Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the effi cacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the effi cacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than fi ve times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Offi ce of the Orphan Product Development, Aegerion Pharmaceuticals.

Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: A single-arm, open-label, phase 3 study

VIGNA, Giovanni Battista;
2013

Abstract

Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the effi cacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the effi cacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than fi ve times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Offi ce of the Orphan Product Development, Aegerion Pharmaceuticals.
2013
Cuchel, Marina; Meagher, Emma A.; Theron, Hendrik Du Toit; Blom, Dirk J.; Marais, A. David; Hegele, Robert A.; Averna, Maurizio R.; Sirtori, Cesare R.; Shah, Prediman K.; Gaudet, Daniel; Stefanutti, Claudia; Vigna, Giovanni Battista; Du Plessi, Anna M. E.; Propert, Kathleen J.; Sasiela, William J.; Bloedon, Leanne T.; Rader, Daniel J.
File in questo prodotto:
File Dimensione Formato  
Lomitapide in Ho FH Lancet12.pdf

solo gestori archivio

Descrizione: Full text ahead of print
Tipologia: Full text (versione editoriale)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 236.87 kB
Formato Adobe PDF
236.87 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
1-s2.0-S0140673612617310-main.pdf

solo gestori archivio

Descrizione: Full text editoriale
Tipologia: Full text (versione editoriale)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 222.36 kB
Formato Adobe PDF
222.36 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
nihms722015.pdf

accesso aperto

Descrizione: Post print
Tipologia: Post-print
Licenza: Creative commons
Dimensione 741.39 kB
Formato Adobe PDF
741.39 kB Adobe PDF Visualizza/Apri

I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2353629
Citazioni
  • ???jsp.display-item.citation.pmc??? 169
  • Scopus 603
  • ???jsp.display-item.citation.isi??? 543
social impact