PTC制药8月4日宣布，药物Translarna（ataluren）获欧盟委员会（EC）有条件批准（conditional approval），用于5岁及以上无义突变型杜氏肌营养不良（nmDMD）非卧床（ambulatory，能走动的）患者的治疗。此次批准，适用于欧盟28个成员国以及欧洲经济区成员国，包括冰岛列支敦士登和挪威。作为有条件上市的一部分，PTC有义务完成在nmDMD中开展的验证性III期ACT DMD研究，并提交来自该研究的额外疗效和安全性数据。
今年1月，欧洲药品管理局（EMA）人用医药产品委员会（CHMP）曾给予Translarna消极意见，随后PTC公司提交额外分析数据，要求重新审查，之后CHMP于今年5月建议有条件批准Translarna。此前，FDA已授予Translarna孤儿药地位。
Translarna的获批，是基于一项IIb期研究的数据及后续分析数据。该项研究是一项48周、安慰剂对照、双盲试验，在174例无义突变型杜氏肌营养不良（nmDMD）患者中开展。数据表明，与安慰剂治疗组相比，Translarna（40mg/kg/天）治疗组6分钟步行距离（6MWD）平均增加31.3米，下床活动下滑速率也较慢。安全性数据表明，Translarna一般耐受性良好，严重不良事件少见。
目前，PTC公司正在开展III期ACT DMD临床研究。Translarna是一种蛋白质修复药物，开发用于由无义突变所致遗传性疾病的患者群体，旨在使含有无义突变的基因，产生功能性蛋白。若基因中存在无义突变，会导致蛋白质合成提前终止，产生无功能的蛋白。目前，Translarna正开发用于囊性纤维化（CF）和杜氏肌营养不良（DMD）的治疗。
包装规格[本品德国上市包装]
125mg
250mg
1000mg

Translarna, ataluren (formerly PTC124）
Translarna est indiqué pour le traitement de la dystrophie musculaire de Duchenne, résultant d'une mutation non-sens dans le gène de la dystrophine, chez les patients ambulatoires âgés de 5 ans ou plus (voir rubrique Propriétés pharmacodynamiques). L'efficacité n'a pas été démontrée chez les patients non ambulatoires.
La présence d'une mutation non-sens dans le gène de la dystrophine doit être déterminée par un test génétique (voir rubrique Mises en garde et précautions d'emploi).
Posologie TRANSLARNA 250 mg Granulé pour suspension buvable Sachets Boîte de 30
L'instauration d'un traitement avec le Translarna est réservée aux médecins spécialistes expérimentés dans la prise en charge de la dystrophie musculaire de Duchenne/Becker.
Posologie
L'ataluren doit être administré par voie orale en 3 prises quotidiennes.
La première dose doit être prise le matin, la seconde à midi et la troisième le soir. Les intervalles posologiques recommandés sont de 6 heures entre la dose du matin et celle du midi, de 6 heures entre la dose du midi et celle du soir, et de 12 heures entre la dose du soir et la première dose le lendemain.
La dose recommandée est de 10 mg/kg le matin, 10 mg/kg à midi, et 20 mg/kg le soir (pour une dose quotidienne totale de 40 mg/kg).
Translarna est disponible en sachets de 125 mg, 250 mg ou 1 000 mg. Le tableau ci-dessous donne des informations sur le/les dosage(s) de sachet à utiliser pour préparer la dose recommandée par tranche de poids.
New Drugs Online Report for ataluren
Information
Generic Name: ataluren  
Trade Name: Translarna 
Synonym: PTC124 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Approved (Licensed) 
EU: Launched 
US: Pre-registration (Filed) 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Comments
Mar 15: Additional launches are expected in other countries throughout 2015. [27]
30/03/2015 12:34:51 
Dec 14: Company commence rolling submission of a New Drug Application (NDA) to the US FDA for Translarna to treat nonsense mutation Duchenne muscular dystrophy (nmDMD). The NDA will be finalised once the ACT DMD confirmatory PIII study completes [26]. 
24/12/2014 08:42:10 
Dec 14: Launched in Germany, first launch in an EU country [25].
05/12/2014 10:24:34 
Aug 14: EU conditional approval of ataluren for DMD caused by a nonsense mutation. The conditional approval allows PTC to market ataluren in all 28 EU member countries for one year, at which point results from an ongoing PIII trial will be evaluated [24].
