Glybera® (alipogene tiparvovec), the first gene therapy approved in the Western world, is used to treat lipoprotein lipase deficiency (LPLD or familial hyperchylomicronemia), a very rare inherited condition that is associated with increased levels of fat in the blood.
One in a million people have damaged copies of a gene which is essential for breaking down fats. Without lipoprotein lipase (LPL), these patients have significantly increased levels of chylomicrons that carry fat throughout the body. Accumulation of these chylomicrons in the pancreas can lead the the often painful and potentially fatal condition pancreatitis.
Gene therapy using an AAV vector. A new gene is inserted into a cell using the AAV protein shell. The new gene often integrates in a precise location and then makes functional protein to treat a disease.
Glybera, developed by Amsterdam-based UniQure and approved in the European Union in November 2012, is administered only once to be effective but will cost around $1.6 million per patient, a new record for pricey modern medicines. Up to this point in time, Alexion Pharmaceuticals’ orphan drug Soliris, which costs about $410,000/patient/year, has been the most expensive orphan drug in the world. The commerical rollout of Glybera is expected in late 2013.
When an important enzyme is missing, one option is to periodically deliver an exogenously produced replacement, which is what millions of people with diabetes do each day. The other, more permanent option, is to induce one’s own cells to produce the enzyme. Glybera is capable of doing this by encasing the correct LPL gene in an adeno-associated virus (AAV) which hones in on muscle cells. When the AAVs reach their target, they deliver the gene and within a few weeks functional protein is being produced.
The Dutch firm uniQure plans on making Glybera available at specialized medical centers throughout the European Union in summer 2013 and is currently seeking regulatory approval in the US, Canada, and other markets. The company is also developing a raft of other gene therapies to treat diseases including blood clotting disorder haemophilia B, metabolic disorder acute intermittent porphyria, central nervous system disorder Parkinson’s and enzyme disorder Sanfilippo B.
Use of gene therapy has been controversial, and not always successful.
Jesse Gelsinger, an 18-year-old student from Arizona with a mild genetic disorder, had volunteered to participate in a gene therapy trial for the rare genetic disease ornithine transcarbamylase deficiency (OTC) at the University of Pennsylvania in Philadelphia in 1999. He died four days later due to a massive immune response. That failure was followed in 2003 by the development of a leukemia-like disease among two French children treated for ‘bubble baby’ syndrome (X-SCID, severe combined immunodeficiency syndrome) and in 2007 by the death of a woman who received a modified gene in an arthritis trial and
Only two other gene therapies (Gendicine and H101) have previously been approved for sale, both in China. Both have so far shown limited success.
In October 2003, China’s State Food and Drug Administration (SFDA) approved Gendicine , the first commercialized gene therapy in the world from Shenzhen-based SiBion, after the medicine showed some promising results in tumor regression among 99 head and neck squamous cell carcinoma patients. Yet after desperate struggles to expand its market, SiBiono was acquired by NASDAQ-listed Chinese pharmaceutical firm Benda for only US$15 million (£7.6 million).
In November 2005, SFDA approved H101, the world’s first commercialized tumor-killing virus, produced by Shanghai Sunway Biotech . A subtype of gene therapy, H101 (commercially sold as Oncorineis a genetically-modified type-five adenovirus which can selectively replicate inside tumour cells with dysfunctional p53 genes, killing them and stopping the cancer’s spread. Oncorine, which hit the market in November 2006, has also reported a minimal market share.