Funding Yes — Chiesi Farmaceutici SpA Background/Synopsis The Lomitapide Observational Worldwide Evaluation Registry (LOWER) is a global multicenter, prospective, observational registry investigating long-term safety and effectiveness of lomitapide in clinical practice. Objective/Purpose To report ten-year safety and efficacy data from the LOWER registry of lomitapide use in patients with homozygous familial hypercholesterolemia. Methods Data have been collected over 10 years since enrollment of the first patient in March 2014. We summarize participant characteristics and clinical data collected until February 29, 2024. Results A total of 234 patients (57.7% female) have enrolled in LOWER. The mean age and baseline LDL-C were 51.1 ± 15.19 years and 243.1 ± 110.7 mg/dL, respectively. Lomitapide doses ranged from 2.5–50 mg/day, with a global mean dose of 12.1 mg/day. Duration of lomitapide exposure ranged from 9 days to ≥10 years (mean 42.06 months). The most common events of special interest (ESI) were gastrointestinal and hepatic; 19.3% of patients experienced at least 1 hepatic ESI. Asymptomatic aminotransferase levels ≥3–<5x and ≥5x, the upper limit of normal, were observed in 10.7% and 8.6% of patients, respectively, and were manageable by dose reduction. One hundred fifty-seven patients (67.4%) experienced a reduction in LDL-C by ≥50% from baseline at any timepoint, with 168 (72.1%), 113 (48.5%) and 84 (36.1%) reaching LDL-C <100 mg/dL, <70 mg/dL and <55 mg/dL, respectively. Conclusions Ten-year LOWER registry data support the long-term lipid-lowering effect and safety of lomitapide. Around half of patients achieved LDL-C <70 mg/dL and over one-third reached LDL-C <55 mg/dL at least once.

BACKGROUND:Enlicitide decanoate, an oral proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, was shown to reduce low-density lipoprotein (LDL) cholesterol levels in a phase 2 trial; longer-term data are needed. METHODS:In this multinational, double-blind, randomized, placebo-controlled trial, we enrolled adults with a history of a major atherosclerotic cardiovascular disease event with an LDL cholesterol level of 55 mg per deciliter or higher and those who were at risk for a first atherosclerotic cardiovascular disease event with an LDL cholesterol level of 70 mg per deciliter or higher. Participants were assigned in a 2:1 ratio to receive enlicitide at a dose of 20 mg or placebo daily for 52 weeks. The primary end point was the mean percent change in LDL cholesterol level from baseline to week 24. Key secondary end points were the mean percent change in LDL cholesterol level at week 52 and the mean percent change in levels of non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B and the percent change in lipoprotein(a) level at week 24. RESULTS:Of the 2909 participants in the intention-to-treat population, 1935 received enlicitide and 969 received placebo (5 did not receive enlicitide or placebo). The mean age of the participants was 63 years, and 39.3% were women. The mean (±SD) LDL cholesterol level at baseline was 96.1±38.9 mg per deciliter. The mean percent change in LDL cholesterol levels at week 24 was -57.1% (95% confidence interval [CI], -61.8 to -52.5) with enlicitide and 3.0% (95% CI, 0.9 to 5.1) with placebo, representing an adjusted between-group difference of -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001). The mean percent change in LDL cholesterol level at week 52, the mean percent changes in non-HDL cholesterol and apolipoprotein B levels at week 24, and the percent change in lipoprotein(a) levels at week 24 were significantly greater with enlicitide than with placebo (P<0.001 for all comparisons). The incidence of adverse events did not appear to differ between the groups. CONCLUSIONS:Among participants who had a history of or were at risk for a first atherosclerotic cardiovascular disease event, treatment with the oral PCSK9 inhibitor enlicitide resulted in significantly lower LDL cholesterol levels than placebo at 24 weeks. (Funded by MSD [Rahway, NJ]; CORALreef Lipids ClinicalTrials.gov number, NCT05952856.).

Funding Yes — Chiesi Farmaceutici SpA Background/Synopsis The Lomitapide Observational Worldwide Evaluation Registry (LOWER) is a global multicenter, prospective, observational registry investigating long-term safety and effectiveness of lomitapide in clinical practice. Objective/Purpose To report outcomes of ≥9 years of lomitapide treatment in seven patients with homozygous familial hypercholesterolemia (HoFH) from LOWER. Methods LOWER (initiated 2014) is a global multicenter, prospective, observational registry designed to investigate the real-world effectiveness and safety of lomitapide in patients with HoFH. Results Seven patients (5 male, 2 female; 4 genetically confirmed) in LOWER received lomitapide for ≥9 years (median dose: 20 [10–40] mg/day). At baseline, the median age was 42 (33–70) years, body mass index (BMI) 27.2 (19.9–40.3) kg/m², and LDL-C 308 (118–479) mg/dL. All were receiving lipid-lowering therapies (4 with evolocumab) and five patients had cardiac disorders. At month 114, the median low-density lipoprotein cholesterol (LDL-C) was 80 (13–172) mg/dL, corresponding to a median reduction from baseline of 64% (44–96%). The median nadir LDL-C was 61 (13–94) mg/dL. All patients achieved LDL-C <100 mg/dL and 71.4% (n = 5) achieved <70 mg/dL at some point during treatment. Six patients experienced treatment-related adverse events (all mild-to-moderate); five had gastrointestinal adverse events (AEs). Treatment was discontinued in 1 patient due to alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥3×upper limit of normal (ULN). Conclusions Outcomes for these seven patients support substantial and sustained LDL-C reduction with lomitapide, with nadir decreases from baseline ranging from 67.8% to 95.8%, over a treatment period of up to 10 years. Treatment was generally well tolerated and consistent with the known safety profile for lomitapide.

Funding Yes — Merck Sharp & Dohme LLC Background/Synopsis Elevated low-density lipoprotein cholesterol (LDL-C) remains a key driver of cardiovascular (CV) events. Enlicitide decanoate is an oral macrocyclic peptide proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor demonstrating robust LDL-C reductions in the Phase 3 CORALreef Lipids and CORALreef heterozygous familial hypercholesterolemia (HeFH) studies. Objective/Purpose To present a pooled analysis of efficacy and safety of enlicitide from CORALreef Lipids and CORALreef HeFH over 1 year of treatment. Methods Pooled analysis integrating participant-level data from 2 multicenter trials (2:1 enlicitide 20 mg vs placebo; 52-week treatment period). Three thousand two hundred twelve total participants. Primary efficacy endpoint: % change from baseline in LDL-C at Week 24. Results Placebo-adjusted mean % change in LDL-C at Week 24 was −59.7% (95% CI −62.0,−57.3), sustained at Week 52 (−53.1%). Robust reductions were also seen in non-HDL-C (−53.3%), ApoB (−50.3%), and Lp(a) (−27.9%). Subgroup analyses showed similar efficacy across age, gender, race/ethnicity, and background therapy. AEs and serious AEs were similar between enlicitide and placebo. Mean adherence was >97%. Conclusions Enlicitide demonstrated LDL-C lowering efficacy similar to injectable PCSK9 inhibitor's with placebo-like safety. As an oral therapy, enlicitide may increase PCSK9 inhibitors utilization and help more patients achieve LDL-C goals.

Background/Synopsis Homozygous familial hypercholesterolemia (HoFH), an ultra-rare inherited condition, affects the low-density lipoprotein (LDL) receptor pathway - and is associated with very high levels of LDL-cholesterol (LDL-C). HoFH leads to early-onset atherosclerotic cardiovascular disease and a reduced life expectancy. Lomitapide is an oral selective inhibitor of microsomal triglyceride transfer protein approved as an adjunctive therapy for HoFH. The Lomitapide Observational Worldwide Evaluation Registry (LOWER) is a global, long-term, prospective, observational registry established to monitor the real-world effectiveness and safety of lomitapide. Objective/Purpose To evaluate the long-term effectiveness and safety of lomitapide in patients with HoFH. Methods LOWER is a registry study of the long-term safety and effectiveness of lomitapide in clinical practice across sites in the US, Europe, Canada, Argentina, and Taiwan. Enrolment began in March 2014 and data collection will continue for 10 years from enrolment of the 300th patient. Results As of February 2023, 226 patients (43.4% male) were enrolled in LOWER, with a mean ±SD [range] age of 51.4 ±15.1 [18–83] years and baseline LDL-C level of 237.1 ±105.4 [71–632] mg/dL. Post-lomitapide data were available for 223 patients (98.7%); mean lomitapide [range] exposure was 38.5 [0.3–118.1] months, with 78.9% receiving lomitapide for ≥12 months and 25.6% for 5–<10 years. Lomitapide doses ranged from 2.5–50 mg/day and the global mean dose was 13.0 mg/day (17.4 mg/day in patients treated in Europe). Figure shows LDL-C reductions from baseline in the full analysis set and in patients who remained on treatment; 68.6% of patients enrolled in LOWER experienced a reduction in LDL-C by ≥50% from baseline. At any time after lomitapide initiation, 73.1% (n=163) patients achieved an LDL-C level <100 mg/dL and 47.1% (n=105) achieved <70 mg/dL. The most common events of special interest (ESI) were gastrointestinal and hepatic in nature. During nine years follow-up, hepatic steatosis was reported in 6.3% of patients (n=14). Asymptomatic elevated aminotransferase levels ≥3–<5x and ≥5x the upper limit of normal were observed in 15.0% and 6.5% of patients, respectively. Conclusions Data from the LOWER registry support the sustained lipid-lowering effect and safety of lomitapide, with ∼50% patients achieving LDL-C <70 mg/dL at some point during follow-up. ESIs in this large cohort were consistent with the known safety profile of lomitapide.

BACKGROUND:Patients with severe hypertriglyceridemia have an increased risk of acute pancreatitis. The efficacy and safety of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III messenger RNA, have not been established in this population. METHODS:We conducted two double-blind, randomized, placebo-controlled trials (CORE-TIMI 72a and CORE2-TIMI 72b). Patients with severe hypertriglyceridemia were assigned in a 1:1:1 ratio to receive olezarsen at a dose of 50 mg, olezarsen at a dose of 80 mg, or placebo monthly for 12 months. The primary outcome was the percent change in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group (placebo-adjusted change). Secondary lipid outcomes included the percent change in the triglyceride level at 12 months and in apolipoprotein C-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at 6 months and 12 months. Acute pancreatitis events were assessed across both trials. RESULTS:A total of 1061 patients were included in the primary analysis (617 in the CORE-TIMI 72a trial and 444 in the CORE2-TIMI 72b trial). At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was -49.2 percentage points in the olezarsen 50-mg group and -54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (P<0.001 for all comparisons of olezarsen with placebo). Decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons). The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001). The incidence of any adverse events appeared to be similar across trial groups. Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000 per microliter) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted. CONCLUSIONS:Among patients with severe hypertriglyceridemia, treatment with olezarsen led to a significantly greater reduction in the triglyceride level at 6 months and in the incidence of acute pancreatitis than placebo. (Funded by Ionis Pharmaceuticals; CORE-TIMI 72a and CORE2-TIMI 72b ClinicalTrials.gov numbers, NCT05079919 and NCT05552326.).

IntroductionGenetic variation in genes coding for enzymes metabolising antihypertensive drugs, may affect the efficacy of angiotensin converting enzyme (ACE) inhibitors such as enalapril, potentially leading to resistant hypertension (RHTN). We set out to evaluate the contribution of genetic variation in CES1 and NOS3 genes on susceptibility to RHTN, as well as estimate the frequencies of CES1 copy number variation (CNV) in African and Mixed Ancestry (MA) populations of South Africa.MethodsUsing a retrospective age, sex and ethnicity matched case-control study design, 379 participants with hypertension belonging to the African and MA ethnic groups were recruited. Cases were participants with RHTN (i.e., blood pressure (BP) ≥140/90 mmHg on ≥3 antihypertensive drugs or BP < 140/90 mmHg on >3 antihypertensive drugs, including a diuretic). Cases were matched to controls with similar characteristics (age (±5 years), sex and ethnicity) in a 1:1 ratio. Controls were participants with hypertension that was under control (BP < 140/90 mmHg on ≤3 antihypertensive drugs). Five polymorphisms in CES1 and NOS3 were characterized using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), quantitative PCR and validated using Sanger sequencing. The additive model of inheritance and multivariable logistic regression were used to determine associations between genotypes and RHTN while adjusting for potential confounding variables.Results and discussionNOS3 rs3918188A/A (aOR: 0.13; CI: 0.04–0.41; P = 0.0009) genotype and NOS3 rs2070744–rs1798883–rs3918188G–T–A haplotype (OR: 0.54; CI: 0.37–0.78; P = 0.001) appeared to confer protection against RHTN among MA participants only. CES1 rs2244613C>A and CES1 CNV were not significantly associated with RHTN. However, there appeared to be quantitative differences in CES1 CNV profiles across ethnic groups. We speculate that NOS3 rs3918188A allele may affect NOS3 gene expression, potentially leading to increased amounts of the vasodilator, nitric oxide (NO) and favourable outcomes in individuals taking antihypertensives drugs such as enalapril.ConclusionNOS3 genetic variation seems important in the susceptibility to RHTN among Africans and requires further studies.

Homozygous familial hypercholesterolaemia (HoFH) is characterized by marked elevation of low-density lipoprotein cholesterol (LDLC) and premature atherosclerotic cardiovascular disease. This is a review of novel pharmacological therapies to lower LDLC in patients with HoFH. Novel therapies can be broadly divided by whether their efficacy is dependent or independent of residual low-density lipoprotein receptor (LDLR) function. Novel LDLR dependent therapies that reduce proprotein subtilisin kexin type 9 levels include monoclonal antibodies (alirocumab and evolocumab) and a small inhibitory RNA (inclisiran). LDLC reductions are highly variable and depend on residual LDLR function. Microsomal triglyceride inhibitors (lomitapide) and therapies that reduce angiopoietin like factor 3 (evinacumab and zodasiran) both reduce LDLC by approximately 50