Korea becomes a battlefield for multinational drugmakers developing ASCVD drugs

Korea is becoming a battleground for multinational pharmaceutical companies to develop atherosclerotic cardiovascular disease (ASCVD) treatment, as Eli Lilly recently scored approval for a phase 3 clinical trial of lepodisiran (LY3819469) in the country, industry sources said Thursday.

Following Amgen's getting the phase 3 approval of a candidate with the same mechanism last year, Novartis also got the Korean regulator’s nod for its small interfering RNA (siRNA) therapy, Leqvio.

On Thursday of last week, the Ministry of Food and Drug Safety (MFDS) approved Lilly's lepodisiran for a phase 3 study. Twenty-one medical institutions will participate in the trial, including Seoul National University Hospital, Asan Medical Center, Severance Hospital, the Catholic University of Korea Seoul St. Mary's Hospital, and Kangbuk Samsung Hospital.

The trial is designed to study the effect of lepodisiran on reducing major adverse cardiovascular events in adults with established atherosclerotic cardiovascular disease or elevated lipoprotein(a) (Lp(a)) at risk for a first cardiovascular event, with the primary endpoint being "time to first occurrence of a component of the major adverse cardiovascular event (MACE)-4 composite endpoint.

Since March, Eli Lilly has conducted a global phase 3 clinical trial (ACCLAIM-Lp(a)) to evaluate the effect of lepodisiran on reducing MACE in adult patients with elevated Lp(a) levels and the Korean phase 3 is part of the global phase 3. The phase 3 target enrollment is 12,500 participants, with an expected deadline of March 2029.

Lepodisiran is a small interfering RNA (siRNA) that reduces Lp(a) levels by blocking the production of apolipoprotein(a), a major component of Lp(a), in the liver. Lp(a) is a form of cholesterol that forms plaque in the arteries, blocking blood flow, and is associated with the risk of cardiovascular disease.

Lepodisiran binds to a specialized sugar (GalNAc) and is effectively delivered to liver cells, where it has been shown in phase 1 to reduce Lp(a) levels by up to 94 percent with a single subcutaneous injection.

Eli Lilly licensed in lepodisiran from its original developer Dicerna Pharmaceuticals in 2018 and has since developed it. Dicerna Pharmaceuticals was subsequently acquired by Novo Nordisk in 2021 for $3.3 billion (about 4.56 trillion won).

If successful, Lepodisiran could effectively lower Lp(a) levels. Existing cholesterol-lowering drugs, including lifestyle modification and statin drugs, have not had a significant impact on Lp(a) levels.

Patients with high Lp(a) levels are treated with apheresis, similar to hemodialysis, but there has been a need for a therapeutic agent. Eli Lilly has expressed hope that lepodisiran could play an important role in preventing cardiovascular disease.

Eli Lilly is not the only global pharmaceutical company using RNA technology to develop cardiovascular disease treatments. Amgen is developing an siRNA-based therapy, olpasiran, to lower Lp(a) levels, similar to lepodisiran, and is conducting phase 3 trials in Korea.

Besides, Novartis' siRNA therapy Leqvio (inclisiran) scored approval from the U.S. Food and Drug Administration in 2021 and won the Korean nod last month as an adjunctive therapy to diet for patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia.