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Regeneron Pharmaceuticals, Inc. Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder caused primarily by mutations in the low-density lipoprotein (LDL) receptor gene and characterized by severely elevated levels of LDL cholesterol (LDL-C), leading to early-onset atherosclerotic cardiovascular disease. Currently, few treatments are available to lower LDL-C levels in pediatric patients with HoFH. In Part B of a three-part open-label study (NCT04233918), the addition of evinacumab, an angiopoietin-like-3 inhibitor, to background lipid-lowering therapies (LLTs) reduced LDL-C from baseline to Week 24 by 48% in patients with HoFH aged 5-11 years. Evaluate the long-term (up to 72 weeks) efficacy and safety of evinacumab in pediatric patients with HoFH. This open-label, three-part study enrolled patients aged 5-11 years with LDL-C >130 mg/dL on optimized LLT, including apheresis and lomitapide. Part A was a Phase 1b, single-dose, 16-week study including six patients who received intravenous (IV) evinacumab 15 mg/kg. Part B was a Phase 3, 24-week open-label treatment study including 14 patients who had not participated in Part A. Part C was a Phase 3, 48-week open-label extension study, with an optional 24-week follow-up period, which included all 20 patients from both Parts A and B. In Parts B and C, patients received IV evinacumab 15 mg/kg every 4 weeks. We report data pooled from Parts B and C that includes results from Part A patients who participated in Part C and had 48 weeks of evinacumab treatment, and Part B patients who participated in Parts B and C and had a total treatment duration of 72 weeks. All 20 patients completed Part C. Mean (standard deviation [SD]) LDL-C at baseline was 301.9 (149.1) mg/dL. Evinacumab reduced mean LDL-C by 44.6% (mean [SD] reduction of 131.1 [90.2] mg/dL) and 40.7% (mean [SD] reduction of 115.8 [101.2] mg/dL) from baseline to Weeks 48 (n=16) and 72 (n=14), respectively. Evinacumab reduced mean apolipoprotein B (Week 48: 38.3%; Week 72: 34.0%), non-high-density lipoprotein cholesterol (Week 48: 45.3%; Week 72: 41.6%), total cholesterol (Week 48: 44.7%; Week 72: 42.2%), and median lipoprotein(a) (Week 48: 17.3%; Week 72: 15.7%). Treatment-emergent adverse events (TEAEs) occurred in all 20 patients. Serious TEAEs occurred in two (10.0%) patients (tonsilitis [n=1]; aortic valve stenosis [n=1]), both were unrelated to the study drug. No treatment discontinuations or deaths were reported. In pediatric patients with HoFH, evinacumab demonstrated substantial and durable reductions in LDL-C and other atherogenic lipids, and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder predominantly caused by mutations in the low-density lipoprotein (LDL) receptor gene and characterized by severely elevated LDL cholesterol (LDL-C) levels, beginning in utero. Although cardiovascular events often occur during childhood and adolescence in HoFH, few treatments effectively lower LDL-C in pediatric patients with HoFH. To evaluate the efficacy and safety of evinacumab, a monoclonal antibody inhibitor of angiopoietin-like 3, in pediatric patients with HoFH. This open-label, three-part study (NCT04233918) enrolled 14 patients 5–11 years old with LDL-C >130 mg/dL on optimized lipid-lowering therapy, including apheresis. Part B, reported here, consisted of an ≤8-week run-in, a 1–2-week screening period, and a 24-week open-label treatment period. The primary endpoint was mean change in LDL-C. Intravenous evinacumab 15 mg/kg every 4 weeks. All patients completed Part B. At Part B baseline, the mean age (standard deviation [SD]) was 9.1 (1.9) years and the mean (SD) LDL-C was 263.7 (91.0) mg/dL. At week 24, the mean percent change in LDL-C from baseline was –48.3% (standard error [SE]: 10.4%). Mean (SE) percent changes in apolipoprotein B (–41.3% [9.0%]), non-high-density lipoprotein cholesterol (–48.9% [9.8%]), and total cholesterol (–49.1% [8.1%]) at Week 24 from baseline were also observed. Treatment-emergent adverse events (TEAEs) occurred in 10 (71.4%) patients. TEAEs were considered treatment-related only in two (14.3%) patients (nausea and abdominal pain; both ongoing). No treatment discontinuations due to TEAEs or deaths were reported. A serious TEAE of tonsilitis occurred in one patient but was not considered treatment related. In children with HoFH and inadequately controlled LDL-C despite pre-existing treatment (including apheresis), evinacumab effectively lowers LDL-C and other atherogenic lipid levels by an additional 40–50%. Evinacumab was generally well tolerated. Yes Regeneron Pharmaceuticals, Inc. [ABSTRACT FROM AUTHOR]

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder that is often associated with extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) due to its impaired clearance from the circulation. Individuals with HoFH also experience increased cardiovascular events and premature mortality. Evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, has demonstrated approximately 50% reductions in LDL-C levels in patients with HoFH independent of residual LDL receptor function compared to placebo. This post-hoc analysis was conducted to assess the effect of evinacumab on the change in apheresis eligibility based on the predefined US apheresis criteria in patients with HoFH. This is an ongoing, single-arm, open-label, phase 3 study (NCT03409744) that enrolled and treated patients with HoFH aged ≥12 years. All evaluable patients (n=106) received intravenous evinacumab 15 mg/kg every 4 weeks. At baseline, 67.9% (72/106) of patients qualified for apheresis and 32.1% (34/106) of patients did not qualify for apheresis using US criteria (LDL-C ≥300 mg/dL or LDL-C ≥100 mg/dL with coronary heart disease or peripheral artery disease). Overall, the mean (standard deviation) reduction in LDL-C was 130.6 (109.3) mg/dL from baseline at Week 56. Of the 72 patients who initially qualified for apheresis at baseline, over half (61.9% [39/63]) no longer qualified for apheresis following 56 weeks of treatment (data missing for 9 patients). The observed reduction in the proportion of patients qualifying for apheresis was overall maintained through to Week 184 (results not shown). Based on US apheresis eligibility criteria, treatment with evinacumab considerably reduced the proportion of patients who would qualify for apheresis. Yes Regeneron Pharmaceuticals, Inc. [ABSTRACT FROM AUTHOR]

Nothing to disclose. Regeneron Pharmaceuticals, Inc. Homozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease, underscoring the need for early and aggressive treatment. Evinacumab, an angiopoietin-like protein 3 inhibitor, is an effective LDL-C lowering drug in adult HoFH patients. The primary objective of the study is to evaluate the safety and tolerability of intravenous evinacumab 15 mg/kg every 4 weeks in adolescent patients with HoFH. This is an interim analysis of an evinacumab open-label phase 3 trial (NCT03409ba744) in adolescent patients (aged 12 to <18 years) with HoFH. Patients who participated in a previous study (NCT03399786) or who were evinacumab-naive received intravenous evinacumab 15 mg/kg every 4 weeks. All patients were genotyped. In total, 13 patients (8 male; mean [range] age 14 [12-17] years) were treated for a mean (range) duration of 34.5 (4-61) weeks. At baseline, mean (standard deviation [SD]) LDL-C was 310.3 [97.3] mg/dL; 8 patients (61.5%) received lipoprotein apheresis. Treatment-emergent adverse events (TEAEs) occurred in 6 (46.2%) patients; no TEAEs were reported in more than 1 patient. One patient reported 2 serious adverse events, both considered unrelated to study drug. LDL-C data were available for 9 patients at week 24. Overall, evinacumab reduced mean LDL-C by 52.4% (mean [SD], 183.4 [101.6] mg/dL; Figure) from baseline to week 24. In patients with null-null (n=4) and non-null (n=5) LDL-receptor variants, evinacumab reduced mean LDL-C levels by 67.2% and 40.6%, respectively. In this small sample of adolescent patients with HoFH, evinacumab markedly reduced LDL-C irrespective of genotype or background treatment in patients with HoFH. Evinacumab was generally well-tolerated with few TEAEs. [ABSTRACT FROM AUTHOR]

Background Mutations in the genes for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR , apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 ( LDLRAP1 ), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH. [ABSTRACT FROM AUTHOR]

Background Mutation(s) in genes involved in the low-density lipoprotein receptor (LDLR) pathway are typically the underlying cause of familial hypercholesterolemia. Objective The objective of the study was to examine the influence of genotype on treatment responses with alirocumab. Methods Patients from 6 trials (n = 1191, including 758 alirocumab-treated; Clinicaltrials.gov identifiers: NCT01266876 ; NCT01507831 ; NCT01623115 ; NCT01709500 ; NCT01617655 ; NCT01709513 ) were sequenced for mutations in LDLR , apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), LDLR adaptor protein 1, and signal-transducing adaptor protein 1 genes. New mutations were confirmed by Sanger sequencing. Results One or more specific gene mutations were found in 898 patients (75%): 387 and 437 patients had heterozygous LDLR defective and negative mutations, respectively; 46 had a heterozygous APOB -defective mutation; 8 patients had a heterozygous PCSK9 gain-of-function mutation; 293 (25%) had no identifiable mutation in the genes investigated. LDL cholesterol reductions at Week 24 were generally similar across genotypes: 48.3% (n = 131) and 54.3% (n = 89) in LDLR -defective heterozygotes with alirocumab 75 mg Q2W (with possible increase to 150 mg at Week 12) and 150 mg Q2W, respectively; 49.7% (n = 168) and 60.7% (n = 88) in LDLR -negative heterozygotes; 54.1% (n = 20) and 50.1% (n = 6) in APOB -defective heterozygotes; 60.5% (n = 5) and 94.0% (n = 1) in PCSK9 heterozygotes; and 44.9% (n = 85) and 55.4% (n = 69) in patients with no identified mutations. Overall rates of treatment-emergent adverse events were similar for alirocumab vs controls (placebo in 5 trials, ezetimibe control or atorvastatin calibrator arm in 1 trial), with only a higher rate of injection-site reactions with alirocumab. Conclusions In this large patient cohort, individuals with a wide spectrum of mutations in genes underlying familial hypercholesterolemia responded substantially and similarly to alirocumab treatment. [ABSTRACT FROM AUTHOR]

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment.Objectives: This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH.Methods: This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment.Results: Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period.Conclusions: In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.). [ABSTRACT FROM AUTHOR]