Arrowhead highlights key pancreatitis data from Phase 3 lipid study to stand out from Ionis

Arrowhead Pharmaceuticals recently shared promising results from a late-stage trial of plozasiran, an RNA interference (siRNA) therapeutic aimed at treating familial chylomicronemia syndrome (FCS), a rare lipid disorder. This announcement follows prior topline data released several months ago. Arrowhead has prioritized the development of plozasiran, even sidelining another investigational drug, zodasiran, to focus on bringing plozasiran to market. The company faces competition from Ionis Pharmaceuticals, which is developing its own RNA-based treatment for lipid disorders.

The Phase 3 PALISADE trial, which involved 75 participants, revealed that less than 5% of patients treated with plozasiran experienced acute pancreatitis events over 12 months, compared to 20% in the placebo group. This translates to an 83% relative risk reduction in pancreatitis episodes, according to Gerald Watts, the principal investigator of the study. These findings were presented at the European Society of Cardiology annual meeting in London.

In contrast, Ionis' antisense oligonucleotide, olezarsen, demonstrated a 100% reduction in acute pancreatitis events in its Phase 3 BALANCE trial. Updated results from April indicated that there was one episode of acute pancreatitis in both the 80 mg and 50 mg olezarsen groups. Acute pancreatitis is a severe condition that can lead to hospitalization for FCS patients.

Watts highlighted that Arrowhead and Ionis’ trials enrolled patients with different baseline histories of pancreatitis. In Arrowhead's study, 89% of patients on the 25 mg dose and 92% on the 50 mg dose had a history of pancreatitis. Meanwhile, Ionis’ trial enrolled at least 65% of participants with a pancreatitis history.

Robert Rosenson, a PALISADE investigator and cardiometabolics director at Mount Sinai Hospital, noted that both trials showed significant reductions in acute pancreatitis, making it challenging to distinguish between the two treatments based solely on this endpoint. The primary difference that may sway physician and patient preference is the dosing frequency: plozasiran is administered quarterly, whereas olezarsen is given monthly. Rosenson emphasized that less frequent dosing could improve long-term adherence to therapy for patients with chronic conditions.

Moreover, plozasiran appears to offer a greater reduction in triglycerides compared to olezarsen. The PALISADE trial's primary endpoint was met, with 80% and 78% median reductions in triglycerides for the 25 mg and 50 mg doses, respectively, compared to a 17% reduction in the placebo group. Plozasiran also met all key secondary endpoints, including changes in APOC3 levels, which are crucial for the clearance of triglycerides. Arrowhead CEO Christopher Anzalone described the data as "best in class."

In comparison, the BALANCE trial showed that 80 mg of olezarsen achieved a 59% placebo-adjusted reduction in triglyceride levels at 12 months. FCS patients have deficient or inactive lipoprotein lipase, an enzyme essential for clearing triglycerides from the blood, leading to triglyceride levels that can be more than ten times the normal amount. Currently, these patients have no treatment options other than adhering to a stringent low-fat diet.

Arrowhead is preparing regulatory filings for plozasiran in FCS. However, TD Cowen analyst Brendan Smith suggested that peak sales estimates might need revision to account for the drug's potential in treating severe hypertriglyceridemia (SHTG), which affects approximately 3.4 million people in the U.S. Plozasiran has already hit the primary endpoint in a Phase 2b trial for SHTG and is undergoing Phase 3 trials named SHASTA-3 and SHASTA-4.

How to obtain the latest research advancements in the field of biopharmaceuticals?

In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!