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美国FDA批准第一个复方组合药对囊性纤维化新治疗

2015-07-05 09:44:20 作者：新特药房来源：互联网浏览次数：77 文字大小：【大】【中】【小】

简介： Orkambi(lumacaftor/ivacaftor)获美国FDA批准上市，为第一个复方药物治疗F508del突变的囊性纤维化（CF）2015年7月2日,美国食品药品监管局(FDA)批准Orkambi的复方组合药为囊性纤维化针对有两个疾病原因特异 ...

关键字：lumacaftor/ivacaftor 商品名orkambi 突破性治疗囊性纤维化优先审评和孤儿药物

Orkambi(lumacaftor/ivacaftor)获美国FDA批准上市，为第一个复方药物治疗F508del突变的囊性纤维化（CF）
2015年7月2日,美国食品药品监管局(FDA)批准Orkambi的复方组合药为囊性纤维化针对有两个疾病原因特异性突变拷贝人们治疗的第一个药物。
现Orkambi(lumacaftor 200mg/依伐卡托 125mg)被批准治疗囊性纤维化(CF)，在12岁和以上患者，有F508del突变，它引起一种扰乱在机体内谁和氯化物转运异常蛋白的产生。这个突变有两个拷贝(分别来自一位双亲)为CF的主要原因。
药品评价和研究中心新药室主任John Jenkins，M.D.说：“FDA鼓励制造商为严重的罕见病像囊性纤维化开发新和创新治疗，” “今天的批准显著地扩展对致囊性纤维化特异性缺陷靶向治疗的可利用性。”
Orkambi接受FDA的突破性治疗指定因为承办单位通过初步临床证据显示药物可能提供超过可得到治疗实质上改善。FDA还在优先审评程序下审评Orkambi。进行一个跨越6个月，或更短的优先审评，替代标准10个月，和被应用于对药物在一个严重的疾病和情况在治疗中可能提供安全性和有效性超过可得到的治疗显著改善。
此外，FDA授予Orkambi孤儿药物指定因为它治疗囊性纤维化，一个罕见病。孤儿药物指定提供财政奖励，像临床试验税收抵免，用户费用减免，和市场独占权的资格，以促进罕见病药物开发。
CF是一个严重的遗传疾病导致在肺，消化道和机体其他部分建立了粘稠粘液的形成，导致严重呼吸和消化问题，以及其他并发症例如感染和糖尿病。
CF，在美国约影响30,000人，是在高加索人中最常见致命性遗传病。F508del突变是CF的最常见原因。有F508del突变的两种拷贝的人，各个来自一位双亲，在美国约占CF人群半数。
在两项双盲，安慰剂对照临床试验在1,108例是12岁和以上有F508del突变有CF参加者研究Orkambi的安全性和疗效。在两项研究中，有CF参加者服用Orkambi，每12小时两药丸，与服用安慰剂比较显示肺功能改善。
尚未确定除F508del突变的CF患者中Orkambi的疗效和安全性。如一例患者的基因型未知时，应使用一个FDA明确的CF突变测试检测在CFTR基因两个等位基因是否存在F508del突变。
Orkambi的最常见副作用包括气短，上呼吸道感染，恶心，腹泻，和皮疹。服用Orkambi妇女还有月经异常增加例如出血增加。
Orkambi是有在波士顿的Vertex制药公司制造。
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453565.htm
ORKAMBI(TM)(lumacaftor/ivacaftor) Tablets
New Drugs Online Report for lumacaftor + ivacaftor
Information
Generic Name: lumacaftor + ivacaftor
Trade Name: Orkambi
Synonym: VX-809
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
Jul 15: The FDA has approved lumacaftor + ivacaftor (Orkambi) for CF in people who have two copies of the F508del mutation, granting breakthrough therapy designation and priority review as studies have demonstrated a substantial improvement over other therapies [20]
03/07/2015 12:20:29
May 15: The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 12 to 1 to recommend a green light for Orkambi (lumacaftor/ivacaftor) for use in CF patients ages 12 and older who carry two copies of the F508del mutation. The FDA is not bound by the Committee´s recommendation but often follows its advice. In any case, a final decision is expected by July 5th [18].
