Novel drug significantly cuts triglyceride levels

The investigational RNAi therapeutic plozasiran significantly reduced triglyceride levels in individuals with severe hypertriglyceridaemia (SHTG) who were at high risk for pancreatitis, according to the final results of the phase IIb SHASTA-2 trial.

“SHTG significantly increases the risk of cardiovascular disease, acute pancreatitis, and other morbidities, often with recurrent attacks requiring repeated hospital admissions and worsening outcomes,” noted study lead author Dr Daniel Gaudet from the University of Montreal, Quebec, Canada, at ACC.24.

“[In this study,] plozasiran produced significant reductions in TG levels below the threshold associated with elevated risk for pancreatitis, with a favourable safety profile,” said Gaudet.

At week 24, the average reduction in TG levels among patients on plozasiran 50 mg was more than fourfold higher than what was achieved with placebo (74 percent vs 17 percent; p<0.0001). Plozasiran 50 mg also trumped placebo at week 48 (53 percent vs 7 percent; p<0.0001). Similar trends were seen with plozasiran 25 mg at both timepoints (p<0.0001 for both). [ACC.24, LBCT II]

A similar pattern favouring plozasiran was seen in terms of mean percent change in APOC3 from baseline to week 24 across all doses (78, 72, and 69 percent [50, 25, and 10 mg, respectively] vs 1 percent [placebo]), which prevailed up to week 48 (p<0.0001 for all).

“Significant and durable dose-dependent reductions in APOC3 and TGs persisted through week 48, or 36 weeks after patients received their second dose of plozasiran,” noted Gaudet.

Week 24 also saw substantial drops in remnant cholesterol with all plozasiran doses vs placebo (mean percent change from baseline, 57, 62, and 60 percent [50, 25, and 10 mg, respectively] vs 2 percent), as well as marked increases in HDL-C (mean percent change from baseline, 68, 63, and 54 percent vs 11 percent; p<0.0001 for all).

Of note, the changes for all endpoints were evident as early as week 4, noted Gaudet. Also, the efficacy of plozasiran was sustained across all parameters even if the injections were only administered twice.

Over 90 percent of plozasiran recipients achieved TG <500 mg/dL which, according to Gaudet, was below the risk threshold for acute pancreatitis. Also, more than half of those on the two higher plozasiran doses achieved TG <150 mg/dL (normal range) at week 24.

The most common treatment-emergent adverse events (TEAEs) tied to plozasiran were COVID-19 and worsening glycaemic control. However, Gaudet pointed out that these reflect the comorbidities and underlying conditions of the participants. Serious TEAEs were deemed unrelated to the study drug, and all resolved without sequelae (apart from two patients with malignancies), he added.

A promising treatment alternative

Treatment alternatives to reduce TG levels below the risk threshold for pancreatitis are limited, noted Gaudet. “Therefore, new therapies are welcome for SHTG patients. SHTG therapy goal is to sustainably reduce TGs below pancreatitis risk.”

The team set out to ascertain the efficacy and safety of plozasiran for lowering TG and atherogenic lipoproteins and the severity/occurrence of acute pancreatitis in SHTG patients, as well as to explore optimal dosing. They randomized 226 participants (mean age 55 years, 78 percent men) 1:1:1:1 to plozasiran 10, 25, or 50 mg, or placebo at baseline and at week 12.

Taken together, the findings underpin the potential of RNAi-mediated silencing of hepatic APOC3 expression via plozasiran as a promising treatment option for SHTG, Gaudet said.

“From the patients’ standpoint, the possibility that in the near future there could be an agent that safely and effectively lowers severely elevated TG levels and reduces or eliminates the risk of developing pancreatitis is extraordinary,” noted Gaudet in a press release.

Despite the small study population, short study duration, and lack of diversity among enrolees, the results support further development of plozasiran in the planned phase III programmes for the treatment of SHTG and chylomicronaemia (ie, very severe HTG [TG >880 mg/dL]). The planned phase III trial aims to include more women and more individuals from racial and ethnic minorities. “We want to know how sustained the effect of plozasiran is in a larger, more diverse cohort,” Gaudet said.