.The risk of atherosclerotic cardiovascular disease and acute pancreatitis is significantly increased with SHTG; patients often experience recurrent attacks with repeat hospital admissions and worsening outcomes.
The likelihood of developing acute pancreatitis is proportional to the number, characteristics and concentration of triglyceride-rich lipoproteins (TRLs), notably chylomicrons, and increases with rising triglyceride levels.
Arrowhead Pharmaceuticals is developing a potential treatment, plozasiran, that may be able to reduce triglycerides below the risk level for pancreatitis.
The first-in-class hepatocyte-targeting RNAi therapeutic is designed to reduce the production of apolipoprotein C-III (APOC3) — a key regulator of triglyceride metabolism that inhibits the breakdown of TRLs by lipoprotein lipase — and the uptake of TRL remnants by hepatic receptors in the liver.
Blocking its action could, therefore, reduce triglyceride levels. A Phase I study was done with some healthy subjects and some with hypertriglyceridaemia.1
They were randomised to receive escalating single or repeat subcutaneous doses (on days 1 and 29) of 10, 25, 50 or 100 mg of plozasiran or a placebo. Further cohorts of both healthy participants and adults with chylomicronaemia were given repeat open-label doses.
Throughout all cohorts, 88 received the drug and 24 got the placebo. Treatment-emergent adverse events of transient mild-to-moderate liver transaminase changes occurred in 10 participants receiving the drug, but these were asymptomatic and levels returned to near normal by the end of the trial.
No thrombocytopenia or platelet declines were reported. In cohorts with SHTG, the day 113 mean decreases in APOC3 from baseline with the increasing doses were 62.0%, 81.7%, 90.1% and 94.4%, respectively, whereas the placebo gave a decrease of just 1.6%.
This correlated to median decreases in triglyceride levels of 65.6%, 69.9%, 81.2%, 81.0% and 2.8%.
In a Phase IIb placebo-controlled, double-blind, dose-ranging randomised clinical trial, 229 patients with SHTG and fasting triglyceride levels of 500–4000 mg/dL while receiving stable lipid-lowering treatment were given two subcutaneous doses of 10, 25 or 50 mg of plozasiran or a matched placebo on day 1 and at week 12.2
They were followed up through week 48. The baseline mean triglyceride level was 897 mg/dL. Plozasiran gave a significant dose-dependent placebo-adjusted least squares mean reduction in triglyceride levels of 57%, driven by placebo-adjusted reductions in APOC3 of 77% at week 24 with the highest dose.
Among those given the drug, 144 of 159 achieved a triglyceride level lower than 500 mg/dL. It was also associated with dose-dependent increases in LDL cholesterol.
Adverse event rates were similar for both the drug and the placebo, with serious adverse events being mild-to-moderate and not considered to be treatment related. Phase III trials are under way.
References
- D. Gaudet, et al., NEJM Evid. 2, EVIDoa2200325 (2023).
- D. Gaudet, et al., JAMA Cardiol. (2024): doi:10.1001/jamacardio.2024.0959.