Lilly’s Lepodisiran Shows Durable Lipoprotein(a) Reduction in Phase 2 Trial

Lepodisiran reduced Lp(a) levels by 93.9% at the highest dose (400 mg) over 60-180 days post-treatment3.

Effects lasted up to 1.5 years, with Lp(a) levels remaining 74.2% below baseline at day 54023.

The drug was well-tolerated, with mild injection site reactions in 14% of patients at the highest dose3.

Lepodisiran's durability may allow for once or twice yearly dosing, potentially providing an advantage over competitors26.

The ALPACA trial included 320 patients with elevated Lp(a) levels (>175 nmol/L)4.

Lilly is also developing an oral version of the drug, offering a dual pipeline strategy2.

Competing therapies include Amgen's olpasiran, Novartis' pelacarsen, and Silence Therapeutics' zerlasiran24.

Phase 3 trials are ongoing to determine if Lp(a) reduction translates to improved cardiovascular outcomes46.

Lepodisiran, Eli Lilly's investigational small interfering RNA (siRNA) therapy, has demonstrated significant and durable reductions in lipoprotein(a) [Lp(a)] levels in a phase 2 trial, potentially offering an advantage over competing treatments in development. The ALPACA study results, presented at the American College of Cardiology 2025 Scientific Sessions, showed that lepodisiran reduced Lp(a) levels by an average of 93.9% over the 60 to 180-day period after treatment with the highest tested dose of 400 mg3.

Durability of Effect

One of the most striking aspects of lepodisiran's performance is the longevity of its effects. Patients 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. Remarkably, Lp(a) levels remained 91.0% below baseline at day 360 (approximately 1 year) and 74.2% below baseline at day 540 (approximately 1.5 years)3. This extended duration of action could potentially allow for once or twice yearly dosing, which may provide lepodisiran with a significant advantage over competitors requiring more frequent administration26.

Safety Profile

Lepodisiran demonstrated a favorable safety profile in the ALPACA trial. Treatment-emergent adverse events related to the study drug occurred in 14% of participants receiving the highest dose, with injection site reactions being the most common side effect. These reactions were generally mild and transient. No serious adverse events related to lepodisiran treatment were reported34.

Competitive Landscape

Lepodisiran joins a growing field of therapies targeting Lp(a), including Amgen's olpasiran, Novartis' pelacarsen, and Silence Therapeutics' zerlasiran24. While these competitors are further along in development, with phase 3 trials scheduled to complete in 2026, lepodisiran's potential for less frequent dosing and Lilly's dual pipeline strategy (including an oral version in development) could provide significant advantages26.

Future Prospects

The promising results from the ALPACA trial have led to the initiation of a phase 3 cardiovascular outcomes trial for lepodisiran3. This study will be crucial in determining whether the significant reductions in Lp(a) levels translate into meaningful clinical benefits, such as reduced risk of heart attacks and strokes. The outcome of this trial, along with those of competing therapies, will likely shape the future landscape of cardiovascular risk management for the estimated 20-25% of adults globally with elevated Lp(a) levels24.

In conclusion, lepodisiran's phase 2 results demonstrate its potential as a potent and durable Lp(a)-lowering therapy. If these findings are confirmed in larger trials and shown to improve cardiovascular outcomes, lepodisiran could become a valuable tool in addressing an important unmet need in cardiovascular disease prevention.

Sources:

2. https://www.ctol.digital/news/lilly-lepodisiran-cuts-heart-risk-94-percent-phase-2/

3. https://www.prnewswire.com/news-releases/lillys-lepodisiran-reduced-levels-of-genetically-inherited-heart-disease-risk-factor-lipoproteina-by-nearly-94-from-baseline-at-the-highest-tested-dose-in-adults-with-elevated-levels-302414699.html

4. https://www.medpagetoday.com/meetingcoverage/acc/114898

6. https://www.fiercebiotech.com/biotech/lilly-links-lepodisiran-durably-lower-lipoprotein-phase-2-providing-edge-over-amgen-and