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Developing medicines that mimic resistance mutations
Cell based therapies in atherosclerosis
NOVEL ANTI-ATHEROSCLEROTIC MRNA-BASED THERAPY
Abstract
Background and Aims
The development of anti-atherosclerotic treatments is hindered by the inability to target therapeutics to atherosclerotic plaques and selectively inhibit plaque forming cells while shielding the vascular protective endothelium.
Methods
To overcome these challenges, we designed a nano-therapy using cell-penetrating peptides and a self-replicating (SR) miRNA switch, which self-assembles into compacted, endonuclease resistant nanoparticles (A).
Results
Systemic administration of nanoparticles containing near infrared fluorescent protein (niRFP) mRNA to ApoE-/- or wire injury mouse models showed it specifically targeted atherosclerotic plaques (B) and endothelial denuded regions (C), respectively, and not the liver, spleen, or kidneys. Moreover, en-face confocal imaging of longitudinally dissected human coronary arteries (from de-identified organ donors, LifeLink foundation) treated with niRFP mRNA nanoparticles for 48 hr showed clear niRFP expression in regions of disrupted endothelium (D). Repeated administration of nanoparticles containing a miRNA switch encoding the cell cycle inhibitor p27 and one complementary sequence of the endothelial cell-specific miR-126 at its 5’UTR drastically reduced neointima formation after wire injury and allowed for vessel reendothelialization (E). HEK293 cells transfected with SR-GFP containingthree tandem copies of miR-126 complementary sequence (SR-GFP-126TS) dramatically inhibited GFP expression in the presence of miR-126 mimics, whereas miR-143 mimics showed no difference in GFP expression which lasted more than 3 months (F & G).
Conclusions
Conclusions: The innovative combination of SR miRNA-switches with self-assembled cell penetrating peptides creates a nano-therapy which targets atherosclerotic plaques and plaque forming cells while protecting the endothelium and has the potential to significantly advance the fight against atherosclerotic cardiovascular disease.
ETESIAN: A PHASE 2B STUDY OF THE EFFICACY, SAFETY AND TOLERABILITY OF AZD8233, A PCSK9-TARGETED ANTISENSE OLIGONUCLEOTIDE, IN PATIENTS WITH DYSLIPIDEMIA
Abstract
Background and Aims
AZD8233 is an effective and well-tolerated antisense oligonucleotide that was shown to reduce PCSK9 and LDL-C in patients with dyslipidemia. Here, we assessed the effect of AZD8233 on LDL-C (direct) vs. placebo after 12 weeks of treatment.
Methods
ETESIAN was a phase 2b, randomized, double-blind, placebo-controlled dose-ranging study in patients with dyslipidemia. Participants aged 18–75 years on statins, with LDL-C ≥70 and <190 mg/dL, fasting triglycerides <400 mg/dL were randomized 1:1:1:1 to subcutaneous injections (days 1, 8, 29, and 57) of AZD8233 90 mg, 50 mg, 15 mg; or placebo, and were followed for up to 16 weeks post-last dose. Secondary objectives included effects of AZD8233 on PCSK9 levels and other lipid parameters vs. placebo, pharmacokinetics and immunogenicity. Safety and tolerability were also assessed.
Results
119 patients were enrolled. AZD8233 reduced LDL-C and PCSK9 in a dose-dependent manner. The percent change from baseline to Week 12 in LDL-C at the 50 mg and 90 mg monthly dose was -72% (95% CI: -78, -65) and -79% (-83, -74), respectively. The percent change from baseline to Week 12 in PCSK9 at the 50 mg and 90 mg monthly dose was -88% (95% CI: -91, -84) and -93% (95% CI: -95, -91), respectively. Significant reductions were also observed in ApoB and non-HDL-C levels. AZD8233 was well tolerated.
Conclusions
In patients with dyslipidemia on statins, AZD8233 reduced LDL-C and PCSK9 levels in a significant and dose-dependent manner.
LOMITAPIDE IN THE LONG-TERM REAL-WORLD MANAGEMENT OF HOFH – EFFECTIVENESS, TOLERABILITY, AND HEPATIC SAFETY DATA FROM THE PAN-EUROPEAN STUDY
Abstract
Background and Aims
Homozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein-cholesterol (LDL-C) and extreme cardiovascular risk. Lomitapide is an adjunctive lipid-lowering agent for HoFH. This study evaluated real-world long-term effectiveness and safety of lomitapide in HoFH.
Methods
This long-term retrospective, observational cohort study conducted by the Italian and European Working Group on Lomitapide in HoFH collected clinical data from HoFH patients treated with lomitapide. LDL-C, adverse events (AEs), major adverse cardiovascular events (MACE) and liver imaging were evaluated.
Results
Of the 75 HoFH patients assessed, 60% had previous MACE. At 108 months, median LDL-C decreased by 60% from 280.5 mg/dL to 121.6 mg/dL. 14 patients (36.8%) discontinued apheresis, 32.0% achieved LDL-C ≤100mg/dL and 18.7% ≤70mg/dL. Incident MACE decreased from 28.8% within 2 years before lomitapide treatment, to 5.3% up to 2 years after treatment. AEs were mostly gastrointestinal – 6 patients stopped lomitapide due to AEs. After up to 9 years hepatic safety follow-up (n=45), there was a significant increase in the proportion of HoFH patients with moderate liver steatosis (5.3% to 17.3%, P=0.05). None developed severe liver fat accumulation. Hepatic stiffness remained normal between baseline and last follow-up (n=24; 3.4±2.3 Kpa vs 4.6±1.3 KPa). Mean change in FIB-4 score (n=25) was small at 0.11±0.62 during maximum 110.4 months.
Conclusions
Lomitapide is an effective long-term treatment for reducing LDL-C in HoFH. Hepatic fat increases were modest and hepatic stiffness remained normal. Additional data are needed to determine the impact of LDL-C reduction with lomitapide on major adverse cardiovascular events in HoFH.