SISANews

Un nuovo inibitore di PCSK9

Si chiama inclisiran, è una piccola molecola sintetica di RNA (siRNA - RNA interferente breve) in grado di interferire con l'RNA messaggero determinandone la precoce degradazione. L'effetto finale è il silenziamento del gene che codifica per PCSK9 (proprotein convertase subtilisin-kexin type 9). Siamo ancora in una fase precoce dello sviluppo del farmaco, ma i dati riportati da Fitzgerald e Coll. sono piuttosto promettenti e tali da lasciare supporre che questo tipo di inibizione di PCSK9 possa efficacemente affiancarsi agli attuali anticorpi monoclonali. A dosi diverse, da 125 mg sottocute una volta la settimana la settimana a 500 mg una volta al mese, il farmaco ha determinato una riduzione anche dell'83.8% del livello di PCSK9, cui si è associata una riduzione del 59.7% del colesterolo LDL e questo anche in pazienti già in terapia con una statina.

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, Wijngaard P, Horton JD, Taubel J, Brooks A, Fernando, C, Kauffman RS, David Kallend, Vaishnaw A, Simon A

New Engl J Med. [Epub ahead of print]

BACKGROUND: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.
METHODS: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated.
RESULTS: The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the ?-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).
CONCLUSIONS: In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months.

New Engl J Med. [Epub ahead of print]