Abstract 21355: Modifications in Triglyceride-Rich Lipoprotein Metabolism Induced by Alipogene Tiparvovec (AAV1-LPLS447X Gene Therapy) Correlate With Clinical Benefit in Patients with Lipoprotein Lipase Deficiency (LPLD)
Background: Alipogene tiparvovec (Glybera®) is designed to express LPL activity in the muscle of LPL deficient patients. We describe the effect of alipogene tiparvovec on fasting triglycerides (TG), TG-rich lipoproteins metabolism, incidence of pancreatitis and other clinical outcomes.
Methods: In two successive open-label studies involving 14 (011-01) and 5 (011-02) LPLD adults respectively, alipogene tiparvovec was administered in a single series of intramuscular injections. Effect of therapy on fasting triglycerides (TG), TG-rich lipoprotein metabolism and clinical outcomes was assessed over a period of 12-14 weeks, with long term follow-up planned for 15 years. In addition, post-prandial testing was included in the 011-02 study.
Results: In both trials reductions in fasting plasma triglyceride (TG) levels of >40% were achieved in 50% of subjects 3-12 weeks after treatment but this effect was transient and TG returned to baseline after 19 weeks. Independendy of effects on fasting TG, significant and sustained changes in (TG)-rich lipoprotein characteristics and metabolism were observed. In the 011-01 study, the amount of TG in the chylomicron (CM) fraction (Sf>400) was significantly reduced after therapy. Apo B, and TG in the VLDL fraction (sf20-400) tended to increase in parallel, suggesting a sustained shift of lipid-lipoprotein distribution profile, still observable after 52 weeks. In the post-prandial study (011-02) up to 91% reduction of 3H-chylomicron AUC was observed in all participants after therapy, indicating an important and consistent improvement of CM clearance following intake of dietary fat. Meanwhile, pancreatitis incidence declined from 0.20 (during prospective pre-administration) to 0.09 (up till 1.5 years after administration) episodes/year/subject and other potential clinical benefits (including improved diabetes control in affected subjects) were noted.
Conclusion: Alipogene tiparvovec, had only a transient effect on plasma fasting TG but significantly modified the characteristics and kinetics of TG-rich lipoproteins in LPLD patients. These modifications may explain the clinical outcomes, including the observed reduction in the incidence of pancreatitis.
- © 2010 by American Heart Association, Inc.