Novel Antisense Therapy Olezarsen Demonstrates Significant Triglyceride Reduction in Phase 2b Trial

Conceitos essenciais

Olezarsen, a novel antisense therapy, significantly reduced triglycerides by approximately 50% compared to placebo in patients with moderate to severe hypertriglyceridemia, with a favorable safety profile.

Resumo

The content presents the results of a phase 2b trial evaluating the efficacy and safety of a novel antisense therapy called olezarsen in patients with moderate to severe hypertriglyceridemia.

Key highlights:

• Olezarsen, administered subcutaneously once monthly, reduced triglycerides by 49.1% (50 mg dose) and 53.1% (80 mg dose) compared to placebo (p<0.001 for both doses).
• The therapy also produced significant improvements in other lipid subfractions associated with cardiovascular risk, including ApoC-III, VLDL cholesterol, ApoB, and non-HDL cholesterol. HDL cholesterol levels were also significantly increased.
• The effect was consistent across key subgroups, including patients with diabetes, obesity, and severe hypertriglyceridemia.
• The safety profile was generally reassuring, with low rates of serious adverse events and discontinuations.
• While the primary endpoint was triglyceride reduction, the discussants noted that the more important benefits may be the improvements in non-HDL cholesterol and ApoB, which are more directly linked to atherosclerotic cardiovascular disease risk.
• Further evaluation of the impact on hepatic function is planned in ongoing extension studies.
• The results were described as "exciting" and a potential major advance in the management of hypertriglyceridemia, a condition that is challenging to treat effectively.

Estatísticas

Triglyceride reduction of 49.1% (50 mg dose) and 53.1% (80 mg dose) compared to placebo (p<0.001 for both doses).
ApoC-III reduction of 64.2% (50 mg dose) and 73.2% (80 mg dose) compared to placebo (p<0.001 for both doses).
VLDL cholesterol reduction of 46.2% (50 mg dose) (p<0.001).
ApoB reduction of 18.2% (50 mg dose) (p<0.001).
Non-HDL cholesterol reduction of 25.4% (50 mg dose) (p<0.001).
HDL cholesterol increase of 39.6% (50 mg dose) (p<0.001).

Citações

"The reduction in triglycerides was greater than that currently possible with any available therapy."
"It is the non-HDL cholesterol and ApoB lowering that will drive the likely benefits from this therapy in CV disease."

Principais Insights Extraídos De

Early Olezarsen Results Show 50% Reduction in Triglycerides

by Ted Bosworth às www.medscape.com 04-09-2024

https://www.medscape.com/viewarticle/early-olezarsen-results-show-50-reduction-triglycerides-2024a10006oz

Perguntas Mais Profundas

What are the potential mechanisms by which olezarsen exerts its favorable effects on the lipid profile beyond just triglyceride reduction?

Olezarsen, an antisense therapy targeting APOC3 RNA, exerts its favorable effects on the lipid profile through multiple mechanisms beyond triglyceride reduction. By inhibiting the expression of ApoC-III, olezarsen leads to decreased levels of triglycerides and other lipid subfractions associated with increased cardiovascular risk. ApoC-III is an upstream driver of triglyceride production and a known cardiovascular risk factor. Additionally, olezarsen significantly reduces levels of very low-density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol while increasing high-density lipoprotein (HDL) cholesterol levels. These combined effects contribute to an overall improvement in the lipid profile and potentially reduce the risk of cardiovascular events.

How do the cardiovascular outcomes with olezarsen compare to other emerging therapies targeting triglyceride-rich lipoproteins, such as those inhibiting ANGPTL3 or PCSK9?

The cardiovascular outcomes with olezarsen, specifically its significant reduction in triglycerides and other lipid subfractions, compare favorably to other emerging therapies targeting triglyceride-rich lipoproteins, such as those inhibiting ANGPTL3 or PCSK9. While therapies targeting ANGPTL3 or PCSK9 have shown efficacy in reducing LDL cholesterol levels and improving cardiovascular outcomes, olezarsen's unique mechanism of action targeting ApoC-III sets it apart. By inhibiting ApoC-III, olezarsen not only reduces triglycerides but also impacts other lipid parameters associated with cardiovascular risk, potentially offering a more comprehensive approach to lipid management. Further head-to-head clinical trials comparing olezarsen to ANGPTL3 or PCSK9 inhibitors would be valuable in determining the relative efficacy and safety of these different therapeutic approaches.

Given the potential importance of non-HDL cholesterol and ApoB reduction, how might the design of future clinical trials with olezarsen be optimized to better capture its impact on atherosclerotic cardiovascular disease risk?

To better capture the impact of olezarsen on atherosclerotic cardiovascular disease risk, future clinical trials could be optimized in several ways. Firstly, incorporating non-HDL cholesterol and ApoB reduction as primary or secondary endpoints alongside triglyceride reduction would provide a more comprehensive assessment of the drug's effects on lipid parameters relevant to cardiovascular risk. Additionally, longer-term follow-up beyond the 6-month duration of the initial trial could help evaluate the sustained benefits of olezarsen on cardiovascular outcomes. Including a larger and more diverse patient population, including those with established cardiovascular disease, could also enhance the generalizability of the results. Finally, conducting outcome trials to assess the impact of olezarsen on actual cardiovascular events, such as myocardial infarction or stroke, would be crucial in determining the drug's clinical utility in reducing atherosclerotic cardiovascular disease risk.