Lilly's Lepodisiran Shows Promise in Reducing Heart Disease Risk

Eli Lilly has reported promising results from a Phase 2 study of lepodisiran, an RNA interference drug designed to lower levels of lipoprotein(a) [Lp(a)], a protein particle increasingly recognized as a significant risk factor for heart disease. The study findings, published in The New England Journal of Medicine and presented at the American College of Cardiology's annual conference, demonstrate the potential of a new class of cardiovascular drugs targeting Lp(a).

Lepodisiran's Efficacy in Reducing Lp(a) Levels

In the Phase 2 trial, lepodisiran demonstrated remarkable efficacy in reducing Lp(a) levels:

• The high dose of lepodisiran reduced Lp(a) levels by approximately 94% over a four-month period.
• Lower doses also showed reductions in Lp(a) levels, albeit to a lesser extent.
• About 14% of participants receiving the high dose experienced treatment-emergent adverse events, none of which were serious or led to study discontinuation.

These results align with previous findings from similar drugs developed by Novartis and Amgen, reinforcing the potential of RNA interference therapies in managing cardiovascular risk factors.

The Race for Lp(a)-Lowering Therapies

Lepodisiran is part of a growing field of drugs targeting Lp(a), with several pharmaceutical companies vying to bring the first approved treatment to market:

• Novartis and Amgen are currently conducting large Phase 3 trials to demonstrate the cardioprotective benefits of Lp(a) reduction.
• Novartis expects results from its late-stage study in 2026, with Amgen likely to follow later that year.
• Lilly is advancing multiple approaches, including lepodisiran, an oral drug called muvalaplin, and exploring gene editing therapies with Verve Therapeutics.
• Merck & Co. recently entered the race by licensing a competing oral medicine from Jiangsu Hengrui Pharmaceutical for $200 million.

The success of these trials could establish Lp(a)-lowering therapies as a third pillar in managing heart disease risk, alongside treatments for LDL cholesterol and triglycerides.

Implications for Cardiovascular Disease Management

While the ability of these drugs to reduce Lp(a) levels is clear, questions remain about the clinical benefits:

• Approximately 20% of Americans are estimated to have elevated Lp(a) levels, highlighting the potential impact of these therapies.
• The threshold of Lp(a) reduction necessary to produce clinical benefits remains uncertain and debated among experts.
• Upcoming Phase 3 trials will be crucial in determining whether Lp(a) reduction translates to improved cardiovascular outcomes.

As the pharmaceutical industry awaits these pivotal results, the development of Lp(a)-lowering therapies represents a significant advancement in the ongoing effort to reduce the burden of cardiovascular disease.