Alipogene tiparvovec

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Alipogene tiparvovec
Gene therapy
Target gene LPL
Vector Adeno-associated virus 1
Clinical data
Trade names Glybera
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Routes of
administration 		Intramuscular injection
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Legal status
  • In general: ℞ (Prescription only)
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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. AAV Gene Therapy.jpg
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.

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]

Contents

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. [8] [4]

As of 2016, only one person had received the drug outside of a clinical trial. [8]

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. [12] 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. [3]

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 [13] 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. [14] [15] [16] The cloning capacity of the vector is limited to replacement of the virus's 4.8 kilobase genome.

See also

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<span class="mw-page-title-main">Lipoprotein lipase</span> Mammalian protein found in Homo sapiens

Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule:

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<span class="mw-page-title-main">Lipoprotein lipase deficiency</span> Genetic disorder in fat handling

Lipoprotein lipase deficiency is a genetic disorder in which a person has a defective gene for lipoprotein lipase, which leads to very high triglycerides, which in turn causes stomach pain and deposits of fat under the skin, and which can lead to problems with the pancreas and liver, which in turn can lead to diabetes. The disorder only occurs if a child acquires the defective gene from both parents. It is managed by restricting fat in diet to less than 20 g/day.

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References

  1. ↑ Pollack A (20 July 2012). "European Agency Backs Approval of a Gene Therapy". The New York Times.
  2. ↑ Gallagher J (2 November 2012). "Gene therapy: Glybera approved by European Commission". BBC News. Retrieved 15 December 2012.
  3. 1 2 Richards S (5 November 2012). "Gene Therapy Arrives in Europe". The Scientist. Retrieved 16 November 2012.
  4. 1 2 3 4 5 6 7 8 9 Crowe K. "The million-dollar drug". CBC News. Retrieved 18 November 2018.
  5. 1 2 Warner E (20 April 2017). "Goodbye Glybera! The World's First Gene Therapy will be Withdrawn". Labiotech.eu. Retrieved 23 June 2019.
  6. ↑ Stroes ES, Nierman MC, Meulenberg JJ, Franssen R, Twisk J, Henny CP, et al. (December 2008). "Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients". Arteriosclerosis, Thrombosis, and Vascular Biology. 28 (12): 2303–2304. doi: 10.1161/ATVBAHA.108.175620 . PMID   18802015.
  7. ↑ Scott LJ (February 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. PMID   25559420. S2CID   31609061.
  8. 1 2 3 Regalado A (4 May 2016). "The World's Most Expensive Medicine Is a Bust". MIT Technology Review. Retrieved 31 July 2020.
  9. ↑ Whalen J (2 November 2012). "Gene-Therapy Approval Marks Major Milestone". Wall Street Journal.
  10. ↑ Morrison C (3 March 2015). "$1-million price tag set for Glybera gene therapy". TradeSecrets. 33 (3): 217–218. doi:10.1038/nbt0315-217. PMID   25748892. S2CID   205266596.
  11. ↑ Harris L (5 November 2012). "Gene therapy approved in Europe for first time". Pensacola, FL: BioNews. Archived from the original on 4 January 2014.
  12. ↑ Sagonowsky E (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.
  13. ↑ Valdmanis PN, Lisowski L, Kay MA (November 2012). "rAAV-mediated tumorigenesis: still unresolved after an AAV assault". Molecular Therapy. 20 (11): 2014–2017. doi:10.1038/mt.2012.220. PMC   3498811 . PMID   23131853.
  14. ↑ 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): 1574–1583. doi:10.1038/sj.gt.3300994. PMID   10490767.
  15. ↑ Hernandez YJ, Wang J, Kearns WG, Loiler S, Poirier A, Flotte TR (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): 8549–8558. doi:10.1128/JVI.73.10.8549-8558.1999. PMC   112875 . PMID   10482608.
  16. ↑ Ponnazhagan S, Mukherjee P, Yoder MC, Wang XS, Zhou SZ, Kaplan J, 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): 203–210. doi:10.1016/S0378-1119(96)00576-8. PMID   9185868.
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