Significant reduction of triglycerides in familial chylomicronemia syndrome with APOC3 ASO

15/04/2024

ACC.24 – Familial Chylomicronemia Syndrome (FCS) is a rare genetic disease causing severe hypertriglyceridemia. The efficacy and safety of the antisense oligonucleotide targeting APOC3 mRNA named olezarsen was evaluated in this patient population.

This summary is based on the presentation of Erik Stroes, MD, PhD (Amsterdam, The Netherlands) at the ACC.24 Scientific Session –A Randomized, Placebo-Controlled Phase 3 Study of Olezarsen in Patients With Familial Chylomicronemia Syndrome – The Balance trial

Introduction and methods

Familial Chylomicronemia Syndrome (FCS) is a rare genetic disease causing severe hypertriglyceridemia. Patients with FCS have a 360-fold increased risk of acute pancreatitis compared with people with normal triglyceride levels. Moreover, the risk of mortality is 2-fold increased with severe hypertriglyceridemia compared with normal triglyceride levels. There is an unmet need of treatment for these patients, as patients have a minimal to no response to conventional TG-lowering therapies.

Olezarsen is a GalNAc3-conjugated antisense oligonucleotide (ASO) designed to target APOC3 mRNA in the liver. Lowering of ApoC-III has been demonstrated to decrease circulating triglyceride levels.

In the Balance trial, patients with genetically identified FCS and fasting TG≥880 mg/dL (10 mmol/L) were randomized to olezarsen 80 mg SC every 4 weeks (n=22), olezarsen 50 mg SC every 4 weeks (n=21) or placebo (n=23). History of pancreatitis within 10 years prior to screening was present in ≥65% of patients. Follow-up was until week 53.

The primary endpoint was the % change in fasting TG from baseline to 6 months. Secondary endpoints were the % change in lipid parameters and the event rate of pancreatitis.

Main results

  • At month 6, placebo-adjusted LSM of % change in fasting TGs was -22.4% (P=0.078) in the olezarsen 50 mg group and -43.5% (P<0.001) in the 80 mg group.
  • Placebo-adjusted LSM % change in fasting ApoC-III was -65.5% in the olezarsen 50 mg group and -73.7% in the olezarsen 80 mg group.
  • Waterfall plots showed sustained ApoC-III reductions through 12 months in the majority of olezarsen-treated patients.
  • There was 1 pancreatitis event in the olezarsen 50 mg group, 1 in the olezarsen 80 mg group and 11 (in 7 patients) in the placebo group. The mean rate ratio for the adjudicated acute pancreatitis endpoint was 0.12 (95%CI:0.022-0.656) with a reduced event rate in the pooled olezarsen group compared with the placebo group.
  • A greater proportion of placebo-treated patients experienced SAEs. There were no drug-related SAEs and no clinically meaningful changes in platelet count or in measures of hepatic and renal function.

Conclusion

In patients with FCS, 80 mg olezarsen -an ASO targeting APOC3 mRNA- significantly reduced TG levels at 6 months in the Balance trial. The effects of olezarsen on TG and APOC-III levels were sustained through months. A signal for reduced pancreatitis events with olezarsen was observed at 12 months. Furthermore, the safety and tolerability profile of olezarsan was favorable.

Erik Stroes concluded: “Olezarsen may represent a novel therapy to reduce plasma TG levels and acute pancreatitis in patients with FCS”.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -

The findings of this study were simultaneously published in N Eng J Med

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