SHASTA 2: Novel RNAi Therapeutic Plozasiran Results in Sustained Reduction In Triglycerides in Severe Hypertriglyceridemia

By Leah Kosyakovsky on

Key Points:

  • Severe hypertriglyceridemia portends high risk of both CVD and acute pancreatitis, but there are limited effective treatment options.
  • A novel RNA interference (RNAi) therapeutic plozasiran can reduce APOC3, a mediator of triglyceride elevation.
  • In the Phase 2B trial SHASTA-2, two doses of plozasiran were compared with placebo in long-term (24 and 48 week) reduction of triglycerides and other cholesterol pathway mediators.
  • All doses of plozasiran was well-tolerated and resulted in sustained reduction in triglycerides, APOC3, and remnant cholesterol with increased HDL-C by 24 weeks, with a still-significant but attenuated effect at 48 weeks.

Severe hypertriglyceridemia (SHTG) is characterized by triglyceride (TG) levels >500 mg/dL and is associated with high risk of cardiovascular events as well as pancreatitis. Unfortunately, there are limited treatment options that specifically target SHTG. In Phase 2 trials, the RNA interference (RNAi) therapeutic plozasiran (ARO-APOC3) successfully reduced APOC3, a mediatory of elevated triglycerides. In a breaking presentation at the 2024 ACC conference today, Dr. Daniel Gaudet (University de Montreal) and his team presented their study: “SHASTA 2: A Double-blind, Phase 2b Placebo-Controlled, Dose Ranging Study Of Plozasiran In Subjects With SHTG.”

The SHASTA-2 trial (NCT04720534) was a double-blind, placebo-controlled trial examining the efficacy and safety of plozasiran vs placebo in lowering TGs and the risk of acute pancreatitis. Participants were required to have a history of SHTG (TG > 500 mg/dL and fasting TG of 500-4,000 mg/dL). Key exclusion criteria were active pancreatitis within 12 weeks, ACS within 24 weeks, or any planned coronary intervention. The primary outcome was % change in TG from baseline to weeks 24 and 48. Key secondary outcomes included percent change from baseline in APOC3, nonHDL-C, LDL-C, HDL-C, APOB, and remnant cholesterol.

A total of 226 patients were 1:1:1:1 randomized to either pooled placebo or 10, 25, or 50 mg of plozasiran, respectively. Plozasiran was administered in two doses at 0 and 12 weeks. The mean age was 56, and 23% were women; the mean baseline APO3 level was 33 mg/dL and the mean baseline TG level was 679 mg/dL. Plozasiran resulted in a significant reduction in triglycerides and APOC3 at 24 and 48 weeks across all 3 doses (p<0.001 for all). Specifically, individuals receiving plozasiran experienced a 66% reduction in TGs in the 10mg group, 70% reduction in the 25mg group, and 74% reduction in the 50mg group at 24 weeks relative to a 17% reduction in the placebo arm, with attenuated but still significant reduction at 48 weeks. The majority of patients achieved TG <500mg/dL by 24 weeks (88%, 93% and 91% for increasing doses of plozasiran, respectively, relative to 54% of the placebo arm). Maximum dose plozasiran also reduced LDL-C by 78% (p<0.001), remnant cholesterol by 57% (p<0.0001), and non-HDL-C by 22% (p=0.0001) by 24 weeks, in addition to raising HDL-C by 68% (p<0.0001).  Serious adverse events occurred in 16.4% of the placebo arm and 7.8% of individuals receiving plozasiran; none were deemed to be related to the treatment itself. 

When discussing the clinical implications of the study at the ACC conference, Dr. Gaudet stated: “Plozasiran decreases mean serum APOC3, TGs, and remnant cholesterol while increasing HDL-C at 24 weeks for all dose levels…with a favorable safety profile at 48 weeks…these data support further development of plozasiran in planned phase 3 programs for the treatment of chylomicronemia and SHTG.”