2015年2月23日，美国食品和药品监管局(FDA)批准Farydak(帕比司他[panobinostat])为多发性骨髓瘤患者的治疗。
多发性骨髓瘤是一种形式对血癌源自浆细胞，骨髓中发现的一种类型白血细胞。按照美国癌症研究所，每年约21,700美国人被诊断有多发性骨髓瘤和10,710 人死于该疾病。
主要地影响老年成年，多发性骨髓瘤致浆细胞迅速地倍增和从骨髓排挤其他健康血细胞。
当骨髓有太多浆细胞，细胞可能移动到身体其他部分，可能减弱机体的免疫系统，导致贫血和致其他骨和肾脏问题。
Farydak通过抑制酶活性起作用，被称为组蛋白去乙酰化酶(HDACs)。这个过程可能减慢在多发性骨髓瘤患者过度-发展的浆细胞或致这些危险细胞死亡。
Farydak是第一个HDAC抑制剂被批准治疗多发性骨髓瘤。它意向为患者曾接受至少两个以前标准治疗，包括硼替佐米[bortezomib]和一个免疫调节剂。Farydak是将与硼替佐米，一种类型化疗，和地塞米松，一种抗炎药物联用。
FDA的药品评价和研究中心血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“Farydak 有一种新作用机制不同于以前被批准的治疗多发性骨髓瘤药物，使它是一种潜在诱人的为多发性骨髓瘤的治疗备选药，” “Farydak对被批准是特别重要因为它曾减慢多发性骨髓瘤的进展。”
2014年11月， FDA的肿瘤药物肿瘤药物咨询委员会建议监管局，根据审评的数据，药物对获益没有胜过它对有复发多发性骨髓瘤患者风险。在会议后，公司递交另一个资料支持 Farydak的对一个不同适应证对使用：有多发性骨髓瘤患者曾接受至少两种以前标准治疗，包括硼替佐米和一种免疫调节剂。
在193例临床试验多发性骨髓瘤参加者，接受至少两次以前治疗包括硼替佐米和一种免疫调节剂，证实Farydak与硼替佐米和地塞米松联用的安全性和疗效。参加者被随机地赋予接受一种Farydak，硼替佐米和地塞米松联用，或单独硼替佐米和地塞米松。
研究结果显示参加者接受Farydak组合见到其疾病进展延缓(无进展生存)共约10.6个月，与之比较用单独硼替佐米和地塞米松治疗参加者至5.8个月。此外，59 %的Farydak-治疗参加者见到治疗后其癌皱缩或消失(反应率)，相比接受硼替佐米和地塞米松参加者为41%。
Farydak带有一个黑框警告警戒患者和卫生保健专业人员，接受Farydak患者中曾发生严重腹泻和严重和致命性心脏事件，心律失常和心电图(ECG)变化。因为这些风险，Farydak正在批准与风险评估和缓解策略(REMS)由一个交流计划告知这些风险卫生保健专业人员和如何缩小风险组成。
Farydak的最常见副作用是腹泻，疲劳，恶心，臂或腿肿胀，食欲减低，发热，呕吐和虚弱。最常见实验室异常是低磷血症，低钾血症)，低钠血症，肌酐增加，血小板减少，白细胞减少和低红细胞计数(贫血)。卫生保健专业人员还应告知患者胃肠道和肺中出血风险，和肝损伤 (肝脏毒性)。
FDA授权Farydak优先审评和孤儿产品指定。优先审评提供对意向治疗某种严重疾病或情况和可能提供超过可得到治疗显著改善药物加快审评。孤儿产品指定是给予意向治疗罕见疾病药物。
FDA 是在监管局的加速批准程序下行动，允许批准治疗某种严重或危及生命疾病根据临床数据显示药物有对一种替代性终点合理地可能预测对患者获益影响。加速批准程序提供患者较早得到鼓舞人有前途新药而公司进行验证性临床试验。尚未对Farydak确定改善生存或疾病-相关症状。公司现在被要求进行验证性试验证明和描述Farydak的临床获益。
Farydak由总部新泽西East Hanover的诺华制药上市。

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm
New Drugs Online Report for panobinostat
Information
Generic Name: panobinostat  
Trade Name: Farydak 
Synonym: LBH 589, LBH589 
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
Feb 15: US FDA approves panobinostat for use with bortezomib and dexamethasone in pts who have received at least two prior standard therapies. It carries a boxed warning alerting pts and doctors that severe diarrhoea and severe and fatal cardiac events, arrhythmias and electrocardiogram changes, have been observed [20].
24/02/2015 13:42:00 
Nov 14: FDA extends its review period by 3 months, moving its decision deadline from December to March [19].
27/11/2014 15:58:34 
Nov 14: FDA Oncologic Drugs Advisory Committee vote 5-2 against panobinostat for patients with previously treated MM when used in combination with bortezomib and dexamethasone [18].
07/11/2014 16:31:18 
Nov 14: Ahead of an advisory FDA committee meeting, FDA reviewers note that PFS results from many patients in the panobinostat arm of a PIII trial were censored due to incomplete and missing assessments. Factoring in all the omitted data, median PFS extension was 2.2 months vs. placebo; median overall survival median was 33.6 months vs. 30.4 months with placebo [17].
