2015年2月，抗癌新药Farydak（panobinostat，LBH589）最终获得FDA批准联合Velcade（bortezomib，硼替佐米）和地塞米松（dexamethasone）用于既往接受至少2种治疗方案（包括Velcade和一种免疫调节（IMiD）药物）治疗失败的多发性骨髓瘤（myltiple myeloma，MM）患者群体。FDA批准Farydak时附带有一项风险评估及减灾策略（REMS），用于宣传和教育医疗卫生专业人员了解可能与Farydak治疗相关的风险。此次批准，也标志着Faryda成为用于治疗多发性骨髓瘤（MM）的首个组蛋白脱乙酰酶（HDAC）抑制剂，该药的表观遗传学活性，可能有助于恢复多发性骨髓瘤细胞的功能。目前，Farydak在全球其他地区的监管审查正在进行中。
Farydak（panobinostat）是一种新型、广谱组蛋白脱乙酰酶（HDAC）抑制剂，具有一种新的作用机制，通过阻断组蛋白脱乙酰酶（HDAC）发挥作用，该药能够对癌细胞施以严重的应激直至其死亡，而健康细胞则不受影响。
Farydak通过FDA的加速审批程序批准。该药的获批是基于一项全球III期临床研究（PANORAMA-1）中一项预定义亚组分析（n=193）的疗效和安全性数据。数据显示，在既往接受硼替佐米和一种免疫调节（IMiD）药物治疗的多发性骨髓瘤（MM）群体中，联合标准治疗方案（硼替佐米+地塞米松）治疗时，与安慰剂（PFS=5.8个月，n=99）相比，Farydak延长了中位无进展生存期（PFS=10.6个月，n=94）。此外，Farydak治疗组有59%的患者在治疗后肿瘤缩小或消失，而安慰剂组数据为41%。
在2014年初，诺华提交panobinostat监管申请时，鉴于其良好的疗效，FDA表示将采用快速审批通道审核该药，使审查周期由通常的12个月缩短至8个月。然而，去年11月底，FDA肿瘤药物顾问委员会（ODAC）以5:2的投票结果建议拒绝批准panobinostat。该委员会表示，panobinostat针对经治多发性骨髓瘤（MM）患者群体确实有效，但该药的副作用过于严重，要求FDA慎重考虑。这一建议也迫使FDA将原定于12月份的最后期限推迟至今年3月。之后，诺华提交了额外的分析数据，同时修改panobinostat适应症，用于既往接受至少2种标准疗法（包括硼替佐米和免疫调节剂）的多发性骨髓瘤（MM）群体。FDA经过仔细审查后，最终批准panobinostat。需要指出的是，Farydak带有黑框警告，提示该药严重的腹泻和严重及致命的心脏事件、心律失常及心电图（ECG）变化。
多发性骨髓瘤（MM）是一种无法治愈且复发率很高的血液癌症。在过去的11年中，武田的抗癌药Velcade（硼替佐米）作为唯一一种已被证明能够延缓新诊和复发性多发性骨髓瘤（MM）总生存期（OS）的药物，在多发性骨髓瘤（MM）的临床治疗中发挥了重要作用。
FARYDAK capsules are packaged in PVC/PCTFE blister packs.
10mg blister packs containing 6 capsules………………………….……..NDC 0078-0650-06
15mg blister packs containing 6 capsules ………………………….…….NDC 0078-0651-06
20mg blister packs containing 6 capsules ………………………….…….NDC 0078-0652-06

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