欧洲药品管理局（EMA）人用医药产品委员会（CHMP）撤销之前的决定，支持批准PTC Therapeutics杜氏肌营养不良(DMD)治疗药物Translarna (Ataluren)。PTC董事长Stuart W. Peltz评论称，这次推荐对DMD患者来说“是一个重要的里程碑，” 该公司指出，这款药物是用于这种潜在疾病因素的首款治疗药物。
今年1月份，CHMP对有条件批准Translarna发布了一项否定的意见，PTC申请对该决定予以重新审查。EMA指出，在重新审查过程中，CHMP认为“Translarna有一些有效证据，这款药物的作用机制是可信的。”CHMP还表示从DMD的严重性及该疾病患者未满足的医疗需求考虑，PTC药物的收益已超过其风险。
CHMP推荐这款药物用于5岁及以上能走动患者DMD的治疗，这次推荐基于一项由174名患者参与的IIb临床试验。根据PTC的信息，研究结果显示，Translarna治疗患者与安慰剂组患者相比，在48周治疗后，患者在6分钟行走距离(6MWD)检测中平均能多走31.3米。此外，试验证明，基于6MWD 恶化10%所用时间的分析，Translarna用药患者行走能力下降较慢。
Peltz评论称，“如之前所披露，我们预期2014年中期招募完全球3期ACT DMD研究的所有受试者。”这位董事长指出，“这项试验的结果对于这款药物在欧盟及美国获得完全批准是至关重要的。”
正在开发DMD治疗药物的其它公司有Sarepta Therapeutics，该公司上个月宣布今年底会向FDA提交其外显子跳跃候选药物Eteplirsen的上市许可申请。
Translarna
Translarna may be available in the countries listed below.
Ingredient matches for Translarna
Ataluren
Ataluren is reported as an ingredient of Translarna in the following countries:
•Germany
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 eva luated [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, eva luation 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 eva luate 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 eva luate 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 eva luating 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 eva luation 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 eva luable 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 eva luations
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