05/08/2014 09:10:11 
May 14: Following a re-examination procedure, the CHMP adopted a positive opinion, recommending the granting of a conditional marketing authorisation for Translarna intended for the treatment of DMD [23].
27/05/2014 10:53:58 
March 14: CHMP plans to await data from an ongoing confirmatory phase III trial, which is expected to complete patient enrolment in mid-2014 and top-line data are subsequently expected in mid-2015. PTC Therapeutics intends to request a re-examination of the negative opinion, with a final outcome expected in the second quarter of 2014 once the study is more fully enrolled. [22]
27/03/2014 14:19:24 
Feb 14: Company has requested a re-examination of CHMP´s negative opinion [20].
25/02/2014 11:09:21 
Jan 14: Enrollment in the PIII study, now required for registration, will be complete mid-2014 with results available mid-2015 [19]. 
02/02/2014 20:45:36 
Jan 14: CHMP negative opinion recommending against EU approval of ataluren for nmDMD. The CHMP noted that the main study failed to show pts taking ataluren could walk in six minutes a greater distance than pts taking placebo. Other measures of effectiveness, including those directly linked to pts’ daily activities, provided only limited supportive evidence. Finally, insufficient data had been provided to determine how the medicine works in the body and how its effects change with the dose [18].
24/01/2014 15:41:35 
Mar 13: Being considered for conditional approval in the EU [16].
09/03/2013 19:09:44 
Dec 12: EMA accepts filing for ataluren to treat pts with nonsense mutation Duchenne muscular dystrophy (nmDMD) [15].
10/12/2012 09:32:11 
Jul 12: Granted orphan drug status in the EU for treatment of Becker muscular dystrophy (EU/3/12/1010) [14].
27/07/2012 12:05:58 
PIIb (n=174) data will be the basis of ‘interactions’ with the US FDA & national regulatory authorities in Europe in 4Q 2010 [10].
20/10/2010 11:41:52 
April 10: Filing on hold due to failure of PIIb study to meet primary endpoint (9)
12/04/2010 10:44:03 
Dec 09: Company hope to file in US mid-2010. Could be approved in 2011 [5].
23/12/2009 09:07:42 
In June 2009, PTC Therapeutics received a four-year grant from the FDA’s Office of Orphan Products Development (worth $US1.6 million), to support the pivotal trial of ataluren. The FDA has also granted Subpart E designation for expedited development, evaluation and marketing [3].
13/09/2009 18:28:08 
PII/III international study started Apr 08 [3].
13/09/2009 18:27:42 
Fast track in US with orphan status. Orphan status in EU (1). PII trials in duchenne muscular dystrophy (2). 
Trial or other data
Mar 14: NCT02090959 A PIII extension study in 220 patients with nonsense mutation dystrophinopathy who participated in a previous PIII study of ataluren to evaluate long term safety.Patients will receive ataluren for 96 weeks. The study starts Mar 14 and is due to complete Jun 17 [21].
21/03/2014 08:53:30
Apr 13: NCT01826487 is a PIII efficacy and safety study of ataluren in 220 patients with nonsense mutation dystrophinopathy. Subjects will be randomized in a 1:1 ratio to ataluren 10-, 10-, 20-mg/kg dose level or placebo. The primary outcome is change in the distance walked during a 6-minute walk test from baseline to 48 weeks. The study started Mar 13 and is due to complete Jun 15. An open-label extension study is planned for patients who successfully complete the double-blind study in countries where ataluren is not commercially available [17]
09/04/2013 09:09:06
Mar 13: PTC plans to start a PIII confirmatory study in H1 2013 involving 220 nmDMD patients, with the 6-minute walking distance test as the primary outcome [16]. 
09/03/2013 19:09:59
Jun 12: NCT01247207 (US based, n=110) and NCT01557400 (multicentre including Europe, n=96) are two open-label PIII extension studies of patients with nonsense mutation dystrophinopathy who received ataluren in a prior PTC-sponsored study. The primary objective is to evaluate the long-term safety of ataluren, as determined by adverse events and laboratory abnormalities. The US study is due to complete Oct 12, and the other, which started May 12,is due to complete in May 13 [13]
07/06/2012 14:59:56
Sep 11: PTC and Genzyme have restructured their collaboration. Under the original agreement, commercial rights were held by PTC for the US and Canada and by Genzyme in all other countries. PTC has now regained worldwide rights to ataluren and Genzyme retains an option to commercialize ataluren in indications other than nonsense mutation Duchenne/Becker muscular dystrophy outside the US and Canada [11]. 
