A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

Distinguishing Lysosomal Acid Lipase Deficiency From Familial Hypercholesterolemia.

Lysosomal acid lipase deficiency (LAL-D) is underrecognized because it manifests clinically with lipid and lipoprotein values similar to those observed in heterozygous familial hypercholesterolemia (FH). Although LAL-D is uncommon, understanding the differences between the 2 diseases has significant management implications. We present a case of LAL-D that masqueraded as FH. (Level of Difficulty: Advanced.).

Longer-Term Efficacy and Safety of Evinacumab in Patients With Refractory Hypercholesterolemia.

Importance: Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Objective: To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia. Design, Setting, and Participants: This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period. Patients from 85 sites across 20 countries were recruited for the study; patients with primary hypercholesterolemia (defined as heterozygous familial hypercholesterolemia or established clinical ASCVD without familial hypercholesterolemia) who entered the 48-week OLTP were included. In addition, the patients' hypercholesterolemia was refractory to maximally tolerated LLTs. Interventions: All patients entering the OLTP received evinacumab, 15 mg/kg, intravenously Q4W. Main Outcomes and Measures: Efficacy outcomes included change in LDL-C level and other lipid/lipoprotein parameters from baseline to week 72 (end of the OLTP). Safety outcomes included assessment of treatment-emergent adverse events (TEAEs). Results: A total of 96 patients (mean [SD] age, 54.4 [11.3] years; 52 female [54.2%]) entered the OLTP, of whom 88 (91.7%) completed the OLTP. Mean (SD) baseline LDL-C level was 145.9 (55.2) mg/dL. At week 72, evinacumab, 15 mg/kg, reduced mean (SD) LDL-C level from baseline by 45.5% (28.7%) in the overall cohort. Evinacumab, 15 mg/kg, reduced mean (SD) apolipoprotein B (38.0% [22.1%]), non-high density lipoprotein cholesterol (48.4% [23.2%]), total cholesterol (42.6% [17.5%]), and median (IQR) fasting triglyceride (57.2% [65.4%-44.4%]) levels at week 72 from baseline in the overall cohort. TEAEs occurred in 78 of 96 patients (81.3%). Serious TEAEs occurred in 9 of 96 patients (9.4%); all were considered unrelated to study treatment. Conclusions and Relevance: In patients with refractory hypercholesterolemia, evinacumab provided sustained reductions in LDL-C level and was generally well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT03175367.

Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry.

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial.

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg-1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of -27.1% (37.4) (95% confidence interval -71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 .

Potential Cardiovascular Events Avoided with Bempedoic Acid Plus Ezetimibe Fixed-Dose Combination Compared with Ezetimibe Alone in Patients with Atherosclerotic Cardiovascular Disease Taking Maximally Tolerated Statins.

BACKGROUND: Patients with atherosclerotic cardiovascular disease who require additional low-density lipoprotein cholesterol (LDL-C) lowering despite maximally tolerated statins have a significant unmet medical need and are at increased risk of future cardiovascular events and a reduced quality of life. OBJECTIVE: We aimed to estimate the percentage of cardiovascular events avoided following treatment with a fixed-dose combination of bempedoic acid plus ezetimibe (BA+EZE FDC) versus ezetimibe (EZE) in patients with atherosclerotic cardiovascular disease receiving maximally tolerated statins across a range of baseline LDL-C levels. METHODS: A Markov cohort simulation model estimated major adverse cardiovascular events avoided over a lifetime horizon among patients with atherosclerotic cardiovascular disease and baseline LDL-C levels from 80 to >200 mg/dL. BA+EZE FDC was compared with EZE based on mean percent LDL-C reductions versus placebo reported in a phase III trial. Health outcomes for the average patient were extrapolated to a US population of 100,000 persons using evidence on contemporary LDL-C levels from the National Health and Nutrition Examination Survey. RESULTS: Among patients with atherosclerotic cardiovascular disease not at the LDL-C goal with maximally tolerated statins, the addition of BA+EZE FDC compared with the addition of EZE was predicted to provide incremental absolute reductions in major adverse cardiovascular events dependent on baseline LDL-C levels at the population level. For those with baseline LDL-C of 101-110 mg/dL (n = 15,237), there were 4.9% (744) fewer events predicted, while for patients with baseline LDL-C of > 200 mg/dL (n = 1689), 10.9% (184) fewer events were predicted through the addition of BA+EZE FDC versus EZE. CONCLUSIONS: Further LDL-C reductions through the addition of BA+EZE FDC to maximally tolerated statins are predicted to reduce major adverse cardiovascular events compared with the addition of EZE. Benefits are potentially greater among those with higher starting LDL-C.

Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).

Defining preventive cardiology: A clinical practice statement from the American Society for Preventive Cardiology.

Remarkable transformations in science and healthcare have resulted in declines in mortality from cardiovascular disease over the past several decades, largely driven by progress in prevention and treatment of persons at risk. However, these trends are now beginning to stall, as our county faces increases in cardiovascular risk factors including overweight and obesity, type 2 diabetes mellitus, and metabolic syndrome. Furthermore, poor long-term adherence to a healthy lifestyle and lifesaving pharmacotherapy have exacerbated these trends, with recent data suggesting unprecedented increases in cardiovascular morbidity and mortality. A paradigm shift is needed to improve the cardiovascular health of our nation. Preventive cardiology, a growing subspecialty of cardiovascular medicine, is the practice of primordial, primary, and secondary prevention of all cardiovascular diseases. Preventive cardiologists and preventive cardiology specialists are well equipped with the knowledge and skill-set necessary to reduce deaths related to the growing burden of heart disease and its risk factors. Despite dedicated efforts, cardiovascular disease remains the leading killer of men and women in the United States. Although there is little debate regarding the importance of prevention, many healthcare professionals question the need for preventive cardiology as a distinct subspecialty. Additionally, the field's growth has been hampered by a lack of organization and standardization, and variability of training within programs across the country. The purpose of this document is to delineate the key attributes that define the field of preventive cardiology according to the American Society for Preventive Cardiology.

Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia.

BACKGROUND: Olezarsen is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apolipoprotein C-III (apoC-III) and triglyceride-rich lipoproteins (TRLs). OBJECTIVE: To define the effect of olezarsen on NMR-derived lipoprotein particle size and concentration. METHODS: Patients (n=114) with or at risk for atherosclerotic cardiovascular disease and fasting triglycerides ≥200 and <500 mg/dL received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. NMR LipoProfile® analysis was performed in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. RESULTS: A dose-dependent relationship was generally noted with increasing cumulative doses of olezarsen in TRL particle (TRLP), LDL particle (LDL-P) and HDL (HDL-P) particle concentrations. In the 50 mg every 4 weeks dose, compared to placebo, olezarsen resulted in a significant reduction in total TRL-P (51%, P<0.0001) with largest reductions in large-size (68%, P<0.0001) and medium-size (63%, P<0.0001) TRL-P. Total LDL-P concentration was not changed, but large LDL-P increased by 186% (p=0.0034), and small LDL-P decreased by 39% (p=0.0713). Total HDL-P concentration increased by 15% (P=0.0006), driven primarily by a 32% increase in small HDL subspecies (diameters <8.3 nm) (P=0.0008). CONCLUSION: Olezarsen results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDL-P. These findings suggest that apoC-III inhibition improves the overall atherogenic risk profile.

Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19). METHODS: In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage in a 1:1:1:1 ratio to receive placebo, aldafermin 0·3 mg, 1·0 mg, or 3·0 mg once daily for 24 weeks at 30 study sites in the USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed. FINDINGS: Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-to-treat population: 43 in the 0·3 mg aldafermin group, 42 in the 1·0 mg group, 43 in the 3·0 mg group, and 43 in the placebo group. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (difference 90% CI 12% [-9 to 33]; p=0·11), five (15%) of 34 patients in the 1·0 mg group (difference -5% [-24 to 13]; p=0·80), and 11 (30%) of 37 patients in the 3·0 mg group (difference 10% [-9 to 30]; p=0·12) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups. INTERPRETATION: Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials. FUNDING: NGM Biopharmaceuticals.

Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a).

Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk.

AIMS: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site. CONCLUSION: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. TRIAL REGISTRATION NUMBER: NCT03385239.

Effect of bempedoic acid plus ezetimibe fixed-dose combination vs ezetimibe or placebo on low-density lipoprotein cholesterol in patients with type 2 diabetes and hypercholesterolemia not treated with statins.

OBJECTIVE: Statins are sometimes associated with worsened glycemic control. Patients with type 2 diabetes mellitus (T2DM) may require non-statin therapies to achieve low-density lipoprotein cholesterol (LDL-C) lowering goals. This study evaluated the efficacy and safety of bempedoic acid 180 mg plus ezetimibe 10 mg fixed-dose combination (BA + EZE FDC) in patients with T2DM and hypercholesterolemia who were not receiving background statins or other lipid-lowering therapy. METHODS: Patients with T2DM and elevated LDL-C levels were enrolled into this phase 2, double-blind study (NCT03531905). Patients received placebo during a 5-week washout period where background lipid-lowering therapies (including statins) were discontinued. Eligible patients were then randomized 1:1:1 to receive either BA + EZE FDC, ezetimibe 10 mg, or placebo once daily for 12 weeks. Assessments included the percent change from baseline to week 12 in LDL-C, other lipid parameters, and high-sensitivity C-reactive protein (hsCRP); and the monitoring of safety and tolerability. RESULTS: Among 179 randomized patients, baseline characteristics following the washout period were similar across treatment groups, with mean LDL-C levels of 142.6 mg/dL and mean glycated hemoglobin of 8.0%. At week 12, BA + EZE FDC therapy lowered mean LDL-C levels by 38.8%, significantly more than ezetimibe alone (19.2%; difference, 19.5% [95% confidence interval (CI), 13.4%-25.7%]; p < 0.001) or placebo (increase of 0.9%; difference, 39.6% [95% CI, 33.4%-45.8%]; p < 0.001). BA + EZE FDC significantly reduced hsCRP levels from baseline vs ezetimibe (29.2%; p = 0.005) and vs placebo (36.7%; p < 0.001). Incidence of treatment-emergent adverse events was low in all treatment groups, with no indication of worsened glycemic control. CONCLUSION: In patients with T2DM and hypercholesterolemia who were not receiving statins or other lipid-lowering drugs, BA + EZE FDC significantly lowered LDL-C levels and was generally well tolerated.

Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS: In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS: Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION: Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.

Geographic variations in lipid-lowering therapy utilization, LDL-C levels, and proportion retrospectively meeting the ACC/AHA very high-risk criteria in a real-world population of patients with major atherosclerotic cardiovascular disease events in the United States.

OBJECTIVE: We assessed national- and state-level geographic variations among patients with a history of ≥1 major atherosclerotic cardiovascular disease (ASCVD) event in: (1) the proportion of patients with retrospectively identified 2018 American College of Cardiology/American Heart Association guideline very high-risk (VHR) ASCVD criteria; (2) utilization of guideline-directed lipid-lowering therapy (LLT); and (3) the proportion of patients with persistent low-density lipoprotein cholesterol (LDL-C) elevations despite statin and/or ezetimibe use. METHODS: A retrospective cohort study using the Prognos LDL-C database linked to IQVIA longitudinal medical and prescription claims databases. The study period was from January 01, 2011, to November 30, 2019 and the index period was from January 01, 2016, to November 30, 2019; the index date was defined as the most recent LDL-C test during the index period. The study included patients aged ≥18 years at index who had a measured LDL-C level during the index period and had ≥1 inpatient/outpatient claim for ASCVD during the 5-year pre-index period. RESULTS: Of patients with any ASCVD (N=4652,468), 1537,514 (33.1%) patients had ≥1 major ASCVD event. Among patients with ≥1 major ASCVD event, the VHR ASCVD criteria were retrospectively identified in 1139,018 (74.1%) patients; Hawaii had the highest (81.7%) and Colorado the lowest (65.0%) proportion of these patients. Nationally, 48.8% and 50.2% of patients with ≥1 major ASCVD event and retrospectively identified VHR ASCVD criteria, respectively, had current LLT use; Massachusetts and Colorado had the highest and lowest proportions, respectively. After standardizing for age and sex, 57.3% and 58.8% of patients with ≥1 major ASCVD event and retrospectively identified VHR ASCVD criteria, respectively, had LDL-C ≥70 mg/dL (≥1.8 mmol/L) despite statin and/or ezetimibe use, with substantial state-level variations observed. CONCLUSIONS: The study highlights high rates of elevated LDL-C and pervasive underuse of LLT in health-insured patients with a history of major ASCVD events treated in the United States, with state-level geographic variations observed.

Evinacumab in Patients with Refractory Hypercholesterolemia.

BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Migraine Patients With Cardiovascular Disease and Contraindications: An Analysis of Real-World Claims Data.

INTRODUCTION: Triptans, the most commonly prescribed acute treatments for migraine attacks are, per FDA labeling, contraindicated in cardiovascular (CV) disease patients and have warnings and precautions for those with CV risk factors. METHODS: Headache specialists, cardiologists, and health economics and outcomes researchers convened to identify diagnostic codes for: (1) CV diseases contraindicating triptans based on FDA labeling; (2) conditions comprising "other significant underlying CV disease"; and (3) CV risk factors included as warnings and precautions for triptans. A retrospective, cross-sectional analysis of commercially insured adult US migraine patients in the 2017 Optum® Clinformatics® Data Mart (CDM) and the 2017 IBM® Watson Health MarketScan® Commercial Claims database was used to estimate the proportion of migraine patients with CV contraindications and warnings and precautions to triptans. RESULTS: Of the 56,662 migraine patients analyzed from Optum CDM, 13.5% had ≥1 CV disease as specified in triptan labeling and an additional 8.5% had ≥1 "other CV disease" judged by the panel to constitute a "significant underlying CV disease" (total: 22.0% migraine patients). Of 176 724 migraine patients analyzed from MarketScan, 12.2% had ≥1 CV disease as specified in the labeling and an additional 8.0% had ≥1 "other significant underlying CV disease" (total: 20.2% of migraine patients). An additional 25.4% and 25.1% of migraine patients had ≥2 CV risk factors in Optum CDM and MarketScan. In total, 47.4% and 45.3% of migraine patients in both databases had a CV disease specified as a contraindication, an "other CV disease" endorsed as significant, or ≥2 CV risk factors identified as warnings and precautions to triptans. CONCLUSIONS: Analyses of more than 230,000 people with migraine showed that ≥20% of commercially insured US migraine patients have a CV condition that specifically contraindicates triptan treatment, and an additional 25% have ≥2 CV risk factors identified as warnings and precautions to triptans.

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia.

AIMS: Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis. METHODS AND RESULTS: This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild. CONCLUSION: Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.