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The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies. Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks. Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (−10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%–55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (−17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%–38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 109/L. This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure. [Display omitted] • Volanesorsen is approved in Europe to treat familial chylomicronaemia syndrome. • Long-term triglyceride reduction (up to 51 months) is maintained with volanesorsen. • No new safety signals were associated with increased exposure to volanesorsen. • Volanesorsen is an effective treatment option for familial chylomicronaemia syndrome. [ABSTRACT FROM AUTHOR]

Carriers of the E40K loss-of-function variant in Angiopoietin-like 4 (ANGPTL4), have lower plasma triglyceride levels as well as lower rates of coronary artery disease (CAD) and type 2 diabetes (T2D). These genetic data suggest ANGPTL4 inhibition as a potential therapeutic target for cardiometabolic diseases. However, it is unknown whether the association between E40K and human diseases is due to linkage disequilibrium confounding. The broader impact of genetic ANGPTL4 inhibition is also unknown, raising uncertainties about the safety and validity of this target. To assess the impact of ANGPLT4 inhibition, we evaluated whether E40K and other loss-of-function variants in ANGPTL4 influenced a wide range of health markers and diseases using 29 publicly available genome-wide association meta-analyses of cardiometabolic traits and diseases, as well as 1589 diseases assessed in electronic health records within FinnGen (n = 309,154). To determine whether these relationships were likely causal, and not driven by other correlated variants, we used the Bayesian fine mapping algorithm CoPheScan. The CoPheScan posterior probability of E40K being the causal variant for triglyceride levels was 99.99 %, validating the E40K to proxy lifelong lower activity of ANGPTL4. The E40K variant was associated with lower risk of CAD (odds ratio [OR] = 0.84, 95 % CI = 0.81 to 0.87, p= 3.6e-21) and T2D (OR = 0.91, 95 % CI = 0.87 to 0.95, p= 2.8e-05) in GWAS meta-analyses, with results replicated in FinnGen. These significant results were also replicated using other rare loss-of-function variants identified through whole exome sequencing in 488,278 participants of the UK Biobank. Using a Mendelian randomization study design, the E40K variant effect on cardiometabolic diseases was concordant with lipoprotein lipase enhancement (r = 0.82), but not hepatic lipase enhancement (r = −0.10), suggesting that ANGPTL4 effects on cardiometabolic diseases are potentially mainly mediated through lipoprotein lipase. After correction for multiple testing, the E40K variant did not significantly increase the risk of any of the 1589 diseases tested in FinnGen. ANGPTL4 inhibition may represent a potentially safe and effective target for cardiometabolic diseases prevention or treatment. [Display omitted] • E40K is the most common loss-of-function variant of ANGPTL4 protein. • The E40K variant was associated with lower risk of coronary artery disease, type 2 diabetes, and aortic stenosis. • Other rarer loss-of-function mutations in ANGPT4 were also associated with the incidence of these diseases. • The E40K variant did not significantly increase the risk of all 1589 diseases tested. • ANGPTL4 inhibition could represent a safe and effective strategy to treat or prevent cardiometabolic diseases. [ABSTRACT FROM AUTHOR]