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Effetti di alirocumab in pazienti con ipercolesterolemia da aumento di PCSK9

Sono tre le cause accertate di ipercolesterolemia familiare autosomica dominante. La più comune è determinata da un difetto del recettore per le LDL, più rara è quella dovuta ad un'alterazione costitutiva dell'apolipoproteina B e la terza, di più recente riscontro, è dovuta ad un eccesso di funzione di PCSK9 (Proprotein convertase subtilisin/kexin type 9), la proteina che degrada il recettore LDL. Quest'ultima forma di ipercolesterolemia familiare è piuttosto rara, finora ne sono stati descritti 164 casi con 16 mutazioni diverse che comportavano alti livelli di colesterolo LDL (da poco più di 150 a oltre 490 mg/dL) e malattia aterosclerotica precoce. Lo studio di Hopkins e Coll. ha coinvolto 13 pazienti con 4 mutazioni diverse. L'aggiunta di alirocumab 150 mg ogni 2 settimane alla terapia ipolipemizzante in corso ha determinato una riduzione media del 73% del colesterolo LDL con il raggiungimento di una concentrazione minore di 70 mg/dl in 12 su 13 pazienti.

Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

Hopkins PN, Defesche J, Fouchier SW, Bruckert E, Luc G, Cariou B, Sjouke B, Leren TP, Harada-Shiba M, Mabuchi H, Rabès JP, Carrié A, van Heyningen C, Carreau V, Farnier M, Teoh YP, Bourbon M, Kawashiri MA, Nohara A, Soran H, Marais AD, Tada H, Abifadel M, Boileau C, Chanu B, Katsuda S, Kishimoto I, Lambert G, Makino H, Miyamoto Y, Pichelin M, Yagi K, Yamagishi M, Zair Y, Mellis S, Yancopoulos GD, Stahl N, Mendoza J, Du Y, Hamon S, Krempf M, Swergold GD

Circ Cardiovasc Genetic 2015;8:823-831

BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported.
METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) =70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001).
CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients.

Circ Cardiovasc Genetic 2015;8:823-831