Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by highly elevated low-density lipoprotein cholesterol (LDL-C) levels and high cardiovascular disease risk. Lomitapide, an oral microsomal triglyceride transfer protein inhibitor, was approved for the treatment of adult HoFH based on a small phase 3 study. We report efficacy and safety results from the phase 3 long-term extension study. Methods: Eligible HoFH patients completing the 78-wk phase 3 pivotal trial were enrolled into a single-arm extension study where lomitapide was administered daily at the maximum tolerated dose (5-60mg/d) until lomitapide was commercially available in the patient’s country. Concurrent lipid-lowering therapies, including apheresis, were permitted. Results: Nineteen of 23 patients who completed the pivotal study entered the extension trial (9/19 apheresis) with 16 patients completing all end of study assessments. Mean treatment duration was 4.8 yrs (range 2.1-5.7 yrs, median 5.1 yrs). Lomitapide efficacy was maintained throughout the study (Table). Reported adverse events were similar to those in the pivotal phase 3 study (chiefly gastrointestinal). Five patients (26%) experienced transient alanine aminotransferase (ALT) elevations ≥5x upper limit of normal (ULN) that were successfully managed by dose adjustment in all but one patient who was discontinued due to persistent excessive alcohol use. One 58 year-old patient with known CAD had sudden cardiac death. Median hepatic fat increased by 10% above baseline after 3 yrs and stabilized through the treatment period (Table). No other clinically relevant findings were identified to date. Conclusions: The long-term efficacy of lomitapide was maintained up to 5.7 yrs in patients completing the phase 3 trial with no new safety signals observed. The clinical significance of the increase in hepatic fat remains unknown.
Long-Term Efficacy and Safety of Lomitapide for the Treatment of Homozygous Familial Hypercholesterolemia: Results of the Phase 3 Extension Trial / Blom, Dirk; Averna, Maurizio; Meagher, Emma; Theron, Hendrik du Toit; Sirtori, Cesare; Hegele, Robert; Shah, Prediman; Gaudet, Daniel; Stefanutti, Claudia; Vigna, Giovanni; Foulds, Pam; Bloedon, Leanne; Rader, Daniel; Cuchel, Marina. - In: CIRCULATION. - ISSN 0009-7322. - ELETTRONICO. - 132 Suppl 3:(2015), p. 12450. (Intervento presentato al convegno Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association (AHA) tenutosi a Orlando, FL - USA nel NOV 07-11, 2015).
Long-Term Efficacy and Safety of Lomitapide for the Treatment of Homozygous Familial Hypercholesterolemia: Results of the Phase 3 Extension Trial
STEFANUTTI, Claudia;
2015
Abstract
Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by highly elevated low-density lipoprotein cholesterol (LDL-C) levels and high cardiovascular disease risk. Lomitapide, an oral microsomal triglyceride transfer protein inhibitor, was approved for the treatment of adult HoFH based on a small phase 3 study. We report efficacy and safety results from the phase 3 long-term extension study. Methods: Eligible HoFH patients completing the 78-wk phase 3 pivotal trial were enrolled into a single-arm extension study where lomitapide was administered daily at the maximum tolerated dose (5-60mg/d) until lomitapide was commercially available in the patient’s country. Concurrent lipid-lowering therapies, including apheresis, were permitted. Results: Nineteen of 23 patients who completed the pivotal study entered the extension trial (9/19 apheresis) with 16 patients completing all end of study assessments. Mean treatment duration was 4.8 yrs (range 2.1-5.7 yrs, median 5.1 yrs). Lomitapide efficacy was maintained throughout the study (Table). Reported adverse events were similar to those in the pivotal phase 3 study (chiefly gastrointestinal). Five patients (26%) experienced transient alanine aminotransferase (ALT) elevations ≥5x upper limit of normal (ULN) that were successfully managed by dose adjustment in all but one patient who was discontinued due to persistent excessive alcohol use. One 58 year-old patient with known CAD had sudden cardiac death. Median hepatic fat increased by 10% above baseline after 3 yrs and stabilized through the treatment period (Table). No other clinically relevant findings were identified to date. Conclusions: The long-term efficacy of lomitapide was maintained up to 5.7 yrs in patients completing the phase 3 trial with no new safety signals observed. The clinical significance of the increase in hepatic fat remains unknown.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
