<p>Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy</p>

Abstract

Severe hypertriglyceridaemia is associated with pancreatitis and chronic pancreatitis-induced diabetes. Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder of lipid metabolism characterised by high levels of triglycerides (TGs) due to failure of chylomicron clearance. It causes repeated episodes of severe abdominal pain, fatigue and attacks of acute pancreatitis. There are few current options for its long-term management. The only universal long-term therapy is restriction of total dietary fat intake to <10-15% of daily calories (15 to 20g per day). Many patients have been treated with fibrates and statins with a variable response, but many remain susceptible to pancreatitis. Other genetic syndromes associated with hypertriglyceridaemia include familial partial lipodystrophy (FPLD). Targeting apolipoprotein C3 (apoC3) offers the ability to increase clearance of chylomicrons and other triglyceride-rich lipoproteins. Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70–80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD. It is now undergoing licensing and payer reviews. Further developments of antisense technology including small interfering RNA therapy to apoC3 as well as other approaches to modulating triglycerides are in development for this rare disorder.

Prevalence of severe hypertriglyceridemia and pancreatitis in familial partial lipodystrophy type 2

“…1 The most common 6 subtype, i.e. Dunnigan-type or FPLD2 (OMIM 151660), is 7 caused by autosomal dominant pathogenic rare variants in 8 the LMNA gene encoding lamin A/C. 2 The FPLD2 clini-9 cal phenotype develops around puberty, with noticeable loss 10 of subcutaneous fat in the extremities, trunk and gluteal re-11 gion and a potential accumulation of fat in the face, neck, 12 back, abdomen and labia majora.…”

Insight Into the Prospects for RNAi Therapy of Cancer

“…Since the first RNAi drug was launched, some RNAi drugs (such as HBV-ISS, mipomersen sodium, nusinesen, inotersen, volanesorsen, patisiran/onpattro, pegaptanib sodium, and viltolarsen) have been used in clinical treatment and have shown unparalleled advantages over other types of drugs ( Moshfeghi and Puliafito, 2005 ; Crooke et al, 2018 ; Hoy, 2018 ; Keam, 2018 ; Mathew and Wang, 2019 ; Parham and Goldberg, 2019 ; Weng et al, 2019 ; Dhillon, 2020 ; Esan and Wierzbicki, 2020 ). Among these, nusinesen will be used as an example to illustrate theefficacy of RNAi drugs in clinical applications.…”

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

“…By degrading transthyretin mRNA via RNase-H degradation, it prevents the formation of deposits of transthyretin amyloid protein in the peripheral nervous system that would be toxic for the body. Volanesorsen, a PS/2′-MOE/m 5 C gapmer targeting apoC3 mRNA for treatment of Familial chylomicronaemia syndrome (FCS) (i.e., patients with high levels of blood triglycerides), was approved by the European regulatory authority (EMA) [ 89 ].…”