Inclisiran and lipoprotein apheresis in statin intolerance heterozygous FH patients: A case series.

Dear Editor, In Familial Hypercholesterolemia (FH), statins treatment is the first choice to lower LDL cholesterol and to reduce cardiovascular morbidity and mortality, however, up to 10% of patients treated with statins report intolerance [1]. Monoclonal antibodies against Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (mAb PCSK9i) could be administered to lower LDL cholesterol in patients with muscle-related adverse events, but intolerance to mAb PCSK9i has also been described [2]. Within this context, Lipoprotein Apheresis (LA) still holds a valuable role, even in the new era of Lipid-Lowering Therapy (LLT) [2]. Inclisiran is a novel small interfering RNA-based drug (siRNA) anti-PCSK9 play a role in patients when optimal LDL-C cannot be achieved by statins and/or mAb PCSK9i [3]. We enrolled 5 patients in chronic LA (mean age 64 ± 8 years, female 60%) affected by heterozygous FH and AtheroSclerotic CardioVascular Disease (ASCVD), with history of statin intolerance and mAb PCSK9i adverse events (flue like syndrome in 3/5 patients, severe CPK increase in 1/5 patient and low therapeutic compliance in 1/5 patient). These patients, after the discontinuation of mAb PCSK9i, were assigned to inclisiran therapy (dosing schedule: 284 mg s.c. injection of at 0–90–180 days and every 6 months thereafter) and followed up for 3 months. The LA treatment was performed at bi-weekly interval by dextran-sulfate (Liposorber-LA systems; Kaneka, Osaka, Japan; 3/5 patients) or heparin-induced LDL precipitation apheresis (HELP, Plasmat Futura; B. Braun, Melsungen, Germany; 2/5 patients). After 3 months of therapy, a significant decrease in total cholesterol ( 19%), LDL cholesterol ( 27%), Apo B lipoprotein ( 24%) and triglycerides ( 13%) levels was observed without significant modification in other parameters (see Table S1). During the study period, the clinical response between inclisiran and mAb PCSK9i showed no difference (see Figure 1). One patient who achieved the recommended therapeutic target for LDL cholesterol and Lp(a) levels (respectively below 55 and 60 mg/dL, as indicated by international guidelines) discontinued LA. Adverse events were reported in 2/5 (40%) of patients: one referred transient episodes of mild difficulty to maintain concentration after 2 weeks of drug administration, another patient presented a cutaneous herpes zoster infection. No injection-site reaction was reported. In contrast to mAb PCSK9i, inclisiran inactivates PCSK9 by inhibition of its hepatic synthesis. The safety, tolerability, and efficacy of inclisiran have been studied within the ORION clinical development program who demonstrated a sustained PCSK9 suppression of about 80% and time-adjusted LDL-C reduction of approximately 50% from baseline. Furthermore, the safety profile of inclisiran was found to be comparable to that of mAb PCSK9i and the most commonly reported adverse effect was a mild-to-moderate transient injection site reaction [3]. It provides a therapeutic opportunity to overcome drugs intolerance and decrease the burden of atherosclerotic cardiovascular disease.