Glybera(alipogene tiparvovec)成为了欧洲首个被推荐上市的基因治疗药物
2014年3月，荷兰小型生物技术公司uniQure于3月17日公布对已接受Glybera治疗的脂蛋白脂肪酶缺乏症（LPLD）患者回顾性收集资料的初步分析数据。该项分析涵括了13例患者治疗后获长达6年的随访数据，这些患者均满足Glybera在欧盟的标签适应症要求。
Glybera是一种基因疗法，于2012年10月获欧盟批准，用于治疗一种极其罕见的遗传性、代谢性疾病——脂蛋白脂肪酶缺乏症（LPLD），目前，Glybera尚未获欧盟以外国家批准。
一个由独立专家组成的外部仲裁委员会对每例患者的档案进行了审查。该项分析，将患者接受Glybera治疗前6年和治疗后6年的时间段进行了对比，以评估既往有严重或反复胰腺炎病史的每例LPLD患者，分别在这2个时间段里遭受胰腺炎发作的次数和严重程度。审查结果表明，Glybera在新胰腺炎事件风险（包括重症胰腺炎事件的发生）方面提供了长期有益影响。这些结果与Glybera治疗后长达3年的复查结果所表现出的积极趋势相符。
LPLD是一种罕见病，发病率不超过百万分之一或二。LPLD患者无法处理血液中的脂肪颗粒，具有急性及潜在致命性胰腺炎症风险。在临床试验中，LPLD患者接受一次Glybera治疗后，就可以显著降低急性胰腺炎发病率。
关于Glybera：
Glybera是一种基因疗法，利用一种腺相关病毒（AAV）将一个功能性LPL基因拷贝传递给骨骼肌，该药用于治疗一种极其罕见的遗传性、代谢性疾病——脂蛋白脂肪酶缺乏症（LPLD）。
Glybera于2012年10月获欧盟批准，是欧洲获批的首个基因治疗药物，是基因治疗领域的重大推动力，同时标志着基因治疗的一个里程碑。

Glybera, alipogene tiparvovec (AMT-011)
Active Substance: alipogene tiparvovec
Common Name: alipogene tiparvovec
ATC Code: C10 AX10
Marketing Authorisation Holder: uniQure biopharma B.V. 
Active Substance: alipogene tiparvovec
Status: Authorised
Authorisation Date: 2012-10-25
Therapeutic Area: Hyperlipoproteinemia Type I
Pharmacotherapeutic Group: Lipid modifying agents
Therapeutic Indication
Glybera is indicated for adult patients diagnosed with familial lipoprotein lipase deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The diagnosis of LPLD has to be confirmed by genetic testing. The indication is restricted to patients with detectable levels of LPL protein.
About Glybera®
uniQure has developed Glybera as a therapy for patients with the genetic disorder lipoprotein lipase deficiency, an orphan disease for which no treatment existed. The disease is caused by mutations in the LPL gene, resulting in highly decreased or absent activity of LPL enzyme in patients. This enzyme is needed in order to break down large fat-carrying particles that circulate in the blood after each meal. When such particles, called chylomicrons, accumulate in the blood, they may obstruct small blood vessels. Excess chylomicrons result in recurrent and severe acute inflammation of the pancreas, called pancreatitis, the most debilitating complication of LPLD. Glybera has orphan drug designation in the EU and US. LPL Deficiency affects 1-2 persons per million.
Glybera has been tested in three interventional clinical studies conducted in the Netherlands and in Canada, in which a total of 27 LPLD patients participated. In all three clinical trials, Glybera was well tolerated, with no relevant safety issues observed. Data from these clinical trials indicate that a single dose administration of Glybera resulted in a long-term biological activity of the LPL protein. For further information on LPLD visit www.lpldeficiency.com.
Lipoprotein lipase is a key 'first step' enzyme in the metabolism of lipoproteins following fat intake with diet. In clinical studies a transient reduction in triglycerides for up to 12 weeks in individual patients could be observed. Furthermore, Glybera allows expression of the LPL protein in injected muscle which is reflected by the improvement of postprandial chylomicron (CM) metabolism observed in a small subset of patients. Glybera (alipogene tiparvovec) contains the human lipoprotein lipase (LPL) gene variant LPLS447X in a vector. The vector comprises a protein shell derived from adeno-associated virus serotype 1 (AAV1), the promoter, a posttranscriptional regulatory element and AAV2 derived inverted terminal repeats.
Glybera is indicated for adult patients diagnosed with familial lipoprotein lipase deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The diagnosis of LPLD has to be confirmed by genetic testing. The indication is restricted to patients with detectable levels of LPL protein.
The most commonly reported adverse reaction is pain in extremity occurring in approximately one third of patients. Given the small patient population and size of the cohorts, observed adverse reactions do not provide a complete perspective on the nature and frequency of these events.
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New Drugs Online Report for alipogene tiparvovec
Information
Generic Name: alipogene tiparvovec  
Trade Name: Glybera 
Synonym: AMT 011, adeno-associated viral vector expressing lipoprotein lipase 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Approved (Licensed) 
EU: Approved (Licensed) 
US: Phase III Clinical Trials 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Comments
Sep 15: The FDA wants to see data from a second PIII trial before considering approval [15].
22/09/2015 11:23:54 
Aug 14: The company decides to incorporate 6 year follow-up data from the AMT011-05 study, in pricing and reimbursement applications. Subsequently, launch in Europe is expected Q1 15 [13].