07/06/2012 11:07:55
Nov 10: A PIII, open-label study (PTC124-GD-016 DMD; NCT01247207) to determine the long-term safety of ataluren in previously-treated pts with nonsense mutation Duchenne/Becker muscular dystrophy began recruiting approx 110 boys at sites in the US. The study is due to complete collection for the primary outcome measures of safety & tolerability in Jul 12 [12].
07/06/2012 11:05:18
Oct 10: data for the PIIb trial (n=174) (see below) for ataluren in the treatment of pts with nonsense mutation dystrophinopathy (nmDBMD; comprising Duchenne and Becker muscular dystrophy), presented at the International Congress of the World Muscle Society. There was a mean difference of 29.7 metres in the change from baseline for the lower dose of ataluren vs. placebo (p=0.058). There was no difference between the high dose & placebo; the authors state that this is consistent with subsequent analysis of non-clinical data, which suggest a bell-shaped dose response curve as a class effect for drugs that promote nonsense suppression [10].
20/10/2010 11:40:02
Mar 10: ataluren failed a 48 week PIIb trial. The primary endpoint -a change in 6-minute walk distance - did not reach statistical significance according to preliminary results. The randomized, double-blind, placebo-controlled trial enrolled 174 participants at 37 sites in North America, Europe, Australia, and Israel. Participants received either a low dose of ataluren (10mg/kg in the morning, 10mg/kg at midday and 20mg/kg in the evening), a high dose of ataluren (20mg/kg in the morning, 20mg/kg at midday and 40mg/kg in the evening), or placebo [8]. 
03/03/2010 22:16:59
Jan 10: NCT01009294, a I year PIIa study started Nov 09, is evaluating the safety, pharmacodynamic activity, and pharmacokinetics of ataluren, while assessing the use of several outcome measures of physical, pulmonary, and cardiac function in patients with advanced disease. Approximately 30 boys and young men with nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD) who have permanently lost the ability to walk independently are being enrolled in the trial at five sites in the US and at one site in the UK. Enrollment will be stratified to ensure evaluation of ~15 participants who are receiving chronic corticosteroid therapy and of ~15 participants who are not. The study is being funded in part by a $1 million grant from the Muscular Dystrophy Association, and will involve MDA´s five-center DMD Clinical Research Network and a site in the UK [6,7].
25/01/2010 11:12:47
PTC Therapeutics is collaborating with Genzyme in the development and commercialization of ataluren. PTC Therapeutics will market ataluren in the US and Canada, while Genzyme will commercialize the product in other regions of the world [4].
13/09/2009 18:45:01
An international pivotal phase II/III trial (NCT00592553) in 174 patients (in the US, Canada, Australia, EU and Israel) with Duchenne/Becker muscular dystrophy due to a nonsense mutation started April 2008. Patients will receive placebo, or one of two doses of ataluren, three times per day for 48 weeks. This will be followed by an open-label extension study. The primary outcome measure is the total distance walked during a six-minute walk test. Results are expected in 2010 [3].
13/09/2009 18:27:54
Shown to restore production of relevant functional proteins in genertic disorders (1). Interim data from the first 2 cohorts of the 3-cohort trial demonstrated that 28 days of PTC 124 (3 dose levels) was associated with increases in muscle dystrophin expression and reductions in serum creatinine kinase values in at least 50% of evaluable patients. 67% of pts receiving the lower dose level and 50% of pts receiving the medium dose level showed an increase in the expression of dystrophin post-therapy.(2)
Evidence Based Evaluations
EPAR  http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002720/WC500171816.pdf 
NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/ataluren-for-nonsense-mutation-dystrophinopathy/ 
References  
Available only to registered users
 Category
BNF Category: Drugs used in neuromuscular disorders (10.02)
Pharmacology: Dystrophin stimulant  
Epidemiology: The incidence of DMD is approximately 1 in 3,600-6,000 male births per year. In the UK, there are approximately 100 boys diagnosed with DMD each year & at any one time there are about 1,500 known to have the disease. Approximately 10-15% of patients have a nonsense mutation, which equates to between 150 and 195 pts in the UK [NHSC review].  
Indication: Duchenne muscular dystrophy 
Method(s) of Administration  
Oral 
Company Information
Name: PTC Therapeutics 
US Name: PTC Therapeutics 
Further Information
Anticipated commissioning route (England) NHSE 
High cost drug list? Yes
Tariff Not routinely commissioned by NHSE - IFR approval [28]
Implications Available only to registered users