Alipogene tiparvovec

Alipogene tiparvovec, sold under the brand name Glybera, is a gene therapy treatment designed to reverse lipoprotein lipase deficiency (LPLD), a rare recessive disorder, due to mutations in LPL, which can cause severe pancreatitis.[1] It was recommended for approval by the European Medicines Agency in July 2012 and approved by the European Commission in November of the same year. It was the first marketing authorisation for a gene therapy treatment in either Europe or the United States.[2][3]

Alipogene tiparvovec
Gene therapy
Target geneLPL
VectorAdeno-associated virus 1
Clinical data
Trade namesGlybera
AHFS/Drugs.comUK Drug Information
License data
Routes of
administration		Intramuscular injection
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Gene therapy using an AAV vector. A new gene is inserted into a cell using the AAV protein shell. Once inside the nucleus, the new gene makes functional protein to treat a disease.

The drug is administered via a series of injections into the leg muscles – as many as 60, all in one session.[4] It is a one-time treatment intended to last at least ten years.

Glybera gained infamy as the "million-dollar drug" and proved commercially unsuccessful for a number of reasons.[4][5] Its cost to patients and payers, together with the rarity of LPLD, high maintenance costs to its manufacturer uniQure, and failure to achieve approval in the US, led to uniQure withdrawing the drug after two years on the EU market. As of 2018, only 31 people worldwide have ever been administered Glybera, and uniQure has no plans to sell the drug in the US or Canada.[4][5]

History

Glybera was developed over a period of decades by researchers at the University of British Columbia (UBC).[4] In 1986, Michael R. Hayden and John Kastelein began research at UBC, confirming the hypothesis that LPLD was caused by a gene mutation. Years later, in 2002, Hayden and Colin Ross successfully performed gene therapy on test mice to treat LPLD; their findings were featured on the September 2004 cover of Human Gene Therapy. Ross and Hayden next succeeded in treating cats in the same manner, with the help of Boyce Jones.[4]

Trials and approval

Meanwhile, Kastelein—who had, by 1998, become an international expert in lipid disorders—co-founded Amsterdam Molecular Therapeutics (AMT), which acquired rights to Hayden's research with the aim of releasing the drug in Europe.

Since LPLD is a rare condition (prevalence worldwide 1–2 per million), related clinical tests and trials have involved unusually small cohort sizes. The first main trial (CT-AMT-011-01) involved just 14 subjects,[6] and by 2015, a total of 27 individuals had been involved in phase III testing.[7] The second phase of testing focused on subjects living along the Saguenay River in Quebec, where LPLD affects people at the highest rate in the world (up to 200 per million) due to the founder effect.

Price

After over two years of testing, Glybera was approved in the European Union in 2012.[8] However, after spending millions of euros on Glybera's approval, AMT went bankrupt and its assets were acquired by uniQure.[4]

Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012[9]—revised to $1 million in 2015[10]—making it the most expensive medicine in the world at the time.[11] However, replacement therapy, a similar treatment, can cost over $300,000 per year, for life.[4]

In 2015, uniQure dropped its plans for approval in the US and exclusively licensed rights to sell the drug in Europe to Chiesi Farmaceutici for €31 million.[12][4]

As of 2016, only one person had received the drug outside of a clinical trial.[12]

In April 2017, Chiesi quit selling Glybera and uniQure announced that it would not pursue the renewal of the marketing authorisation in the European Union when it was scheduled to expire that October, due to lack of demand.[13] Afterwards, the three remaining doses in Chiesi's inventory were administered to three patients for €1 each.[4]

Mechanism

The adeno-associated virus serotype 1 (AAV1) viral vector delivers an intact copy of the human lipoprotein lipase (LPL) gene to muscle cells. The LPL gene is not inserted into the cell's chromosomes but remains as free floating DNA in the nucleus. The injection is followed by immunosuppressive therapy to prevent immune reactions to the virus.[14]

Data from the clinical trials indicates that fat concentrations in blood were reduced between 3 and 12 weeks after injection, in nearly all patients. The advantages of AAV include apparent lack of pathogenicity, delivery to non-dividing cells, and much smaller risk of insertion[15] compared to retroviruses, which show random insertion with accompanying risk of cancer. AAV also presents very low immunogenicity, mainly restricted to generating neutralising antibodies, and little well defined cytotoxic response.[16][17][18] The cloning capacity of the vector is limited to replacement of the virus's 4.8 kilobase genome.

