Review of the clinical development of alipogene tiparvovec gene therapy
for lipoprotein lipase deficiency
Alipogene tiparvovec (AAV1-LPLS447X) gene therapy is developed to prevent complications and decrease the clinical morbidity of lipoprotein lipase deficiency (LPLD). LPLD is an autosomal recessive disease associated with severe hypertriglyceridemia (hyperTG), severe chylomicronaemia, and low HDL. Acute pancreatitis, the most frequent serious clinical LPLD complication, is a complex and heterogeneous inflammatory condition having many causes including hyperTG and chylomicronaemia. In many patients, low fat diet and currently available lipid lowering drugs are ineffective to prevent hyperTG or pancreatitis in LPLD. The clinical development program of alipogene tiparvovec includes observational studies as well as phase I/II and II/III clinical trials. Pooled data are collected on safety and efficacy issues, including the incidence of pancreatitis.
Gene Therapy Coming of Age – Prevention of Acute Pancreatitis in
Lipoprotein Lipase Deficiency Through Alipogene Tiparvovec
Lipoprotein lipase deficiency (LPLD) is a rare autosomal recessive disorder caused by loss-of-function mutations in the LPL gene. It causes hyperchylomicronaemia and severe hypertriglyceridaemia leading to various clinical manifestations, including attacks of acute pancreatitis, which can cause severe morbidity and even death. Recurrent attacks of acute pancreatitis also put LPLD patients at risk of developing chronic pancreatitis. The psychological and social burden of this disease is substantial. Progressive loss of pancreatic parenchymal tissue leads to exocrine and endocrine insufficiency, each with its own sequelae and associated morbidity and mortality. Concurrent with other causes of hereditary pancreatitis manifesting at young age, LPLD patients most likely have a substantially increased risk of developing pancreatic cancer. Currently, patients with LPLD are instructed to adhere to a diet with severe fat restriction in order to avoid pancreatitis. Such a diet is extremely difficult to maintain, does not abolish hyperchylomicronaemia and hypertriglyceridaemia and does not prevent pancreatitis in all cases. A novel gene therapy approach with the administration of alipogene tiparvovec, containing the human gain-offunction LPL gene variant LPLS447X, shows promising results with persistent LPL expression and biological activity and reduction in pancreatitis risk.
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
Amsterdam Molecular Therapeutics BV is developing alipogene tiparvovec (Glybera, AMT-011, AAV1-LPLS447X), a Ser447X variant of the human lipoprotein lipase (LPL) gene (LPLSer447X) in an adeno-associated virus vector, as a potential intramuscular gene therapy for the treatment of LPL deficiency. Familial LPL deficiency is a rare, autosomal-recessive disorder of lipoprotein metabolism that is characterized by severe hypertriglyceridemia with episodes of abdominal pain, acute pancreatitis and eruptive cutaneous xanthomatosis. The lack of functional LPL in patients with LPL deficiency causes an accumulation of triglyceride (TG)-rich lipoproteins in the plasma. The LPLSer447X variant is associated with decreased levels of plasma TGs and increased HDL cholesterol concentrations compared with wild-type LPL. Preclinical studies evaluating alipogene tiparvovec in a mouse model of LPL deficiency demonstrated a long-term, dose-dependent correction of the lipid abnormalities. The first clinical trials in patients with LPL deficiency appear promising, with a significant decrease in the levels of plasma TGs observed in the first 3 months following the administration of alipogene tiparvovec, and an increase in local LPL activity and protein levels observed after 6 months. In addition, a decrease in pancreatitis frequency was observed during a 3-year follow-up period. At the time of publication, a phase II/III trial in patients with LPL deficiency, being conducted to further support the submission of an MAA to the EMEA for alipogene tiparvovec, was ongoing. The compound is also under investigation for the treatment of type V hyperlipoproteinemia, Syndrome X and non-alcoholic steatohepatitis.