MSD develops first oral PCSK9 inhibitor

FDA approves drug for two indications, including familial hypercholesterolemia

Demonstrates up to 59% LDL-C reduction…raises expectations for a shift from injectables

MSD's launch of the world's first oral PCSK9 inhibitor is expected to reshape the dyslipidemia treatment market.

The arrival of an oral therapy is likely to intensify competition over treatment convenience in a market that has until now evolved primarily by extending dosing intervals of injectable therapies.

Oral PCSK9 inhibitor Lipfendra

According to industry sources, the U.S. Food and Drug Administration (FDA) approved Lipfendra (enlicitide) on July 16 for reducing low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia and heterozygous familial hypercholesterolemia (HeFH).

Lipfendra is an oral PCSK9 inhibitor taken once daily at a 20mg dose as an adjunct to diet and exercise.

PCSK9 inhibitors are indicated for patients whose LDL-C levels remain inadequately controlled despite lipid-lowering therapy, including high-intensity statins and ezetimibe, or for those requiring additional LDL-C reduction because of a high risk of atherosclerotic cardiovascular disease (ASCVD).

All currently marketed PCSK9 inhibitors are injectables. Amgen's ‘Repatha (evolocumab)’ and Sanofi/Regeneron's ‘Praluent (alirocumab)’ are monoclonal antibodies administered every two weeks.

Novartis' ‘Leqvio (inclisiran)’ is an siRNA therapy that suppresses PCSK9 production in the liver. After the initial administration, the second dose is administered after three months, and then every six months.

While the PCSK9 inhibitor market has focused on reducing injection frequency and extending dosing intervals, Lipfendra has differentiated itself with oral administration.

Lipfendra is a macrocyclic peptide-based oral PCSK9 inhibitor. It inhibits PCSK9 to increase hepatic clearance of LDL cholesterol and targets the same pathway as injectable PCSK9 inhibitors as an oral formulation.

However, there are certain restrictions during its intake. Lipfendra may be taken with water, coffee, or tea, but patients must avoid eating for at least 30 minutes afterward to ensure adequate drug absorption.

Approval supported by two global Phase III trials

Lipfendra's approval was based on results from the CORALreef Lipids and CORALreef HeFH studies, part of MSD's global Phase III CORALreef program.

CORALreef Lipids was a multicenter, randomized, double-blind, placebo-controlled Phase III trial involving 2,904 patients with hypercholesterolemia.

Participants were those receiving stable lipid-lowering therapy, including moderate- or high-intensity statins that still required additional LDL-C reduction.

In the trial, Lipfendra reduced LDL-C by 56% versus placebo at Week 24. LDL-C fell 57% from baseline in the Lipfendra group, while it increased by 3% in the placebo group.

In the CORALreef HeFH study, which involved 303 patients with heterozygous familial hypercholesterolemia, Lipfendra reduced LDL-C by 59% versus placebo at Week 24. LDL-C declined 58% from baseline in the Lipfendra group but increased by 3% in the placebo group.

Beyond LDL-C reduction, Lipfendra also lowered non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB), both associated with ASCVD risk.

Among patients with hypercholesterolemia, Lipfendra reduced non-HDL-C by an average of 54% and ApoB by 50%. In patients with HeFH, the corresponding reductions were 52% and 48%, respectively.

Overall safety was comparable to placebo. In the hypercholesterolemia study, adverse event rates were similar between the two groups. In the HeFH study, however, diarrhea and dizziness occurred more frequently with Lipfendra.

Diarrhea was reported in 7% of patients receiving Lipfendra versus 2% with placebo, while dizziness occurred in 9% and 4%, respectively. Treatment discontinuation due to adverse events was similar between groups.

Although Lipfendra has demonstrated robust LDL-C lowering, it has yet to demonstrate reduction in major cardiovascular events such as myocardial infarction, stroke, or cardiovascular death.

MSD is currently evaluating its effects on cardiovascular events and mortality in the CORALreef Outcomes trial involving more than 14,500 participants. Patient enrollment has been completed.

The overall CORALreef clinical program includes more than 19,000 patients with hypercholesterolemia. In addition to the cardiovascular outcomes trial, MSD is conducting long-term extension studies as well as trials in pediatric patients and combination therapy with Lipfendra.

Lipfendra is also expected to play an important role in MSD's long-term growth strategy. Its oral formulation and relatively lower price may act in favor when seeking to expand into the injectable-dominated PCSK9 inhibitor market.

Lipfendra is priced at USD 315 per month in the United States. This is lower than some of the currently marketed PCSK9 therapies.

The market expects Lipfendra to become one of MSD's key growth drivers following the loss of patent exclusivity for Keytruda (pembrolizumab), with peak annual global sales projected at up to USD 5 billion.