Arrowhead's RNAi therapy effective in rare lipid disorder study

Arrowhead Pharmaceuticals has announced that their investigational RNA interference (RNAi) therapeutic, plozasiran (ARO-APOC3), has successfully met both primary and key secondary endpoints in a Phase III clinical trial involving patients with familial chylomicronaemia syndrome (FCS). FCS is an extremely rare genetic disorder characterized by exceptionally high levels of triglycerides.

The Phase III trial, named the PALISADE study, involved 75 patients who were randomly assigned to receive either 25mg or 50mg doses of plozasiran, or a matching placebo, once every three months. The trial's top-line results indicate that plozasiran achieved significant reductions in triglyceride levels compared to placebo. After ten months, patients who received the 25mg dose saw a median reduction in triglycerides of 80%, while those on the 50mg dose experienced a 78% reduction. At the one-year mark, these reductions were 78% and 73%, respectively. In contrast, the placebo group exhibited a median triglyceride reduction of 17% at ten months and only 7% at twelve months.

Beyond its primary endpoint, plozasiran also succeeded in key secondary measures. These included significant reductions in fasting triglycerides and marked decreases in apolipoprotein C-III (ApoC-III) levels, which plozasiran targets through its RNAi mechanism. Specifically, ApoC-III levels dropped by 88% at ten months and 94% at one year. Additionally, there was a statistically significant reduction in the incidence of acute pancreatitis events in patients treated with plozasiran compared to those on placebo.

Bruce Given, Arrowhead's chief medical scientist, emphasized the significance of these results, noting that they "build upon the promising results from the Phase II SHASTA-2 and MUIR studies." These earlier studies had investigated plozasiran in patients with severe hypertriglyceridaemia and mixed hyperlipidaemia. Given highlighted the potential of plozasiran as a promising therapy for various cardiometabolic disorders.

The safety and tolerability profile of plozasiran in the PALISADE trial was also favourable. Treatment-emergent adverse events were reported at similar rates between the plozasiran and placebo groups. However, severe and serious adverse events were less common in the plozasiran-treated patients. The most frequently reported side effects included abdominal pain, nasopharyngitis, headache, and nausea.

Arrowhead Pharmaceuticals plans to discuss potential regulatory filings for plozasiran in the treatment of FCS. The company also intends to continue advancing several ongoing Phase III studies to evaluate plozasiran in other patient populations.

In summary, the Phase III PALISADE study has demonstrated that plozasiran significantly reduces triglyceride levels and has a favourable safety profile in patients with FCS. These findings support the potential of plozasiran as a treatment option for individuals with this rare genetic disorder and other related cardiometabolic conditions. Arrowhead Pharmaceuticals is poised to move forward with regulatory discussions and further clinical evaluations to expand the therapeutic use of plozasiran.