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Date: 2017-04-20

Type of information: Withdrawal of a market application in the EU

Product name: Glybera®

Compound: alipogene tiparvovec

Therapeutic area: Rare diseases - Genetic diseases

Action mechanism: gene therapy. Glybera® is an adeno-associated viral vector (AAV1) based gene therapy, administered intramuscularly (IM) at multiple-sites in a single session. AAV1 carrying the human variant LPLS447X gene is delivered to skeletal muscle, where it becomes active. The LPL protein is expressed and transported to the capillary endothelium where it binds to chylomicrons and VLDL. Alipogene tiparvovec is intended as a curative measure for patients with LPLD and, as well as enhancing chylomicron metabolism, may prevent episodes of pancreatitis.

Company: uniQure biopharma B.V. [previously Amsterdam Molecular Therapeutics] (The Netherlands)

Disease: lipoprotein lipase deficiency demonstrating hyperchylomicronaemia or having a history of acute pancreatitis.

Latest news: • On April 20, 2017, uniQure announced that it will not pursue the renewal of the Glybera® (alipogene tiparvovec) marketing authorization in Europe when it is scheduled to expire on October 25, 2017. "The decision to not pursue marketing authorization renewal of Glybera® in Europe involved a thoughtful and careful evaluation of patient needs and the clinical use of the therapy, and is not related to any risk-benefit concern," stated Matthew Kapusta, chief executive officer of uniQure. "Glybera's usage has been extremely limited and we do not envision patient demand increasing materially in the years ahead." In October 2012, the European Commission granted a five-year marketing authorization for Glybera® under exceptional circumstances as a treatment for a small subset of patients with familial lipoprotein lipase deficiency (LPLD), an ultra-rare genetic disorder. As part of Glybera's approval, uniQure was required to establish a global registry for the long-term surveillance of patients, conduct a post-approval clinical study, submit for annual regulatory reassessments and implement additional risk management procedures. All of these activities required a significant infrastructure for uniQure that included the Company bearing the full costs of maintaining commercial manufacturing capabilities, managing development and validation of numerous assays and supporting regulatory interactions and inspections. uniQure has initiated discussions with the European Medicines Agency (EMA) to discuss steps to wind down these various activities and review plans for ongoing patient monitoring. As a result of the withdrawal of Glybera, uniQure expects to reduce future expenses related to the product by approximately $2 million annually, beginning in 2018 and net of any payments to Chiesi. These cost savings will be in addition to those previously announced by the Company related to the consolidation of manufacturing into the Company's Lexington facility. uniQure continues to expect its existing cash resources will be sufficient to fund operations into 2019. • On August 4, 2014, uniQure and Chiesi Farmaceutici provided an update on preparations relating to the launch of Glybera® (alipogen tiparvovec), the first gene therapy product approved in the European Union, for the treatment of the orphan disease lipoprotein lipase deficiency (LPLD). Chiesi has exclusive rights to commercialize Glybera in the EU and selected additional territories. Expanding on the original launch strategy, Chiesi and uniQure decided to include in the pricing and reimbursement applications for launch, the six-year follow-up pancreatitis data from the study AMT 011-05, announced June 3, 2014. As a consequence, Chiesi now expects to launch Glybera® in the fourth quarter of 2014/first quarter of 2015. • On February 5, 2013, Xenon, a clinical stage biopharmaceutical company developing novel therapeutics for rare diseases, has announced that it has received a milestone payment from uniQure BV for the European Commission marketing approval of Glybera®. Xenon exclusively licensed to uniQure its rights to the LPLS447X genetic variant that causes a gain of function in the lipoprotein lipase (LPL) gene in humans. Humans with the LPLS447X variant have been shown on average to have lower triglyceride and higher HDL cholesterol levels than those without LPLS447X. Glybera® developed by uniQure is an adeno-associated virus based human gene therapy that contains LPLS447X and in clinical studies Glybera® was effective in reducing blood fat levels and episodes of pancreatitis in patients with LPLD. In addition to the milestone payment Xenon is also entitled to receive from uniQure BV royalty payments on sales of Glybera®, which is expected to start selling in Europe in 