nausea (4.5%), vomiting (5.5%), thrombocytopenia (43.6%), anemia (7.9%), neutropenia (16.5%) and lymphopenia (8.1%). This article summarizes the scientific review of the application leading to regulatory approval in the European Union. The full scientific assessment report and product information, including the Summary of Product Characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landing_page.jsp&mid=). Farydak was approved in the European Union in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD). The addition of panobinostat to bortezomib and dexamethasone resulted in a clinically meaningful and statistically significant improvement of progression‐free survival compared with bortezomib and dexamethasone, and an additional therapeutic option with a new mechanism of action was considered valuable. Although the toxicity associated with panobinostat combination was significant, at the time of the marketing authorization of panobinostat, it was considered that it was acceptable and that it should be left to the clinician and the patient to decide whether the panobinostat combination is the preferred treatment option or not.
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影响因子：
11.4
作者：
Kumar SK;Lee JH;Lahuerta JJ;Morgan G;Richardson PG;Crowley J;Haessler J;Feather J;Hoering A;Moreau P;LeLeu X;Hulin C;Klein SK;Sonneveld P;Siegel D;Bladé J;Goldschmidt H;Jagannath S;Miguel JS;Orlowski R;Palumbo A;Sezer O;Rajkumar SV;Durie BG;International Myeloma Working Group
通讯作者：
International Myeloma Working Group
影响因子：
45.3
作者：
San-Miguel, Jesus F.;Richardson, Paul G.;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
20.3
作者：
Richardson, Paul G.;Schlossman, Robert L.;Lonial, Sagar
通讯作者：
Lonial, Sagar
影响因子：
7.5
作者：
Costa, Luciano J.;Brill, Ilene K.;Brown, Elizabeth E.
通讯作者：
Brown, Elizabeth E.
多发性骨髓瘤：诊断和治疗。
影响因子：
8.9
作者：
Rajkumar SV;Kumar S
通讯作者：
Kumar S