Abstract 4338231: Inclisiran Nonresponse with PCSK9 Variant and Successful LDL-C Lowering with Evinacumab in a Patient with Homozygous Familial Hypercholesterolemia

Abstract

Background: Patients with homozygous familial hypercholesterolemia (HoFH) often require intensive lipid-lowering therapies (LLT) to prevent ASCVD. Inclisiran, a small interfering RNA (siRNA) that degrades PCSK9 messenger RNA thus increasing LDL clearance from circulation, was recently approved for use. There has been variable response to Inclisiran among patients with HoFH. Case: We present the case of a 34-year-old male with compound heterozygous FH (HeFH) (two pathological mutations in LDLR: c.502G>A, c.1295T>C) with peak LDL >600mg/dL and premature ASCVD: anterior STEMI at age 25 requiring PCI to LAD complicated by VF arrest, and NSTEMI s/p PCI to LAD at age 32. LLT was escalated to achieve target LDL. Despite adherence to maximum doses of LLT (Rosuvastatin, Ezetimibe, Bempedoic acid, Alirocumab) and aggressive lifestyle modifications (12lbs weight loss and a vegan diet), he did not reach target LDL <55mg/dL. Alirocumab was replaced with Inclisiran for convenience. However, after Inclisiran 2nd dose, his LDL doubled (Figure 1). Genetic panel was notable for a PCSK9 variant of unknown significance (0.63_65dupGCT) and APOB variant of unknown significance (c.905-15C>G).Alirocumab was resumed as he was deemed as a nonresponder to Inclisiran. Evinacumab was added to LLT resulting in LDL ~55 mg/dL. Discussion: This case highlights a patient with compound HeFH that should be treated as HoFH requiring multiple 2nd line LLT, and showed different response to Alirocumab and Inclisiran. The effectiveness of PCSK9-based therapies can be partly determined by underlying genetic abnormality, as it requires LDLR activity to effectively lower LDL. Given the robust responsiveness to Rosuvastatin and Alirocumab, he likely has significant LDLR function. His PCSK9 variant might play a role in unresponsiveness to RNA interference by Inclisiran. We were unable to verify the patient’s PCSK9 variant as the targeted site of Inclisiran– this may be useful to elucidate the difference in response to PCSK9 inhibition by monoclonal antibody and reduced PCSK9 production by siRNA.In this patient, Evinacumab, an angiopoietin-like-protein 3 (ANGPTL3) inhibitor, was effective to achieved LDL target. Evinacumab works by facilitating clearance of lipoproteins via lipoprotein lipase and endothelial lipase and is independent of LDLR/PCSK9 pathway. This case highlights the importance of recognizing limitations in existing lipid-lowering strategies and the need for personalized treatment.