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Alipogene Tiparvovec: A Review of Its Use in Adults with Familial Lipoprotein Lipase Deficiency

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Abstract

Alipogene tiparvovec (Glybera®; AMT-011, AAV1-LPLS447X) is an adeno-associated virus serotype 1-based gene therapy for adult patients with familial lipoprotein lipase (LPL) deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. It is administered as a one-time series of intramuscular injections in the legs. LPLD, a rare autosomal recessive disorder, results in hyperchylomicronaemia and severe hypertriglyceridaemia, which in turn, are associated with an increased risk of clinical complications, the most debilitating of which is recurrent severe and potentially life-threatening pancreatitis. In clinical studies (n = 27 patients), one-time administration of alipogene tiparvovec was associated with significant reductions in plasma triglyceride levels during the 12 or 14 week study period post administration. Although triglyceride levels returned to pre-treatment levels within 16–26 weeks after administration, patients had sustained improvements in postprandial chylomicron metabolism, with sustained expression of functional copies of the LPL S477X gene and of biologically active LPL in skeletal muscle. Moreover, after up to 6 years’ follow-up post administration, there were clinically relevant reductions in the incidence of documented pancreatitis and acute abdominal pain events consistent with pancreatitis. Alipogene tiparvovec was generally well tolerated, with most adverse events being localized, transient, mild to moderate injection-site reactions. This article reviews the pharmacology of alipogene tiparvovec and its efficacy and safety in adults with LPLD.

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References

  1. Gaudet D, Methot J, Kastelein J. Gene therapy for lipoprotein lipase deficiency. Curr Opin Lipidol. 2012;23(4):310–20.

    Article  CAS  PubMed  Google Scholar 

  2. Munigoti SP, Rees A. Hypertriglyceridaemia, LPL deficiency and pancreatitis: pathogenesis and therapeutic options. Brit J Diabetes Vasc Dis. 2011;11(3):107–12.

    Article  CAS  Google Scholar 

  3. Bruno M. Gene therapy coming of age: prevention of acute pancreatitis in lipoprotein lipase deficiency through alipogene tiparvovec. Eur Gastroenterol Hepatol Rev. 2010;6(1):48–53.

    Google Scholar 

  4. Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency. Atheroscler Suppl. 2010;11(1):55–60.

    Article  CAS  PubMed  Google Scholar 

  5. Tong G-X, Geng Q-Q, Chai J, et al. Association between pancreatitis and subsequent risk of pancreatic cancer: a systematic review of epidemiological studies. Asian Pac J Cancer Prev. 2014;15(12):5029–34.

    Article  PubMed  Google Scholar 

  6. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818.

    Article  PubMed  Google Scholar 

  7. Wierzbicki AS, Hardman TC, Viljoen A. New lipid-lowering drugs: an update. Int J Clin Pract. 2012;66(3):270–80.

    Article  CAS  PubMed  Google Scholar 

  8. Burnett JR, Hooper AJ. Alipogene tiparvovec, an adeno-associated virus encoding the Ser447X variant of the human lipoprotein lipase gene for the treatment of patients with lipoprotein lipase deficiency. Curr Opin Mol Ther. 2009;11(6):681–91.

    CAS  PubMed  Google Scholar 

  9. Rip J, Nierman M, Sierts J, et al. Gene therapy for lipoprotein lipase deficiency: working toward clinical application. Hum Gene Ther. 2005;16(11):1276–86.

    Article  CAS  PubMed  Google Scholar 

  10. European Medicines Agency. Glybera (alipogene tiparvovec): summary of product characteristics. 2013. http://www.ema.europa.eu. Accessed 9 Oct 2014.

  11. Yla-Herttuala S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European Union. Mol Ther. 2012;20(10):1831–2.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Haddley K. Alipogene tiparvovec for the treatment of lipoprotein lipase deficiency. Drugs Today. 2013;49(3):161–70.

    CAS  PubMed  Google Scholar 

  13. Rip J, Sierts JA, Vaessen SF, et al. Adeno-associated virus LPLS447X gene therapy in LDL receptor knockout mice. Atherosclerosis. 2007;194:55–61.

    Article  PubMed  Google Scholar 

  14. Rip J, van Dijk KW, Sierts JA, et al. AAV1-LPLS447X gene therapy reduces hypertriglyceridemia in apoE2 knock in mice. Biochim Biophys Acta. 2006:1163–8.

  15. Ross C, Twisk J, Bakker A, et al. Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. Hum Gene Ther. 2006;17:487–99.

    Article  CAS  PubMed  Google Scholar 

  16. Ross C, Twisk J, Meulenberg J, et al. Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPLS447X beneficial mutation. Hum Gene Ther. 2004;15:906–19.

