LY3875383 / Eli Lilly - LARVOL DELTA

Effects of HA1, a probucol analogue, and APOC3 siRNA on lipoprotein and amyloid-β metabolism and neurovascular dysfunction in type 2 diabetic mice. (PubMed, Front Pharmacol) - "Dysregulated lipoprotein and Aβ metabolism are associated with neurovascular dysfunction and anxiety-like behaviour in diabetes. HA1 shows therapeutic potential by modulating Aβ metabolism and improving neurovascular and behavioural outcomes."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Diabetes • Dyslipidemia • Inflammation • Metabolic Disorders • Mood Disorders • Psychiatry • Type 2 Diabetes Mellitus • APOB • Aβ42

Apolipoprotein and inflammatory biomarker changes following marked triglyceride reduction with the GalNAc-conjugated APOC3 siRNA RBD5044 (ESC 2026) - "Profound TG reduction achieved by APOC3 siRNA therapy is associated with an apolipoprotein pattern resembling APOC3 heterozygous deficiency, as well as a coordinated anti‑inflammatory response. These findings suggest that deep APOC3 silencing remodels lipoprotein composition and may contribute to inflammation resolution by modulating apoptosis-related pathways."

Biomarker • Cardiovascular

Discovery of long-acting APOC3 siRNA for treating patients with hypertriglyceridemia. (PubMed, Nucleic Acids Res) - "APOC3 mRNA, primarily synthesized by hepatocytes, is an ideal target for GalNAc-conjugated RNA-targeted therapies such as the antisense oligonucleotide (ASO) oleszarsen and small-interference RNA (siRNA) plozasiran. Additionally, selectivity and tolerability assessments in human cells, rodents, and nonhuman primates showed excellent safety and tolerability. A comparative analysis of the lead APOC3 siRNA with a surrogate of a clinical-stage APOC3 siRNA drug suggests the potential for similar or better potency and efficacy combined with less frequent dosing, potentially reducing the treatment burden on patients with hypertriglyceridemia."

Journal • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Hypertriglyceridemia • Pancreatitis

SHASTA-5 rationale and design: Randomized, double-blind, placebo-controlled study to evaluate plozasiran efficacy and safety in sHTG at risk for AP (NLA 2025) - "Secondary endpoints include percent change in fasting TG from baseline to month-12 with plozasiran; proportion of patients who achieve fasting TG of < 880 mg/dL; achievement of fasting TG of < 500 mg/dL; time to first major abdominal pain event occurring; and change from baseline in patient-reported productivity and activity impairment (WPAI-SHP score) and health status (EQ-5D-5L score). Conclusions SHASTA-5 is designed to determine whether the quarterly-dosed APOC3 siRNA plozasiran safely reduces the rate of AP in patients with sHTG."

Clinical • Dyslipidemia • Hypertriglyceridemia • Pain • Pancreatitis • Severe Hypertriglyceridemia • LPL

A Study of LY3875383 in Healthy Participants and Participants With Hypertriglyceridemia (clinicaltrials.gov) - P1 | N=41 | Terminated | Sponsor: Eli Lilly and Company | Completed ➔ Terminated; The study was terminated due to a change in risk/benefit ratio, which no longer favoured continued development.

Trial termination • Dyslipidemia • Hypertriglyceridemia

Rationale and Design of the MUIR-3 Study: Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults with Hypertriglyceridemia (CMHC 2024) - "Key exclusion criteria include use of any hepatocyte targeted siRNA treatments that target lipids and/or TG within 1 year (except inclisiran administered at least 4 weeks prior to enrollment), siRNA or ASO within 60 days, and active pancreatitis within 4 weeks of screening. MUIR-3 is designed to determine whether the APOC3 siRNA plozasiran, as an add on to standard of care lipid lowering therapy, safely reduces TG levels thereby contributing to decreasing the residual cardiovascular disease risk in individuals with HTG."

Clinical • P3 data • Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Pancreatitis • LPL

Assessing the clinical potential of plozasiran, an APOC3 siRNA therapy for severe hypertriglyceridemia. (PubMed, Expert Opin Investig Drugs) - No abstract available

Journal • Dyslipidemia • Hypertriglyceridemia • Severe Hypertriglyceridemia

Rationale and design of the SHASTA-3 and SHASTA-4 studies: randomized, double-blind, placebo-controlled, phase 3 studies of plozasiran in patients with severe hypertriglyceridemia (ESC 2024) - "Key exclusion criteria include use of any hepatocyte targeted siRNA treatments that target lipids and/or TGs within 1 year (except inclisiran at least 4 weeks prior to enrollment), siRNA or ASO within 60 days, known FCS diagnosis, and AP within 4 weeks of screening. Adjudicated major adverse cardiovascular event rates, safety and tolerability will be assessed. SHASTA-3 and SHASTA-4 are designed to determine whether the quarterly-dosed APOC3 siRNA plozasiran, added to standard of care, safely reduces TG levels and the rate of AP in patients with sHTG."

Clinical • P3 data • Atherosclerosis • Cardiovascular • Dyslipidemia • LPL

A Study of LY3875383 in Healthy Participants and Participants With Hypertriglyceridemia (clinicaltrials.gov) - P1 | N=41 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed | N=120 ➔ 41

Enrollment change • Trial completion • Dyslipidemia • Hypertriglyceridemia

APOC3 siRNA and ASO therapy for dyslipidemia. (PubMed, Curr Opin Endocrinol Diabetes Obes) - "Inhibition of apoC3 is effective across all the spectrum of hypertriglyceridemia, might have a favorable effect on hepatic steatosis (NAFLD) and the effect of apoC3 inhibition on cardiovascular risk is not limited to its effect on plasma triglycerides. APOC3 GalNAc-conjugated ASO and siRNA are both effective in decreasing plasma apoC3 and triglyceride levels."

Journal • Addiction (Opioid and Alcohol) • Cardiovascular • Dyslipidemia • Hematological Disorders • Hepatology • Hypertriglyceridemia • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Thrombocytopenia • LPL

A Study of LY3875383 in Healthy Participants and Participants With Hypertriglyceridemia (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Dyslipidemia • Hypertriglyceridemia

A Study of LY3875383 in Healthy Participants and Participants With Hypertriglyceridemia (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Aug 2024 ➔ Jan 2024 | Trial primary completion date: Aug 2024 ➔ Jan 2024

Trial completion date • Trial primary completion date • Dyslipidemia • Hypertriglyceridemia

A Study of LY3875383 in Healthy Participants and Participants With Hypertriglyceridemia (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Dyslipidemia • Hypertriglyceridemia

A Study of LY3875383 in Healthy Participants and Participants With Hypertriglyceridemia (clinicaltrials.gov) - P1 | N=120 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial • Dyslipidemia • Hypertriglyceridemia