Figure 1: This illustrates how volanesorsen works to prevent the formation of apoC-III protein
Familial chylomicronemia syndrome (FCS) is a rare, genetic disease characterized by mutations in genes affecting the production or functionality of lipoprotein lipase (LPL), an enzyme necessary for the metabolism of triglycerides (TG). People living with FCS can present with severe hypertriglyceridemia (HTG) and an elevated risk of TG-induced pancreatitis. Apolipoprotein C-III (apoC-III), a 79 amino acid glycoprotein that is synthesized principally in the liver, is a key regulator of serum TG. It is an exchangeable apolipoprotein that is found on the surface of apoB-containing TG-rich lipoproteins, or TRLs (VLDL and chylomicrons), as well as HDL. HTG is closely associated with plasma apoC-III levels.
Mechanistically, it has been demonstrated that apoC-III modulates plasma TG levels through inhibition of LPL, as well as other LPL-independent pathways that include blunting of receptor mediated clearance of TRLs from the liver, inhibition of hepatic lipase activity and, finally, promotion of the intrahepatic assembly and secretion of TG rich VLDL particles. In the past several years, apoC-III has also been shown to be a genetically validated target for drug development. Humans with loss of function mutations in the APOC3 gene exhibit lower plasma TG and LDL-C levels, increased HDL-C levels, reduced cardiovascular disease (CVD) and increased longevity.
Given the importance of apoC-III in lipid metabolism and its pathophysiological role in CVD and other metabolic disorders, it was an obvious target for therapeutic intervention. The most advanced pharmacological inhibitor of apoC-III is volanesorsen, (formerly ISIS-APOCIII RX), a generation 2.0+, 2’-O-(2-methoxyethyl) (2’-MOE) antisense oligonucleotide (ASO). Unlike traditional small molecule therapeutic agents that interfere with or modulate the function of proteins, ASOs are single stranded, chemically modified, DNA-like drugs that bind with high affinity and selectivity to RNA targets through Watson-Crick base pairing.
Volanesorsen is an exemplar of antisense technology, demonstrating all of the optimal properties inherent in this drug class. It is highly water soluble and can be administered in saline via subcutaneous injection without special formulation. It is also unable to cross the placenta and blood brain barrier, so systemic administration affects specific targets in the periphery. Because of its design and unique chemical modifications, volanesorsen is highly specific for reducing apoC-III mRNA translation, while significantly reducing the potential for unintended off-target pharmacology. Additionally, its unique chemical modifications make the drug extremely stable in vivo, providing an extended tissue half-life that enables relatively infrequent once weekly injection. Finally, as antisense drugs are not metabolized by the CYP450 system, volanesorsen has a low likelihood of interacting with drugs metabolized through these pathways.
After systemic administration, volanesorsen is widely distributed to various organs throughout the body, including the liver, where apoC-III is synthesized. Figure 1 illustrates how the drug works to prevent the formation of apoC-III protein. Volanesorsen distributes within the liver and crosses the hepatocyte cell and nuclear membranes. In the nucleus, it selectively binds to a specific site in the 3’ untranslated region of the apoC-III mRNA, forming a sense/antisense complex. This binding event effects the recruitment of RNase H1, a ubiquitous cellular enzyme, which then degrades the targeted mRNA strand of the DNA/RNA duplex, preventing the translation of apoC-III.
Clinical Trials
After successful completion of a Phase 1 and two Phase 2 double-blind, placebo-controlled clinical trials in patients with high to very high TG levels, an exploratory study was also performed with volanesorsen in patients with FCS. Patients with FCS often have severely elevated TG levels (e.g. fasting TGs > 1,000 mg/dL), and are at significant risk for recurrent and potentially fatal pancreatitis and other serious conditions. At these high levels of TGs, the bulk of triglycerides are packaged in chylomicrons, low-density particles that may obstruct capillaries in the pancreas, leading to local ischemia and inflammatory processes that can manifest as pancreatitis. Treatment options are limited and usually consist of a severely restricted fat diet and drugs such as fibrates, which are often insufficient to reduce TG to levels necessary to avoid the risk of these complications and other related health concerns.
In an open label trial, three patients possessing LPL mass but no, or extremely low levels of LPL enzymatic activity, were administered 300 mg/wk of volanesorsen for 13 weeks via subcutaneous injection. Consistent with previous clinical observations with this drug in non-FCS HTG patients, volanesorsen produced significant, rapid and prolonged reductions in mean fasting plasma apoC-III (-81%) and TG (-69%) levels (Figure 2). During the study, all patients achieved a TG level < 500 mg/dL, a level that has been reported in the literature to significantly lower the risk of pancreatitis. In response to volanesorsen therapy, there was a decrease in fasting TG levels in chylomicrons and also in plasma apoB-48 levels, an index of the number of chylomicron particles. Postprandial TG levels were also measured in one patient after consumption of a standard liquid meal, and both plasma TG and chylomicron-TG were greatly reduced after 13 weeks of treatment. Because volanesorsen produced such robust activity in patients with FCS this suggests that: 1) it may have the potential to reduce the risk of acute pancreatitis and other complications caused by severely elevated TG levels; and 2) apoC-III is a central regulator of the metabolism of TG-rich lipoproteins.
Table 1 shows the consistent effect of 300 mg/wk of volanesorsen administered for 13 weeks in patients with high to very high TG levels from the Phase 2 program. Volanesorsen produced substantial lowering of apoC-III and TG in patients with very high TG as well as, in combination with fibrates, and, as described above, as a single agent in FCS patients. In Type 2 diabetics with high TG levels on stable doses of metformin, volanesorsen also significantly reduced apoC-III and TG levels and improved glucose control by multiple measures, including decreased HbA1c levels, improved insulin sensitivity and decreased fasting glycated albumin and fructosamine. The drug also produced equal reductions (as a reduction in percentage vs. baseline) in TG regardless of baseline TG levels. Additionally, in all of these patient populations, volanesorsen increased HDL (high density lipoproteins).
Volanesorsen was well tolerated in about 100 healthy subjects and patients in the Phase 1 and 2 studies. Adverse events seen in these studies were minimal, including infrequent injection site reactions. Finally, there were no flu-like symptoms or renal function changes, and liver enzymes remained similar to placebo treatment.
At present, volanesorsen is in two Phase 3 studies — one for FCS (the APPROACH study, NCT02211209) and a second for another ultra-orphan indication, familial partial lipodystrophy (FPL-the BROADEN study, NCT02527343), a rare genetic disorder characterized by high triglycerides, abnormal fat distribution across the body and a range of metabolic disorders, including severe insulin resistance, dyslipidemia manifested by high triglycerides and low HDL-C, hepatic steatosis and, in affected women, features of hyperandrogenism. Patients with FPL are also at risk of pancreatitis, in addition to premature heart and liver disease.
Drug Development
Volanesorsen is based on the proprietary antisense technology of Ionis Pharmaceuticals Inc. and is being developed with plans for commercialization by Akcea Therapeutics, a wholly-owned subsidiary of Ionis. Based in Cambridge, Mass., Akcea is a development and commercialization company focused on agents to treat serious cardiometabolic lipid disorders. Ionis was formerly known as Isis Pharamceuticals, which changed its name in December 2015 to avoid any confusion with the Islamic extremist group.
Read the related article "Cross-specialty Care in Management of Familial Chylomicronemia Syndrome."
Editor’s Note: Rosanne Crooke, Ph.D., is vice president of cardiovascular research at Ionis Pharmaceuticals.
August 14, 2024 
