Eli Lilly and Company 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.ⁱParticipants 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.