title: Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis.
abstract: Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.
authors.affiliation: 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.affiliation: 2 Academic Medical Center , Amsterdam, The Netherlands.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Stroes
authors.affiliation: 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Méthot
authors.affiliation: 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Brisson
authors.affiliation: 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Tremblay
authors.affiliation: 2 Academic Medical Center , Amsterdam, The Netherlands.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Bernelot Moens
authors.affiliation: 3 Chiesi Farmaceutici , Parma, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iotti
authors.affiliation: 3 Chiesi Farmaceutici , Parma, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Rastelletti
authors.affiliation: 3 Chiesi Farmaceutici , Parma, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Ardigo
authors.affiliation: 4 uniQure B.V. , Amsterdam, The Netherlands.
authors.forename: Deyanira
authors.initials: D
authors.lastname: Corzo
authors.affiliation: 4 uniQure B.V. , Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
authors.affiliation: 4 uniQure B.V. , Amsterdam, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Andersen
authors.affiliation: 5 Beaujon Hospital, Denis Diderot University , Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
authors.affiliation: 6 University Hospital of North Midlands , Stoke-on-Trent, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Deakin
authors.affiliation: 7 Erasmus Medical Centre , Rotterdam, The Netherlands .
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Bruno
mesh_terms: D000328:Adult; D000229:Dependovirus / Q000235:genetics; D005060:Europe; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000150:complications* / Q000235:genetics; D008071:Lipoprotein Lipase / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis / Q000209:etiology / Q000628:therapy*; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult
chemical_list: D008071:Lipoprotein Lipase
keywords: chylomicronemia; gene therapy; lipoprotein lipase deficiency; pancreatitis