    Article  CAS  PubMed  Google Scholar 

  17. Ross CJ, Guoqing L, Kuivenhoven JA, et al. Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation. Arterioscler Thromb Vasc Biol. 2005;25:2143–50.

    Article  CAS  PubMed  Google Scholar 

  18. Gaudet D, Methot J, Dery S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther. 2013;20(4):361–9.

    Article  CAS  PubMed  Google Scholar 

  19. Stroes ES, Nierman MC, Meulenberg JJ, et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol. 2008;28(12):2303–4.

    Article  CAS  PubMed  Google Scholar 

  20. Kaeppel C, Beattie SG, Fronza R, et al. A largely random AAV integration profile after LPLD gene therapy. Nat Med. 2013;19(7):889–91.

    Article  CAS  PubMed  Google Scholar 

  21. Salmon F, Grosios K, Petry H. Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera). Expert Rev Clin Pharmacol. 2014;7(1):53–5.

    Article  CAS  PubMed  Google Scholar 

  22. Mingozzi F, Meulenberg JJ, Hui DJ, et al. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood. 2009;114(10):2077–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Ferreira V, Petry H, Salmon F. Immune responses to AAV-vectors, the Glybera example from bench to bedside. Front Immunol. 2014;5:82.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Ferreira V, Twisk J, Kwikkers K, et al. Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPLS447X) in a phase II clinical trial of lipoprotein deficiency gene therapy. Hum Gene Ther. 2014;25(3):180–8.

    Article  CAS  PubMed  Google Scholar 

  25. European Medicines Agency. European public assessment report: Glybera. 2012. http://www.ema.europa.eu. Accessed 20 Oct 2014.

  26. Basner-Tschakarjan E, Mingozzi F. Cell-mediated immunity to AAV vectors, evolving concepts and potential solutions. Front Immunol. 2014;5:350.

    PubMed Central  PubMed  Google Scholar 

  27. Mingozzi F, Maus M, Hui D, et al. CD8(+) responses to adeno-associated virus capsid in humans. Nat Med. 2007;13(4):419–22.

    Article  CAS  PubMed  Google Scholar 

  28. Mueller C, Chulay JD, Trapnell BC, et al. Human Treg responses allow sustained recombinant adeno-associated virus-mediated gene expression J Clin Invest. 2013;123(12):5310–8.

    CAS  Google Scholar 

  29. Carpentier AC, Frisch F, Labbe SM, et al. Effect of alipogene tiparvovec (AAV1-LPLS447X) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab. 2012;97(5):1635–44.

    Article  CAS  PubMed  Google Scholar 

  30. Gaudet D, Stroes E, Bruno M, et al. Gene therapy with alipogene tiparvovec (Glybera®) for the prevention of LPLD induced pancreatitis: follow-up data suggests long-term clinical benefit [abstract]. Atherosclerosis. 2014;235(2):e13.

    Article  Google Scholar 

  31. Twisk J, Frisch F, Ferreira V, et al. Long-term transgene expression and biological effect following IM administration of AAV1-LPLS447X to LPL deficient patients [abstract no. 55]. Mol Ther. 2012;20(Suppl 1):S23.

    Google Scholar 

  32. De Wal J, Dery S, Gagne C, et al. Alipogene tiparvovec (AAV1-LPLS447X gene therapy) is long-term safe and efficacious in patients with lipoprotein lipase deficiency [abstract no. O-057]. J Inherit Metab Dis. 2011;34(Suppl 3):S233.

    Google Scholar 

  33. uniQure. uniQure’s Glybera first gene therapy approved by European Commission [media release]. 2012. http://www.uniqure.com. Accessed 9 Oct 2014.

  34. Aalbers CJ, Tak PP, Vervoordeldonk MJ. Advancements in adeno-associated viral gene therapy approaches: exploring a new horizon. F1000 Med Rep. 2011;3(1).

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Disclosure

The preparation of this review was not supported by any external funding. Lesley Scott is a salaried employee of Adis/Springer. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.

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    Lesley J. Scott

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Correspondence to Lesley J. Scott.

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The manuscript was reviewed by: P. F. Boudes, PFB Consulting, Penington, NJ, USA; H. Büning, Center for Molecular Medicine, Cologne, University of Cologne, Cologne, Germany and Department I of Internal Medicine, German Centre for Infection Research Partner Site Bonn-Cologne, Cologne, Germany; Z. Reiner, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia; A. S. Wierzbicki, Department of Metabolic Medicine/Chemical Pathology, Guy’s and St. Thomas’ Hospitals, London, UK.

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Scott, L.J. Alipogene Tiparvovec: A Review of Its Use in Adults with Familial Lipoprotein Lipase Deficiency. Drugs 75, 175–182 (2015). https://doi.org/10.1007/s40265-014-0339-9

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