Patients with severe hypertriglyceridemia (SHTG) are at increased risk of acute pancreatitis (AP). Current treatments have failed to reduce triglycerides (TG) below the threshold for the risk of AP. Plozasiran (ARO-APOC3) is a small interfering ribonucleic acid (siRNA) that targets hepatocytes and lowers circulating TG by interfering with the production of APOC3, a key regulator of TG metabolism.
On April 7, local time, at the 73rd American College of Cardiology Annual Meeting (ACC.24) "Late-Breaking Clinical Trials" session, Dr. Daniel Gaudet from the University of Montreal, Canada, announced the final results of the SHASTA-2 study, suggesting that ARO-APOC3 injection can significantly and durably reduce the TG level of SHTG patients with good safety.
About Plozasiran
Apolipoprotein C3 (APOC3) inhibits triglyceride-rich lipoprotein (TRL) catabolism and hepatic clearance, leading to an increase in TG. RNA interference (RNAi) is a natural process that uses short fragments of RNA molecules to interfere with the translation of mRNA into related proteins. The Plozasiran RNAi mode targets APOC3 and promotes TRL catabolism and hepatic clearance by silencing APOC3, thereby reducing TG (Figure 1).
Fig.1 Mechanism of action of Plozasiran
Study design
SHASTA-2 is a randomized, placebo-controlled, Phase 2b study to evaluate the efficacy and safety of plozasiran in the treatment of SHTG. Patients with a history of SHTG, TG > 500 mg/dL, and fasting TG of 500~4000 mg/dL during screening were included. Eligible patients (n=229) were randomized in a 3:1 ratio to receive 2 doses of Plozasiran (10 mg, 25 mg, or 50 mg) or matching placebo at day 1 and week 12, respectively, and followed up to 48 weeks (Figure 2).
Figure 2 Study design
The primary endpoint is the percentage change from baseline in fasting TG at 24 weeks. Secondary endpoints included percent change from baseline in APOC3 at 24 weeks and every 4 weeks up to 48 weeks, and percent change in fasting TG levels every 4 weeks up to 48 weeks.
Findings:
A total of 229 patients from eight countries were included, with a mean age of 55 years, 78% male and 90% Caucasian. The mean TG level at baseline was approximately 900 mg/dL. Most people have at least three risk factors: increased risk of cardiovascular disease or history of cardiovascular disease, diabetes, low high-density lipoprotein cholesterol (HDL-C), and high body mass index (Table 1).
Table 1 Baseline characteristics
Plosed可 APOC3,有 于 TG (图3)。
Fig.3 Changes in APOC3 and TG
Plozasiran lowers residual cholesterol and increases HDL-C levels (Figure 4).
Fig.4 Changes in residual cholesterol and HDL-C
At 24 weeks, TG levels decreased to <500 mg/dL (accepted threshold for increased risk of AP) in more than 90% of patients treated with high-dose (25 mg or 50 mg) Plzasiran, and TG levels < 150 mg/dL (i.e., within normal limits; Figure 5) in more than 50% of patients treated with high-dose Plzasiran.
Figure 5 TG level
Plzasiran has a good safety profile, and treatment-emergent adverse events (TEAEs) are not associated with Plzasiran treatment. There were no sequelae of all severe TEAEs (except for 2 patients with malignant tumors), and there were no deaths (Table 2).
Table 2 Safety results
Conclusions and discussion of the study
Plzasiran is highly effective and durable in reducing TG levels, with more than 90% of patients receiving Plzasiran < 500 mg/dL, below the risk threshold for AP, at 24 weeks of treatment with Plzasiran. There was also an improvement in key lipoprotein parameters that lead to atherosclerosis. The safety profile of Plzasiran was good at all doses. These data support the initiation of a pivotal study of Plozasiran for the treatment of SHTG.
According to the principal investigators of this study, SHTG is a challenging disease and there is currently no effective treatment. Plozasiran significantly reduced TG levels (below the threshold associated with increased risk of AP) and had a good safety profile.
However, the study was relatively small, short in duration, and lacked diversity in the inclusion of patients. Future Phase 3 studies are planned to include a broader population, including more women and racial/ethnic minority patients.
bibliography
[1] ACC official website
[2] Plozasiran Reduces Triglyceride Levels by 74% at 24 Weeks——Novel drug shows promise for treating severe hypertriglyceridemia in patients at high risk for pancreatitis. ACC.24. April 7, 2024.
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