13/05/2015 17:23:43
May 15: Ahead of an advisory committee meeting on 12 May, reviewers question whether lumacaftor contributes any added benefit over that of ivacaftor alone, and if combination studies had included an ivacaftor alone arm whether treatment effects for ivacaftor alone would also have been significant [17].
12/05/2015 12:20:14
Nov 14: An accelerated review has been granted in Europe. In the US, Vertex is seeking a priority review to shorten review time from 12 to 8 months [16].
07/11/2014 16:04:40
Nov 14: Applications submitted in the US and Europe for approval of lumacaftor plus ivacaftor for pts with CF in homozygous F508del pts.[15]
06/11/2014 09:02:09
Aug 14: Lumacaftor plus ivacaftor in CF granted orphan drug status in the EU [14].
01/10/2014 17:22:37
Jan 13: FDA awards Breakthrough Therapy status to lumacaftor in combination with ivacaftor for CF [10].
17/05/2013 12:08:17
Oct 12: Vertex plans to start a pivotal programme in homozygous patients in early 2013 [6].
12/10/2012 14:42:16
Lumacaftor has orphan drug & fast track status in the US [5].
12/10/2012 14:40:53
Trial or other data
May 15: Results from PIII TRAFFIC and TRANSPORT studies published in NEJM. Lumacaftor in combination with ivacaftor improved FEV1 and reduced the rate of pulmonary exacerbations in 1,108 patients with cystic fibrosis who were homozygous for the Phe508del CFTR mutation [19].
20/05/2015 09:55:52
June 14: Results from PIII TRAFFIC and TRANSPORT studies. All four 24-week treatment arms achieved primary endpoint of mean absolute improvement in FEV1 compared to placebo, with a range of 2.6 to 4.0 percentage points (p≤0.0004); mean relative improvement of 4.3% to 6.7% (p≤0.0007). The combination regimens were generally well tolerated. The most common adverse events, regardless of treatment group, were infective pulmonary exacerbation, cough, headache and increased sputum. [13]
08/07/2014 08:33:46
Jun 14: PII (NCT01225211) study published in The Lancet Respiratory Medicine. Cohort 1 (n=64) included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo. Together, cohorts 2 and 3 included 96 phe508del CFTR homozygous and 28 heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9·1 mmol/L (p<0·001) during the combination treatment period in cohort 1. In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group −9·1 mmol/L, p<0·001; lumacaftor 600 mg once per day group −8·9 mmol/L, p<0·001; lumacaftor 400 mg every 12 h group −10·3 mmol/L, p=0·002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5·6 percentage points, p=0·013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4·2 percentage points, p=0·132), but did during the combination period (difference +7·7 percentage points, p=0·003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1 [12].
26/06/2014 10:31:12
Jun 14: Vertex announces positive data from its two pivotal PIII studies in homozygous pts. For pts who typically can expect to suffer a decline in FEV of 2% a year until their expected death sometime in their late 20s or 30s, there were mean improvements of 2.6% and 4.0% from baseline in the four treatment arms (2 arms of 600mg daily and two of 400mg twice daily) vs. placebo. Rates of pulmonary exacerbations decreased by between 28% and 43% vs. placebo. Other key successful endpoints reached in the study included an improvement in weight and the proportion of pts who experienced a mean relative improvement in FEV of at least 5%. A secondary endpoint for patient-reported respiratory symptoms failed to hit a statistically significant rate of improvement [11].