See also
  • List of gene therapies
  • Health care costs

References
  1. European Agency Backs Approval of a Gene Therapy July 20, 2012
  2. Gallagher, James. (2012-11-02) BBC News – Gene therapy: Glybera approved by European Commission. Bbc.co.uk. Retrieved on 2012-12-15.
  3. Richards, Sabrina. "Gene Therapy Arrives in Europe". The Scientist. Retrieved 16 November 2012.
  4. Crowe, Kelly. "The million-dollar drug". CBC News. Retrieved 18 November 2018.
  5. Warner, Evelyn. "Goodbye Glybera! The World's First Gene Therapy will be Withdrawn". Labiotech.eu. Retrieved 23 June 2019.
  6. Stroes, E. S.; Nierman, M. C.; Meulenberg, J. J.; Franssen, R.; Twisk, J.; Henny, C. P.; Maas, M. M.; Zwinderman, A. H.; Ross, C.; Aronica, E.; High, K. A.; Levi, M. M.; Hayden, M. R.; Kastelein, J. J.; Kuivenhoven, J. A. (2008). "Intramuscular Administration of AAV1-Lipoprotein LipaseS447X Lowers Triglycerides in Lipoprotein Lipase-Deficient Patients". Arteriosclerosis, Thrombosis, and Vascular Biology. 28 (12): 2303–2304. doi:10.1161/ATVBAHA.108.175620. ISSN 1079-5642. PMID 18802015.
  7. Scott, Lesley J. (2015). "Alipogene Tiparvovec: A Review of Its Use in Adults with Familial Lipoprotein Lipase Deficiency". Drugs. 75 (2): 175–182. doi:10.1007/s40265-014-0339-9. ISSN 0012-6667. PMID 25559420. S2CID 31609061.
  8. "The World's Most Expensive Medicine Is a Bust". MIT Technology Review. Retrieved 31 July 2020.
  9. Jeanne Whalen (2 November 2012). "Gene-Therapy Approval Marks Major Milestone". Wall Street Journal.
  10. Chris Morrison (3 March 2015). "$1-million price tag set for Glybera gene therapy". TradeSecrets.
  11. Gene therapy approved in Europe for first time
  12. Regalado, Antonio (4 May 2016). "The World's Most Expensive Medicine Is a Bust". MIT Technology Review.
  13. Sagonowsky, Eric (20 April 2017). "With its launch fizzling out, uniQure gives up on $1M+ gene therapy Glybera". FiercePharma. Archived from the original on 1 September 2017. Retrieved 7 August 2017.
  14. "Gene Therapy Arrives in Europe". TheScientist. 6 November 2012.
  15. Valdmanis PN, Lisowski L, Kay MA (November 2012). "rAAV-mediated tumorigenesis: still unresolved after an AAV assault". Molecular Therapy. 20 (11): 2014–17. doi:10.1038/mt.2012.220. PMC 3498811. PMID 23131853.
  16. Chirmule N, Propert K, Magosin S, Qian Y, Qian R, Wilson J (September 1999). "Immune responses to adenovirus and adeno-associated virus in humans". Gene Therapy. 6 (9): 1574–83. doi:10.1038/sj.gt.3300994. PMID 10490767.
  17. Hernandez YJ, Wang J, Kearns WG, Loiler S, Poirier A, Flotte TR (1 October 1999). "Latent Adeno-Associated Virus Infection Elicits Humoral but Not Cell-Mediated Immune Responses in a Nonhuman Primate Model". Journal of Virology. 73 (10): 8549–58. doi:10.1128/JVI.73.10.8549-8558.1999. PMC 112875. PMID 10482608.
  18. Ponnazhagan S, Mukherjee P, Yoder MC, et al. (April 1997). "Adeno-associated virus 2-mediated gene transfer in vivo: organ-tropism and expression of transduced sequences in mice". Gene. 190 (1): 203–10. doi:10.1016/S0378-1119(96)00576-8. PMID 9185868.
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