Lilly's lepodisiran reduced levels of genetically inherited heart disease risk factor, lipoprotein(a), by nearly 94% from baseline at the highest tested dose in adults with elevated levels

Rhea-AI Summary

Eli Lilly (NYSE: LLY) announced positive Phase 2 results for lepodisiran, an investigational siRNA therapy targeting lipoprotein(a) [Lp(a)]. The ALPACA study demonstrated that lepodisiran reduced Lp(a) levels by 93.9% at the highest tested dose (400 mg) over 60-180 days, meeting its primary endpoint.

Key findings include:

• 16 mg dose achieved 40.8% reduction
• 96 mg dose achieved 75.2% reduction
• 400 mg dose maintained 91% reduction at 1 year
• 74.2% reduction persisted at 1.5 years

The treatment showed a favorable safety profile with minimal adverse events. About 20% of Americans have high Lp(a) levels, which can double or triple heart attack risk. The company is currently conducting the ACCLAIM-Lp(a) Phase 3 trial to evaluate cardiovascular outcomes in adults with elevated Lp(a).

Positive

• Significant efficacy with 93.9% Lp(a) reduction at highest dose
• Long-lasting effects up to 1.5 years after treatment
• Strong safety profile with minimal adverse events
• Additional benefit of reducing apoB levels by 14.1%

Negative

• Effect of additional doses beyond two administrations remains undetermined
• One death occurred in the 16 mg dose group (due to chronic coronary disease)

Insights

Clinical Research Expert

Eli Lilly's lepodisiran Phase 2 ALPACA results represent a significant breakthrough in targeting elevated lipoprotein(a), a genetically inherited cardiovascular risk factor affecting approximately 20% of Americans. The data is remarkably strong - demonstrating an average 93.9% reduction in Lp(a) at the highest dose over 60-180 days post-treatment.

What's particularly impressive is the durability of response. Patients receiving two 400mg doses maintained 91.0% reductions at one year and 74.2% reductions at approximately 1.5 years. This suggests potential twice-yearly dosing, addressing a key challenge in cardiovascular disease management where patient adherence often diminishes with frequent dosing requirements.

The siRNA mechanism represents sophisticated genetic medicine - directly inhibiting apolipoprotein(a) production rather than attempting to clear existing Lp(a). This approach is especially valuable since conventional lipid-lowering therapies and lifestyle modifications are ineffective against Lp(a).

The secondary finding of 14.1% ApoB reduction adds another dimension of cardiovascular benefit beyond the primary Lp(a) target. Safety data appears favorable with treatment-related adverse events occurring in only 14% of patients at the therapeutic dose with no serious adverse events.

While these results are highly encouraging, the ongoing Phase 3 ACCLAIM-Lp(a) trial will be crucial to determine whether these biomarker reductions translate to meaningful reductions in cardiovascular events - the ultimate clinical goal for high-risk patients.

Pharmaceutical Market Analyst

Lilly's lepodisiran data presents a compelling opportunity in the untapped market for Lp(a) reduction therapies. With approximately 25% of the global population having elevated Lp(a) levels that significantly increase cardiovascular risk, the addressable market is substantial.

The 93.9% reduction achieved at the highest dose exceeds typical efficacy benchmarks for cardiovascular risk factor modifiers. The durability of effect - with significant reductions persisting for 1.5 years after dosing - suggests a commercially attractive treatment regimen that could drive patient adherence and payer acceptance.

Lepodisiran represents Lilly's strategic expansion into genetic medicine approaches for cardiovascular disease, diversifying beyond their traditional metabolic and oncology focus areas. The siRNA platform technology could have broader applications across Lilly's pipeline if successful.

Publication in the New England Journal of Medicine and presentation at ACC 2025 signals strong medical community interest, which typically correlates with favorable reimbursement positioning and adoption rates post-approval.

Market differentiation is clear: lepodisiran would be positioned as a first-in-class therapy for a genetic risk factor with no existing treatment options. Additionally, the dual reduction of both Lp(a) and ApoB could potentially address multiple cardiovascular risk components simultaneously.