2013. The LPLS447X technology in Glybera® was conceived and developed by Xenon’s former CSO Michael Hayden at the Center of Molecular Medicine, University of British Columbia. • On November 2, 2012, uniQure announced it has received approval from the European Commission for the gene therapy Glybera® (alipogene tiparvovec). The approval makes Glybera® the first gene therapy approved by regulatory authorities in the Western world. As part of the approval, patients will receive treatment with Glybera® through dedicated centers of excellence and by specially trained doctors. uniQure will also build a patient registry to further improve the understanding of this devastating, under-researched disease and the effects of Glybera® treatment. Marketing Authorisation covers all 27 European Union member states. uniQure is preparing to apply for regulatory approval in the US, Canada, and other markets. • On, July 20, 2012, the CHMP has recommended the authorisation of Glybera® for marketing in the EU. Glybera® is the first gene therapy medicine to be recommended for authorisation in the European Union. The CHMP recommended the granting of the marketing authorisation under 'exceptional circumstances'. The company that markets Glybera® will be required to provide data from a registry set up to monitor outcomes in patients treated with Glybera®, which the Agency will review as they become available. • On April 20, 2012, the CHMP announced that it maintained its recommendation not to grant a marketing authorisation for the orphan medicine Glybera®.This followed a request of the European Commission in January 2012 to review the benefit risk of Glybera® in a restricted group of patients with severe or multiple pancreatitis attacks. When evaluating Glybera® in patients with severe or multiple pancreatitis attacks, the CHMP concluded that the evidence that Glybera® reduced pancreatitis attacks in the small number of patients assessed (data from only 12 patients were available) was not sufficiently convincing. In addition, the reduced risk of pancreatitis seen in a few of the patients could have been due to other factors (such as changes in lifestyle and diet, and the natural cours e of the disease). In its discussions, the Committee recognised the difficulty of obtaining and assessing data in this very rare disease. However, after careful consideration of all the evidence and circumstances of the disease, the Committee maintained its previous recommendation not to grant a marketing authorisation. • On January 30, 2012, Amsterdam Molecular Therapeutics has announced that the company was informed on Friday January 27, 2012 after business hours that the European Commission’s Standing Committee discussed on Monday January 22, 2012 the implementation decision not to grant marketing authorization for Glybera® as recommended by the CHMP. After the discussion no clear position in favor or against granting a marketing authorization for Glybera® was reached. Instead the Standing Committee considered it necessary to request additional information to the CHMP in the EMA. A formal vote by the Standing Committee will be made on review of the additional information. • On October 21, 2011, Amsterdam Molecular Therapeutics announced that the CHMP has maintained its earlier opinion that Glybera® is not approvable at this time. The decision was made contrary to the positive recommendation of CHMP Rapporteurs, the Scientific Advisory Group (SAG), an expert panel specifically selected to evaluate clinical results and the science of the product, and the CAT. These expert groups after extensive review and analysis of the data advised the CHMP that Glybera® should be approved now under exceptional circumstances. The CHMP Rapporteurs, SAG and the CAT concluded that data from three Glybera® clinical trials demonstrated meaningful evidence of clinical efficacy, without any major safety concerns. • On July 8, 2011, Amsterdam Molecular Therapeutics announced that it has filed a request for re-examination of the marketing authorisation application for Glybera® with the European Medicines Agency. • On June 24, 2011, the CHMP announced that, on the basis of the opinion of the Committee for Advanced Therapies (CAT), it recommended not granting a marketing authorisation for Glybera®, gene-therapy product intended for the treatment of adult patients diagnosed with lipoprotein lipase deficiency demonstrating hyperchylomicronaemia or having a history of acute pancreatitis.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE: 2009-12

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization:

UE authorization: 2012-10-25

Favourable opinion UE: 2012-07-20

Favourable opinion USA:

Orphan status USA:

Orphan status UE: 2004-03-08

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes