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RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

ABSTRACT: Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean T_max of 6.0-10.5 h and clearance from plasma within 24-48 h after dosing with a mean t_½ of 3.9-6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85 days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.

SUBMITTER: Watts GF

PROVIDER: S-EPMC10504078 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

Watts Gerald F GF Schwabe Christian C Scott Russell R Gladding Patrick A PA Sullivan David D Baker John J Clifton Peter P Hamilton James J Given Bruce B Melquist Stacey S Zhou Rong R Chang Ting T San Martin Javier J Gaudet Daniel D Goldberg Ira J IJ Knowles Joshua W JW Hegele Robert A RA Ballantyne Christie M CM

Nature medicine 20230825 9

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic ...[more]

PMID: 37626170

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Project description:ImportancePopulation mean levels of total cholesterol and fasting triglycerides have decreased substantially in the US in recent decades, but improvements in cardiometabolic health may have slowed among younger cohorts. Conversely, prevalence of diabetes (types 1 and 2) and obesity has increased, especially among adults younger than 65 years. It is unclear how trends in cholesterol, triglyceride, and glucose levels have changed across different birth cohorts and whether adverse trends in obesity are associated with these patterns.ObjectiveTo quantify national trends in total cholesterol, fasting triglyceride, and fasting glucose levels among cohorts born between 1920 and 1999 and examine the potential association of these patterns with body mass index (BMI).Design, setting, and participantsThis serial cross-sectional study used National Health and Nutrition Examination Survey (NHANES) data from the 1999-2000 to 2017-2020 cycles. Data were analyzed between November 1, 2023, and July 31, 2024. Participants included nonpregnant and noninstitutionalized US adults 18 years or older, born between 1920 and 1999, who had data collected from 1999 to 2020.ExposureEight 10-year birth cohorts (from 1920 to 1999).Main outcomes and measuresTotal cholesterol, fasting triglyceride, and fasting glucose levels and BMI. Quantile regression models reported average marginal effects to quantify mean change in cardiometabolic outcome measures per decade of birth years. Parametric regression models estimated the association of birth cohort with outcomes, assessing BMI as the mediator.ResultsOf 52 006 participants weighted to represent 264 664 915 US adults, weighted median age was 46 (IQR, 33-60) years and 50.6% were women. For the 50th percentile of measures, mean difference per 1-decade younger birth cohort was -7.1 (95% CI, -8.2 to -6.1) mg/dL for total cholesterol level, -13.1 (95% CI, -15.1 to -11.1) mg/dL for fasting triglyceride level, and 2.7 (95% CI, 2.3-3.1) mg/dL for fasting glucose level. BMI appeared to attenuate the associations between birth cohort and lipid levels and enhanced the associations between birth cohort and fasting glucose levels. However, up to 80% of the associations between birth cohorts and cardiometabolic outcomes were not mediated through BMI.Conclusions and relevanceIn this cross-sectional study of 52 006 participants representing 264 664 915 US adults, population-level improvements in total cholesterol and triglyceride levels decelerated and adverse trends in glucose levels accelerated in more recent birth cohorts, which was partially mediated by concurrent increases in BMI. Public health initiatives that target antecedent health behaviors are needed to improve cardiometabolic health across generations.

Project description:PurposeAT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.MethodsThis phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks.ResultsThe most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.ConclusionsAlthough both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.Trial registrationEudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.

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RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

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RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

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