With the Phase 3 cardiovascular outcomes trial already enrolling, Lilly is aggressively advancing this program, recognizing its potential to address a significant unmet need in cardiovascular risk management where therapeutic options for genetic factors remain

In Phase 2 ALPACA results, lepodisiran significantly reduced levels of genetically inherited cardiovascular risk factor, with some patients sustaining reductions for nearly 1.5 years

These data were presented at the American College of Cardiology 2025 Scientific Sessions and simultaneously published in the New England Journal of Medicine (NEJM)

INDIANAPOLIS, March 30, 2025 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced positive Phase 2 results for lepodisiran, an investigational small interfering RNA (siRNA) therapy designed to lower the production of lipoprotein(a) [Lp(a)], a genetically inherited risk factor for heart disease. In the Phase 2 ALPACA study, lepodisiran significantly reduced Lp(a) levels by an average of 93.9% over the 60 to 180-day period after treatment with the highest tested dose (400 mg), meeting the primary endpoint.ⁱ Participants who received the 16 mg and 96 mg lepodisiran doses experienced a 40.8% reduction and a 75.2% reduction in Lp(a) levels over the same time period, respectively.ⁱ

Lepodisiran also met additional secondary endpoints, showing reductions in Lp(a) levels following one or two administrations of each of the three tested doses across all timepoints assessed throughout the nearly 18-month-long study.ⁱⁱ Lepodisiran was administered twice at each dose (16 mg, 96 mg, or 400 mg), once at baseline and at day 180, with a separate group receiving 400 mg at baseline and placebo at day 180. The effect of additional doses of lepodisiran remains undetermined.

"Nearly a quarter of the world's population has elevated levels of Lp(a), putting them at a significantly higher risk of cardiovascular events such as heart attacks and strokes. Unfortunately, there are no approved cholesterol-lowering therapies specifically for this genetic risk factor, and lifestyle changes like diet and exercise do not provide meaningful reductions," said Steven Nissen, M.D., chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic. "These significant and sustained Lp(a) reductions are encouraging and suggest that siRNA approaches like lepodisiran could potentially offer durable benefits with long-term dosing."

About 20% of Americans have high levels of Lp(a), which increases their risk of cardiovascular disease.^1,2 Elevated Lp(a) levels can double or even triple the risk of a heart attack and are associated with other cardiovascular issues such as stroke and heart valve narrowing (aortic valve stenosis).^3,4,5 Lepodisiran is an investigational siRNA therapy designed to reduce levels of Lp(a) by inhibiting the production of apolipoprotein(a) (apo[a]), a key component of Lp(a).

"Reducing the inherited cardiovascular risk for patients with high Lp(a) has long been a critically unmet need. These results offer hope for a long-term, durable treatment option," said Ruth Gimeno, group vice president, diabetes, obesity and cardiometabolic research at Lilly. "These data underscore Lilly's commitment to advancing genetic medicine to address one of the world's most pressing healthcare challenges. We will continue to evaluate the potential benefits of lepodisiran in the ongoing Phase 3 cardiovascular outcomes trial." 

Results from additional secondary endpoints showed:

• Participants who received 400 mg of lepodisiran at both baseline and day 180 experienced a 94.8% reduction in average Lp(a) levels over the day 30 to 360 period, which remained 91.0% below baseline at day 360 (~1 year) and 74.2% below baseline at day 540 (~1.5 years).ⁱⁱ
• Lepodisiran also reduced apolipoprotein B (apoB) levels, a separate cholesterol biomarker. The highest dose (400 mg) of lepodisiran showed 14.1% and 13.7% ApoB reductions from baseline at day 60 and 180, respectively. A second 400 mg lepodisiran dose at day 180 sustained these apoB reductions through day 540.ⁱⁱ

Treatment-emergent adverse events (TEAEs) related to the study drug occurred in 1% (1/69) of the placebo group, 3% (1/36) of the 16 mg group, 12% (9/74) of the 96 mg group and 14% (20/141) of the pooled 400 mg group. There were no serious adverse events related to lepodisiran treatment. A single death occurred in the 16 mg dose group due to complications of chronic coronary disease. One participant in the placebo group was withdrawn from the study drug due to a TEAE; however, no participants receiving lepodisiran experienced a TEAE leading to withdrawal from treatment or the study.

