Modelling the potential long-term survival benefit of evinacumab treatment vs. standard of care in patients with homozygous familial hypercholesterolaemia.

Despite intensive lipid-lowering therapies (LLTs), most patients with homozygous familial hypercholesterolaemia (HoFH) do not achieve guideline recommended low-density lipoprotein cholesterol (LDL-C) targets and are at increased risk of premature cardiovascular death. This analysis aimed to predict the impact of evinacumab and standard-of-care LLTs on life expectancy in an HoFH population using mathematical modelling. Mathematical models were developed using efficacy data for evinacumab from the phase 3 ELIPSE HoFH trial plus efficacy data for standard-of-care LLTs from peer-reviewed publications. Treatment strategies evaluated included (i) untreated, (ii) high-intensity statin (HIS) only, (iii) HIS plus ezetimibe, (iv) HIS plus ezetimibe plus proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and (v) HIS plus ezetimibe plus PCSK9i plus evinacumab. Markov analyses were used to assess differences in survival probability for different LLT strategies. The median survival for untreated HoFH patients was only 33-43 years, depending on different assumptions on baseline untreated LDL-C levels. In the most robust model, we estimated that HIS increased median survival by 9 years and ezetimibe further increased median survival by an additional 9 years. When PCSK9i was added on top of HIS plus ezetimibe, median survival was further improved by 14 years. Finally, the addition of evinacumab to standard-of-care LLTs was estimated to increase median survival by ∼12 years. In this mathematical modelling analysis, evinacumab treatment could potentially increase long-term survival vs. standard-of-care LLTs for patients with HoFH.

Gu J ，Kuznik A ，Quon P ，Chauhan A ，Sravya TS ，Raal FJ ... -  《-》

Contemporary lipid-lowering management and risk of cardiovascular events in homozygous familial hypercholesterolaemia: insights from the Italian LIPIGEN Registry.

The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting. The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016). Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH.

D'Erasmo L ，Bini S ，Casula M ，Gazzotti M ，Bertolini S ，Calandra S ，Tarugi P ，Averna M ，Iannuzzo G ，Fortunato G ，Catapano AL ，Arca M ，LIPIGEN HoFH group ... -  《-》

The Effect of PCSK9 Inhibitors on LDL-C Target Achievement in Patients with Homozygous Familial Hypercholesterolemia: A Retrospective Cohort Analysis.

Alshahrani A ，Kholaif N ，Al-Khnifsawi M ，Zarif H ，Mahzari M ... -  《-》

Evinacumab and Cardiovascular Outcome in Patients With Homozygous Familial Hypercholesterolemia.

Béliard S ，Saheb S ，Litzler-Renault S ，Vimont A ，Valero R ，Bruckert É ，Farnier M ，Gallo A ... -  《-》

The Long-Term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is characterized by early-onset atherosclerotic cardiovascular disease due to the high low-density lipoprotein cholesterol (LDL-C) burden. Patients with null-null low-density lipoprotein receptor (LDLR) variants respond poorly, if at all, to statins and proprotein convertase subtilisin/kexin type 9 inhibitors, which act by upregulating LDLR expression. The 24-week double-blind treatment period (DBTP) of the phase 3 ELIPSE HoFH (Evinacumab Lipid Studies in Patients with Homozygous Familial hypercholesterolemia; NCT03399786) study demonstrated significant LDL-C reductions in patients with HoFH; LDL-C reductions were also observed in those with null-null LDLR mutations. The purpose of this study was to evaluate longer-term efficacy and safety of evinacumab in patients with HoFH from the ELIPSE HoFH study. Patients with HoFH on stable lipid-lowering therapies (LLTs) ± lipoprotein apheresis and screening LDL-C ≥70 mg/dL who completed the DBTP entered the 24-week open-label treatment period (OLTP) and received intravenous evinacumab 15 mg/kg every 4 weeks. OLTP results were summarized descriptively. A total of 64 patients completed the DBTP and received open-label evinacumab. Despite multiple LLTs, the mean baseline LDL-C at DBTP entry was 250.5 ± 162.3 mg/dL. From baseline to week 48 (end of OLTP), evinacumab reduced mean LDL-C by 46.3% (mean reduction, 134.3 ± 117.3 mg/dL), with similar mean LDL-C reductions for patients with null-null (47.2%) and non-null variants (45.9%). Adverse events occurred in 47 (73.4%) patients; 4 (6.3%) patients experienced adverse events considered evinacumab-related (drug hypersensitivity, infusion-related reaction and asthenia, generalized pruritis, and muscle spasms). In patients with HoFH, evinacumab demonstrated substantial and sustained LDL-C reduction regardless of LDLR function, and was generally well tolerated.

Raal FJ ，Rosenson RS ，Reeskamp LF ，Kastelein JJP ，Rubba P ，Duell PB ，Koseki M ，Stroes E ，Ali S ，Banerjee P ，Chan KC ，Khilla N ，McGinniss J ，Pordy R ，Zhang Y ，Gaudet D ... -  《-》