07/11/2014 15:44:08 
Jun 14: Filed in the EU under the centralised procedure [15].
01/07/2014 16:52:42 
Apr 14: Filed in the US in March 14 [14].
18/06/2014 15:00:01 
Apr 14: EU application has not yet been filed [12].
01/05/2014 11:11:50 
Jan 14: EU application has not yet been filed [11].
01/05/2014 11:10:48 
Oct 13: Filings now planned for 2014 [9].
09/12/2013 12:06:53 
Oct 13: EU filing will be via the centralised procedure [10].
09/12/2013 12:01:56 
Dec 12: Orphan designation (EU/3/12/1063) granted in the EU for the treatment of multiple myeloma [7].
14/12/2012 12:20:05 
Sep 12: Granted orphan drug status in the US for MM [6].
18/09/2012 10:28:05 
Aug 11: Filing planned for 2013 [5].
16/08/2011 10:54:08 
Filing planned for 2013 onwards [3].
22/03/2010 13:32:10 
PIII study started Dec 09 [1].
12/12/2009 22:50:32 
Trial or other data
Sep 14: PANORAMA-1 study published in The Lancet Oncology (n=768). Median follow-up was 6·47 months (IQR 1·81—13·47) in the panobinostat group and 5·59 months (2·14—11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33—12·94] vs 8·08 months [7·56—9·23]; hazard ratio [HR] 0·63, 95% CI 0·52—0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34—not estimable) for the panobinostat group and 30·39 months (26·87—not estimable) for the placebo group (HR 0·87, 95% CI 0·69—1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7—65·6] for panobinostat vs 208 [54·6%, 49·4—59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2—32·4] vs 60 [15·7%, 12·2—19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76—14·92) in the panobinostat group and 10·87 months (9·23—11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41—1·64) in the panobinostat group and 2·00 months (1·61—2·79) in the placebo group [16].
22/09/2014 11:09:13
June 14: Results from P3 PANORAMA-1 study presented at 50th ASCO. There was a 37% improvement in progression-free survival when using panobinostat in combination with bortezomib and dexamethasone vs. treatment with same regimen with placebo (HR=0.63, 95% CI 0.52 to 0.76, p<0.0001). In the panobinostat arm, there was a 4-month prolongation of median PFS (12 months versus 8 months in the placebo arm). [13]
04/06/2014 08:37:59
Dec 13: Top-line results from a PIII trial show panobinostat significantly extended PFS in patients with relapsed or relapsed and refractory MM in combination with bortezomib and dexamethasone, compared with the latter two drugs alone. Full results from the study will be presented at an upcoming medical congress and discussed with regulatory authorities worldwide [8].
06/12/2013 16:38:16
The PII ALPHA-MM study is being conducted by Novartis & the Multiple Myeloma Research Consortium (MMRC). It began recruitment of 144 pts with relapsed or refractory MM from the US, Canada & Europe in Aug 07; pts must have received at least two prior therapies & have disease progression on their most recent therapy. Prior therapy must have included bortezomib or lenalidomide. Safety & efficacy data have been reported; the trial did not meet its objective (≥3 responses in 25 pts) in stage 1 required to proceed to stage 2 [4].
05/04/2011 09:59:02
Jun 10: Novartis initiated the PANORAMA II PII trial (NCT01083602) of panobinostat plus bortezomib & dexamethasone in pts with relapsed MM refractory to bortezomib & have received at least two prior lines of therapy. The trial is designed to evaluate the effectiveness of the combination, and will recruit approx 47 US pts [4].
05/04/2011 09:56:12
NCT01023308 a multinational, randomized, double-blind, placebo-controlled, parallel group PIII study to compare progression-free survival of two combination therapies - panobinostat with bortezomib and dexamethasone or placebo with bortezomib and dexamethasone - in 676 patients with previously treated MM whose disease has recurred or progressed. The study started in Dec 09 and is expected to complete Jun 13 [2].
12/12/2009 22:51:27
Evidence Based Evaluations
NICE scope  http://www.nice.org.uk/guidance/indevelopment/gid-tag477/documents 
NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/panobinostat-faridak-for-relapsed-or-refractory-mu/ 
References  
Available only to registered users
 Category
BNF Category: Other antineoplastic drugs (08.01.05)
Pharmacology: First-in-class pan-deacetylase (HDAC) inhibitor  
Epidemiology: Multiple myeloma affects not more than 3.2 in 10,000 people in the EU, equivalent to a total of not more than 162,000 people [7]  
Indication: Multiple myeloma (MM) 
Additional Details: relapsed 
Method(s) of Administration  
Oral 
Company Information
Name: Novartis 
US Name: Novartis 
Further Information
Anticipated commissioning route (England) NHSE 
High cost drug list? Awaiting Update
In NICE timetable: Yes 
When: Jan / 2016 
Note: www.nice.org.uk/guidance/indevelopment/gid-tag477 
Implications Available only to registered users