ACC: Arrowhead on target in lipid disorder as it shoots into phase 3 behind Ionis

Arrowhead Pharmaceuticals has hit the target in severe hypertriglyceridemia (SHTG), linking its RNAi drug candidate to improved outcomes through Week 48 to stay on Ionis Pharmaceuticals’ tail in the race to market. 

Investigators randomized 229 participants who had mean fasting triglycerides of at least 500 mg/dL at screening to receive one of three doses of plozasiran or placebo in the phase 2 trial. The triglyceride threshold for participation is the level associated with increased risk of acute pancreatitis, which is one of two key complications of SHTG. The other key complication is cardiovascular disease.

Arrowhead shared a look at 24-week data from the clinical trial late last year, revealing that triglycerides and other markers of SHTG fell in patients who received plozasiran. The updated data set, presented at the American College of Cardiology expo in Atlanta, shows how the patients fared over the next 24 weeks.

Participants received the second and final dose of plozasiran at Week 12, and, as such, the 48-week data show how durability holds up in the absence of treatment. APOC3, which is silenced by plozasiran, and triglycerides increased over the second half of the study but remained down on the placebo cohort. 

At the 25-mg dose that Arrowhead is taking into phase 3, investigators tracked a 58% drop in triglycerides at Week 48. That drop is down on the 70% reduction seen at Week 24 but still better than the 7% dip in the placebo group. Similar trends played out across other endpoints, with the effect of plozasiran fading in the absence of a third dose but still beating the placebo arm.

Worsening glycemic control was the most common adverse event in the 25-mg cohort, affecting 16% of participants. Almost 12% of people in the placebo group experienced worsening glycemic control. Serious treatment-emergent adverse events were more common in the placebo group than in the plozasiran arm.

Arrowhead began preparing to run phase 3 trials in SHTG after an earlier look at the data. The biotech tweaked its plans earlier this year when Bruce Given, M.D., Arrowhead’s interim chief medical scientist, told investors about changes intended to “accelerate enrollment and enable regulatory filings in the U.S. and other key markets as quickly as possible” and “maximize the probability to show an effect on severe abdominal pain and acute pancreatitis.”

Given called acute pancreatitis “a significant differentiator from other triglyceride-lowering therapies,” adding that data on the outcome could help Arrowhead in value and access discussions with payers. The FDA has approved fibrates and fatty acids such as icosapent ethyl in SHTG, but Arrowhead could also face competition from another new entrant to the market, Ionis.

Ionis started three phase 3 SHTG clinical trials of its antisense candidate olezarsen in 2021 and 2022. That puts Ionis ahead of Arrowhead, which plans to start dosing in a pair of phase 3 trials in the coming months, but safety and efficacy data could nullify the impact of that head start. 

The pair are also going toe to toe in familial chylomicronemia syndrome (FCS), a severe form of SHTG caused by pathogenic variants in the lipoprotein lipase pathway. Ionis has published phase 3 data in FCS, and Arrowhead’s pivotal program is underway.