25/06/2014 09:21:00
Apr 13: Vertex announces data from a PII study of VX-661 & ivacaftor that showed statistically significant improvements in lung function among adults with homozygous CF. The study evaluated four dose levels of VX-661 (10, 30, 100 and 150 mg) dosed once daily for 28 days in combination with ivacaftor (150 mg) dosed twice daily. The study also evaluated a separate group of pts who received VX-661 (10, 30, 100 and 150 mg) dosed without ivacaftor for 28 days. Dose-dependent, mean relative improvements in lung function (percent predicted forced expiratory volume in one second; FEV1), both within group and versus placebo, were observed across the combination dosing groups. Pts in the 100 and 150 mg combination dose groups showed statistically significant mean relative improvements in lung function, versus placebo, of 9.0% (p=0.01) and 7.5% (p=0.02), respectively, at Day 28. In contrast, pts who received placebo showed a 0.03% mean relative change in lung function at Day 28 (within-group). The mean relative FEV1 across the combination dose groups returned toward baseline during the post-treatment 28-day washout period. VX-661 was generally well-tolerated, both as monotherapy and in combination with ivacaftor, and most adverse events were mild to moderate in severity and similar between the treatment groups and those who received placebo. Vertex plans to conduct additional studies of VX-661 to further evaluate its potential for late-stage development, pending regulatory discussions [9].
22/04/2013 10:09:28
Mar 13: NCT01807949 (TRANSPORT) and NCT01807923 (TRAFFIC) PIII studies are due to complete Oct 14 [8]
11/03/2013 10:09:39
Feb 13: Vertex has reported the start of a global pivotal PIII development programme for fixed-dose combinations of VX-809 (lumacaftor) and ivacaftor in people aged aged ≥12 with CF who have two copies (homozygous) of the F508del mutation in the CFTR gene. Two 24-week PIII studies, TRAFFIC and TRANSPORT will each enrol ~500 subjects and include two treatment groups evaluating VX-809 (600mg daily or 400mg 12hourly) in combination with ivacaftor (250mg 12hourly) vs placebo. The studies have the same design and will be conducted in North America, Europe and Australia. The primary endpoint is relative improvement in lung function (% predicted FEV1) at 24 weeks. Safety and tolerability will also be assessed. Key secondary endpoints include absolute improvement in FEV1, change in body mass index (BMI) or weight gain, number of pulmonary exacerbations and improvements in patient-reported outcomes as measured by the CF Questionnaire Revised (CFQ-R), among others. The initial 24-week treatment period will be followed by a separate rollover double-blind extension study where all eligible patients, including those who received placebo, will receive one of the combination regimens for up to an additional 96 weeks. A pharmacokinetics and safety study in children with CF ages 6 to 11 who have two copies of the F508del mutation is also planned [7].
28/02/2013 09:49:06
Jun 12: Final results of PII study of lumacaftor in combination with ivacaftor. In heterozygous pts treated with lumacaftor 600mg there was an mean absolute improvement in FEV1 (days 28-56) vs. placebo; this was smaller than the improvement seen in homozygous pts. Additional clinical studies will be conducted in heterozygous pts. [4]
29/06/2012 09:20:35
Jun 12: Final results from PII study of lumacaftor in combination with ivacaftor in 109 pts with CF and one (heterozygous) or two (homozygous) copies of the F508del mutation. Homozygous pts treated with the highest lumacaftor dose (600mg) had a mean absolute improvement in lung function (FEV1) of 8.6% vs. placebo (p<0.001) and a mean absolute improvement of 6.1% within group (p<0.001). Improvement from baseline at day 56 with lumacaftor 600mg compared to placebo was 6.7% (p=0.002) and there was a 3.4% improvement within group (p=0.03). Pts treated with placebo experienced a 3.3% decline (p=0.03). Sweat chloride did not decrease in the placebo group (days 0-28 and 28-56) but those treated with lumacaftor 600mg had a reduction of 6.4mmol/L vs. placebo (p=0.01, days 0-28) and 3.7mmol/L vs. placebo (p=NS, days 28-56). Improvements in FEV1 and reductions in sweat chloride were also seen in homozygous pts treated with lumacaftor 200mg and 400mg but these were smaller than those seen with 600mg. [4]
29/06/2012 09:18:07
May 12: Vertex corrects & provides additional data from recent interim analysis of PII combination study of VX-809 & ivacaftor in pts with CF who have two copies of the F508del mutation. Corrected Data: Responder analysis showed 35% of pts experienced an absolute improvement in FEV1 of at least 5% & 19% had at least a 10 % improvement when treated with VX-809 & ivacaftor. Additional Data: Pts treated with combination therapy experienced an 8.5% mean absolute improvement in lung function vs. placebo (p=0.002) [3].