22/09/2015 11:22:20 
Jun 14: The company reports that initial launches in the EU are planned in Germany, UK, Netherlands, Sweden and Austria [13]
22/09/2015 11:21:53 
March 14: In July 2013, uniQure and Chiesi Farmaceutici SpA entered into a commercialisation agreement, whereby Chiesi was granted exclusive rights to commercialise alipogene tiparvovec (Glybera®) in Europe. No further updates re: estimated launch. [12]
27/03/2014 11:12:38 
Nov 12: Approved in the EU. Glybera is the first gene therapy licensed for use in the Western World (China has already approved a gene therapy). Launch is planned for 2013 & UniQure plans to file licence applications in the US & Canada [11].
02/11/2012 16:49:40 
Jul 12: CHMP has issued a positive opinion recommending marketing authorization as a treatment for lipoprotein lipase deficiency (LPLD) under exceptional circumstances. As part of the approval, treatment will be offered through dedicated centres with expertise in treating LPLD. uniQure has also committed to building a patient registry. The Company is now preparing to file in the US [10].
24/07/2012 09:06:40 
Apr 12: CHMP decision not to recommend approval maintained [9].
23/04/2012 10:31:49 
Jan 12: EU Standing Committee of the European Parliament discussed the implementation decision not to grant marketing authorisation for alipogene tiparvovec as recommended by the CHMP. No clear position in favour or against granting a marketing authorisation was reached. The Standing Committee considered it necessary to request additional information to the CHMP. A formal vote by the Standing Committee will be made on review of the additional information. It is currently unclear when a final decision will be reached. [7] 
30/01/2012 16:53:16 
Oct 11: CHMP has re-examined the initial opinion, and maintained its recommendation that Glybera should not be granted a marketing authorisation [6]. 
24/10/2011 16:28:47 
June 11: Amsterdam Molecular Therapeutics (AMT) has announced it filed a request for re-examination of the MAA with the EMA for Glybera. The Company expects that the re-examination of the dossier will be completed by the end of 2011. [5]
11/07/2011 08:25:06 
June 11: The CHMP concluded that the three studies in 27 pts presented in support of the MAA had not shown a consistent long-lasting benefit of aliopogene, there was insufficient evidence of a clinically relevant persistent lowering of blood fats or reduction in rate of pancreatitis & too little long-term data available. In view of the uncertainty over alipogene´s benefits & insufficient evidence of safety, the CHMP concluded that the benefits of alipogene had not been shown to outweigh its risks [4]. 
24/06/2011 17:02:46 
Jun 11: EU negative opinion for alipogene tiparvovec to treat adults with lipoprotein lipase deficiency having hyperchylomicronaemia or history of acute pancreatitis [4].
24/06/2011 14:17:29 
Orphan drug status in EU. Around 1000 people in EU affected [3].
02/06/2011 11:45:49 
Aug 10: The EMA requested further data, but not an additional clinical trial, in May 10. The company intend to respond by the end of 2010 and anticipate approval in mid-2011 [2].
01/09/2010 08:47:42 
Jan 10: Filed in EU for lipoprotein lipase deficient patients [1].
13/01/2010 18:53:28 
Trial or other data
Dietary restriction is currently the only management option. Diagnosis has to be confirmed by genetic testing. Patients must adhere to a lipid-restricted diet and need short-term (12 weeks) immunosuppression with ciclosporin and mycophenolate mofetil. The product contains genetically-modified organisms requiring use of biosafety procedures.
29/09/2015 10:42:58
Mar 12: Results of an open label clinical trial (CT-AMT-011-02) announced: 5 LPLD pts were administered alipogene tiparvovec (1012 genome copies/kg). The triglyceride (TG) content of the chylomicron fraction and the chylomicron-triglyceride (TG)/total plasma TG ratio were reduced throughout the postprandial period. The postprandial peak chylomicron level and chylomicron AUC were greatly reduced (by 79% and 93%, 6- and 24 hours after the test meal, respectively). There were no significant changes in plasma fatty acid and glycerol appearance rates. Plasma glucose, insulin and C-peptide also did not change [8].
29/03/2012 11:41:38
Company has conducted two clinical studies for lipoprotein lipase deficiency (LPLD) in Europe and Canada and long term follow-up from these is ongoing, as is a further study in Canada. In these three studies Glybera has been associated with a decrease in the incidence of pancreatitis, the most debilitating complication of LPLD [1].
13/01/2010 18:55:16
Evidence Based Evaluations
EPAR  http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002145/WC500135476.pdf 
NHSC  http://www.haps.bham.ac.uk/publichealth/horizon/outputs/documents/2009/jan-apr/AMT-011.pdf 

References  
Available only to registered users
 Category
BNF Category: Metabolic disorders (09.08)
Pharmacology: Gene transference, Lipoprotein lipase stimulants  
Epidemiology: Debilitating and potentially lethal orphan disease caused by mutations in the LPL gene [1]. Around 1 in 1,000,000 people are affected; equates to 52 people in England and Wales (NHSC)  
Indication: Hyperlipoproteinaemia 
Additional Details: Lipoprotein lipase deficiency 
Method(s) of Administration  
Intramuscular 
Company Information
Name: Chiesi 
US Name: Amsterdam Molecular Therapeutics 
Further Information
Anticipated commissioning route (England) NHSE 
High cost drug list? Yes
Tariff Not routinely commissioned by NHSE - IFR approval [14]
Implications Available only to registered users