The ACCLAIM-Lp(a) Phase 3 clinical development program, investigating the effect of lepodisiran on the reduction of cardiovascular events in adults with elevated Lp(a), is currently enrolling.

About ALPACA
ALPACA was a randomized, double-blind, placebo-controlled Phase 2 study designed to investigate the efficacy and safety of lepodisiran in adults with elevated Lp(a). A total of 320 participants were randomized to receive either placebo or one of three doses of lepodisiran (16 mg, 96 mg, or 400 mg) both at baseline and day 180. An additional group received 400 mg of lepodisiran at baseline and placebo at day 180. Results from the two groups receiving 400 mg of lepodisiran were pooled for the primary analysis. The primary endpoint was placebo-adjusted, time-averaged percent change in Lp(a) serum concentration from day 60 to 180.

About Lilly
Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram, and LinkedIn. P-LLY

Trademarks and Trade Names
All trademarks or trade names referred to in this press release are the property of the company, or, to the extent trademarks or trade names belonging to other companies are references in this press release, the property of their respective owners. Solely for convenience, the trademarks and trade names in this press release are referred to without the ® and ™ symbols, but such references should not be construed as any indicator that the company or, to the extent applicable, their respective owners will not assert, to the fullest extent under applicable law, the company's or their rights thereto. We do not intend the use or display of other companies' trademarks and trade names to imply a relationship with, or endorsement or sponsorship of us by, any other companies.

ⁱ Placebo-adjusted values based on the treatment-regimen estimand.
ⁱⁱ Placebo-adjusted values based on the efficacy estimand, which represents efficacy prior to discontinuation of study drug or initiation of medications known to affect lipoprotein(a).

Cautionary Statement Regarding Forward-Looking Statements
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about lepodisiran as a potential treatment for people with high risk for cardiovascular events and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that lepodisiran will prove to be a safe and effective treatment for the reduction of cardiovascular events associated with a reduction in Lp(a), that lepodisiran will receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

References

1. Family Heart Foundation. Lipoprotein(a) - Family Heart Foundation. Last accessed Feb. 20, 2025.
2. Family Heart Foundation. Diagnosing High Lipoprotein(a) - Family Heart Foundation. Last accessed Feb. 20, 2025.
3. Harvard Medical School. Heart Health: The Latest on Lipoprotein(a), an Inherited Cause of Early Heart Disease. Last accessed Feb. 20, 2025.
4. NIH National Heart, Lung, and Blood Institute. Research Feature – Lipoprotein(a): What to know about elevated levels. Access here: https:// https://www.nhlbi.nih.gov/news/2024/lipoproteina-what-know-about-elevated-levels. Last accessed Feb. 20, 2025.
5. Khan, M. I., et al. Role of Lipoprotein (A) in aortic valve stenosis: Novel disease mechanisms and emerging pharmacotherapeutic approaches. IJC Heart & Vasculature 2024;55, 101543.

Refer to:	Stefanie Prodouz; stefanie.prodouz@lilly.com; 317-287-9899 (Media)
	Michael Czapar; czapar_michael_c@lilly.com; 317-617-0983 (Investors)

 

 

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FAQ

What were the Phase 2 ALPACA trial results for Lilly's (LLY) lepodisiran?

Lepodisiran reduced lipoprotein(a) levels by 93.9% at the highest dose (400 mg) over 60-180 days, with effects lasting up to 1.5 years.

How long did the reduction in Lp(a) levels last in LLY's lepodisiran trial?

The 400 mg dose maintained 91% reduction at 1 year and 74.2% reduction at 1.5 years after initial treatment.

What are the safety results for Lilly's (LLY) lepodisiran in Phase 2?

Treatment-related adverse events were low (14% in 400 mg group), with no serious adverse events related to lepodisiran treatment.

What is the current development status of Lilly's (LLY) lepodisiran?

After positive Phase 2 results, the drug is currently in Phase 3 ACCLAIM-Lp(a) trial evaluating cardiovascular outcomes in adults with elevated Lp(a).