06/06/2012 12:54:21
May 12: Interim analysis of data after approximately half of the study pts had completed 56 days of treatment in a PII study of VX-809 & ivacaftor showed statistically significant improvements in lung function (FEV1) (p=0.002) across the combined treatment groups relative to baseline vs. placebo ; 37 homozygous F508del pts & 11 pts with one or two copies of the F508del mutation who received placebo. Of those who received VX-809 & ivacaftor (250mg, q12h), approximately 46% (17/37) experienced an absolute improvement from baseline to Day 56 in lung function of 5% or more, & approximately 30% (11/37) experienced an absolute improvement from baseline to Day 56 of 10% or more. None of the pts treated with placebo (0/11) achieved a 5% or more improvement from baseline to Day 56 in lung function. Most adverse events were mild or moderate in severity and comparable between treatment and placebo groups. The study is ongoing and complete data, including statistical analyses for all patient gps, will be available in mid-2012 [1].
08/05/2012 10:39:16
Jul 11: Vertex completes the first part of a PII study evaluating the safety, efficacy, pharmacokinetics & pharmacodynamics of lumacaftor as monotherapy & in combination with ivacaftor in pts with cystic fibrosis homozygous for the F508del-CFTR mutation (NCT01225211). The three-part trial aims to recruit up to 160 pts at sites in the US, Australia, Belgium, Germany & New Zealand. Vertex reports they are on track to start the second part of the trial in Sep 11, which includes dosing of lumacaftor alone for ≥4 weeks followed by ivacaftor + lumacaftor for ≥4 weeks. The trial is expected to evaluate higher doses of lumacaftor than the 200mg dose studied in the first part of the trial and to enrol pts with CF who have either one or two copies of the F508del mutation [2].
08/05/2012 10:33:43
Feb 10: Preliminary data from the PIIa trial (NCT00865904) showed lumacaftor once daily at both the 100mg and 200mg doses for 28 days significantly decreased sweat chloride levels vs. baseline and placebo. In addition it showed a dose-response for change in sweat chloride across all four dose groups (25, 50, 100 and 200mg) [2].
08/05/2012 10:31:33
Mar 09: PIIa trial (VX08-809-101; NCT00865904) of lumacaftor begins enrollment of 89 pts with CF who are homozygous for the F508del-CFTR gene mutation. The trial evaluates the safety, tolerability and pharmacokinetics of the drug, as well as its potential effect on measures of CFTR function. Lumacaftor is given in a capsule formulation, at one of four dose levels, once daily for 28 days. Patients are being enrolled in the US, Canada, Belgium, the Netherlands & Germany, and is expected to complete in Jan 10 [2].
08/05/2012 10:29:24
Vertex also has a "potentiator" compound (ivacaftor), which directly increases the gating ability of the defective ion channel, in clinical trials [2].
08/05/2012 10:27:20
Evidence Based Evaluations
NHSC/NIHR http://www.hsc.nihr.ac.uk/topics/lumacaftor-and-ivacaftor-combination-therapy-for-c/
References
Available only to registered users
Category
BNF Category: Mucolytics (03.07)
Pharmacology: Fixed dose combination. A corrector molecule, one of two new classes of ion channel modulators. The corrector modulators enhance the number of channels of the CFTR protein at the cell surface.
Epidemiology: There are more than 1,800 known mutations in the CFTR gene. In people with the most common mutation, F508del, little to no CFTR protein reaches the cell surface. Globally, 46% of people with CF have two copies of the F508del mutation & one-third have one copy of the F508del mutation [1].
Indication: Cystic fibrosis
Additional Details: in homozygous F508del pts
Method(s) of Administration
Oral
Company Information
Name: Vertex
US Name: Vertex
Further Information
Anticipated commissioning route (England) NHSE
High cost drug list? Yes
Implications Available only to registered users