Biologics for the treatment of dyslipidemias: a look beyond conventional therapy

To evaluate the monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) in the management of dyslipidemias.

MEDLINE/PubMed, NHS Evidence, TRIP database and EMBASE searches were conducted using the terms proprotein convertase subtilisin/kexin type 9, PCSK9, and monoclonal antibody. No date limits were utilized; search results were current to September 2013.

Articles were limited to phase 2 or 3 clinical trials of monoclonal antibodies to PCSK9 assessing surrogate markers of clinical end points.

AMG145 and REGN727/SAR236553 are human monoclonal antibodies to PCSK9, a serine protease responsible for low-density lipoprotein cholesterol (LDL-C) regulation. PCSK9 binds to LDL receptors targeting them for intracellular degradation. AMG145 and REGN727/SAR236553 blocks the interaction between PCSK9 and the LDL receptor, increasing LDL receptor availability and allowing the removal of LDL-C from the circulation. These therapies have been evaluated as monotherapy and in combination with statins and ezetimibe in phase 2 trials and have demonstrated significant and dose-related reductions in LDL-C. LDL-C reductions were as high as 72% with REGN727/SAR236553 and 66% with AMG145. These agents were generally well tolerated; nasopharyngitis and injection site reactions were the most common reactions with both agents. Gastrointestinal disturbances and infections were also common with REGN727/SAR236553.

These agents may eventually play a role as add-on therapy in those with dyslipidemias because of their significant effect on LDL-C. Further explorations in large phase 3 clinical trials are warranted to evaluate the effect of these therapies on cardiovascular clinical outcomes and long-term safety.