Alipogene tiparvovec

Alipogene tiparvovec
Clinical data
Trade names Glybera
AHFS/Drugs.com UK Drug Information
Legal status
  • ℞ (Prescription only)
Routes of
administration		 Intramuscular injection
Identifiers
CAS Number 929881-05-0
ATC code C10AX10
ChemSpider none
UNII 20OK4AFR4Y YesY
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 (marketed under the trade name Glybera) is a gene therapy treatment that compensates for lipoprotein lipase deficiency (LPLD), a rare inherited disorder which can cause severe pancreatitis.[1] In July 2012, the European Medicines Agency recommended it for approval, the first recommendation for a gene therapy treatment in either Europe or the United States. The recommendation was endorsed by the European Commission in November 2012[2][3] and commercial rollout is expected in late 2014.[4][5]

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.[6]

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[7] compared to retroviruses, which show random insertion with accompanying risk of cancer. AAV also presents very low immunogenicity, mainly restricted to generating neutralizing antibodies, and little well defined cytotoxic response.[8][9][10] The cloning capacity of the vector is limited to replacement of the virus's 4.8 kilobase genome.

Development

Trials

LPLD is a very rare condition (prevalence worldwide 1–2 per million) and as such its clinical testing has involved unusually small cohort sizes. The first main trial (CT-AMT-010-01) involved just 14 subjects[11] and as of 2015 a total 27 individual individuals have been involved in Phase III testing.[12]

Approval

Being the fist gene therapy treatment approved for human use in either Europe or the United States, in addition to the difficulties in finding large numbers of patients to test on, has left to several reviews of the approval process surrounding Alipogene tiparvovec.[13][14]

Cost

Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[15] revised to $1 million in 2015,[16] making it the most expensive medicine in the world at the time.[17]

See Also

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. ↑ Press Release. UniQure (2012-11-02). Retrieved on 2012-12-15.
  5. ↑ "Chiesi and uniQure delay Glybera launch to add data". Biotechnology. The Pharma Letter. August 4, 2014. Retrieved 2014-08-28.
  6. ↑ "Gene Therapy Arrives in Europe". TheScientist. November 6, 2012.
  7. ↑ 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. PMID 23131853.
  8. ↑ 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.
  9. ↑ 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. PMC 112875. PMID 10482608.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Watanabe, Natsumi; Yano, Kazuo; Tsuyuki, Kenichiro; Okano, Teruo; Yamato, Masayuki (2015). "Re-examination of regulatory opinions in Europe: possible contribution for the approval of the first gene therapy product Glybera". Molecular Therapy — Methods & Clinical Development 2: 14066. doi:10.1038/mtm.2014.66. ISSN 2329-0501.
  14. ↑ Bryant, Laura M.; Christopher, Devin M.; Giles, April R.; Hinderer, Christian; Rodriguez, Jesse L.; Smith, Jenessa B.; Traxler, Elizabeth A.; Tycko, Josh; Wojno, Adam P.; Wilson, James M. (2013). "Lessons Learned from the Clinical Development and Market Authorization of Glybera". Human Gene Therapy Clinical Development 24 (2): 55–64. doi:10.1089/humc.2013.087. ISSN 2324-8637.
  15. ↑ Jeanne Whalen (November 2, 2012). "Gene-Therapy Approval Marks Major Milestone". Wall Street Journal.
  16. ↑ Chris Morrison (March 3, 2015). "$1-million price tag set for Glybera gene therapy". TradeSecrets.
  17. ↑ Gene therapy approved in Europe for first time
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