Combination Therapy In Dyslipidemia by Maciej Banach

Author:Maciej Banach
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Strategies for PCSK9 Inhibition

Several therapeutic approaches to the inhibition of PCSK9 have been proposed [38], including inhibition of PCSK9 synthesis by gene-silencing agents, such as antisense oligonucleotides (ASOs) or small interfering RNA (siRNA); inhibition of PCSK9 binding to LDLR by mAbs, small peptides, or adnectins; and inhibition of PCSK9 autocatalytic processing by small molecule inhibitors. These strategies targeting either extracellular or intracellular PCSK9 have been extensively described in recent reviews [39–43].

Preclinical studies on inhibition of PCSK9 synthesis by ASOs were promising, but the development of two ASOs by BMS/ISIS (BMS-84421) and Santaris Pharma (SPC5001) was stopped in Phase I [43]. siRNA is another approach [44, 45]. In rats, siRNA targeting PCSK9 reduced LDL-C level by around 30 %, and in nonhuman primates, single-dose administration of 5 mg of the drug decreased LDL-C by 56–70 % [44]. In a phase I trial of ALN-PCS, an siRNA developed by Alnylam Pharmaceuticals, a dose-dependent reduction in LDL-C was observed, with a 40 % reduction with the highest dose, associated with a 70 % reduction in plasma PCSK9 concentrations [46]. Inhibition of PCSK9 binding to LDLR by small peptide inhibitors such as SX-PCK9 (Serometrix, East Syracuse, NY, USA) or adnectins such as BMS-962476 (BMS/Adnexus, Waltham, MA, USA) are in preclinical development or phase I [39–41]. On the basis of the discovery of a LOF mutation in the autocatalytic cleavage site of PCSK9 [47], inhibition of PCSK9 autocatalytic processing is the approach chosen by Cadila Healthcare and Shifa Biomedical [39] with molecules in preclinical development phase. Finally, mAbs [48] are the most studied and advanced approach in terms of clinical development with published phase I, II, and III human trials. An alternative approach for PCSK9 inhibition could be a peptide-based anti-PCSK9 active vaccination approach providing the opportunity for long-term LDL-C management [49].

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