Abstract 2093: AAV1-LPLS447X Gene Therapy With Alipogene Tiparvovec Prevents Pancreatitis in Lipoprotein Lipase Deficiency
Introduction: Lipoprotein lipase deficiency (LPLD) is the most common cause of familial chylomicronemia and severe hypertriglyceridemia. Acute pancreatitis is a common, life threatening complication. No effective therapy is available. The AMT-010 and AMT-011– 01 studies assessed safety and efficacy of alipogene tiparvovec, containing LPLS447X, a gain of function mutation in a non-replicating, non-integrating adeno associated virus, in patients with LPLD. These interventional trials were preceded by observation ‘Prep’ studies to assess baseline parameters such as TG levels and pancreatitis frequency.
Methods: Prep-01 enrolled 18 and Prep-02 22 adult patients. In AMT-010 8 subjects (4 patients with 1×1011 and 4 with 3×1011 gc/kg IM) and in AMT-011 14 subjects (6 3×1011 gc/kg and 8 1×1012 gc/kg IM) received AAV1-LPLS447X, and in the latter study all but 2 patients also received 12 weeks of immunosuppression. Safety and efficacy were evaluated over an initial period of 12 weeks with long term follow-up for ≥5 years planned for both studies.
Results: No serious adverse events were recorded in the first 12 weeks following therapy. A reduction in fasting TG levels (p<0.01) was observed in the 3–12 weeks period compared to Prep values, with an apparent dose-range effect. During follow-up of 25.3 months on average, no treatment-related serious adverse event has been recorded. Whereas fasting TG levels returned towards pretreatment values after a quarter, assays from muscle biopsies taken half a year post injection indicated continued biologic activity. Also, pancreatitis episodes were reduced during 1–3.5 years of clinical follow up from 0.33 episodes/year/patient during the observation period to 0.06 episodes/year after AAV1-LPLS447X administration (p<0.05 post vs. pre-injection), without a dose range effect being obvious and without an apparent effect of immunosuppression.
Conclusion: Gene therapy with alipogene tiparvovec in LPLD is safe, also during follow up. A single dose is associated with significant reduction in pancreatitis incidence.