Last week, the FDA approved the first oral PCSK9 inhibitor, adding another treatment to our toolkit.
The medication is called enlicitide, and will be marketed as Lipfendra.
Now, cholesterol-lowering medication is not a new category.
Lipfendra uses a different mechanism of action than statins and follows the lead of Repatha (an injectable PCSK9 inhibitor).
In today's newsletter article, we will unpack together how a PCSK9 inhibitor works at a high level, the impressive trial results that got this medication approved, and how this drug can change the cholesterol-lowering landscape.
How Do PCSK9 Inhibitors Work?
A quick recap on how this medication lowers LDL-C and Apolipoprotein B (ApoB), the atherogenic/dangerous lipoprotein particles.
PCSK9 is a protein your liver naturally makes that acts like a demolition crew for LDL receptors.
Here's the normal cycle: your liver cells display LDL receptors on their surface, those receptors grab LDL particles out of your bloodstream and pull them inside the cell, and then the receptor is supposed to recycle back to the surface to do it again.
PCSK9 interrupts that recycling step:
It binds to the LDL receptor
Tags it for destruction
Your liver ends up with fewer receptors
Fewer receptors mean less LDL cleared from your blood, and your LDL-C climbs.
Here's where PCSK9 inhibitors come into play.
They block PCSK9, and you protect the recycling process so more receptors stay on the surface, more LDL gets pulled out of circulation, and your numbers drop.
How well does it work? Let's look at the data.
CORALreef Trial Results
Patients took 20 mg once daily, on an empty stomach in the morning, with no food or beverages (other than water) for at least 30 minutes after dosing.
The approval leaned on two Phase 3 studies from Merck's CORALreef program:
CORALreef Lipids, in adults with hypercholesterolemia, showed LDL-C dropped by roughly 57% on enlicitide versus a slight increase on placebo at 24 weeks — a placebo-adjusted difference of about 56%.
CORALreef HeFH, in patients with heterozygous familial hypercholesterolemia, showed a similarly strong response, with non-HDL-C and ApoB both falling by roughly 58.2% from baseline.
This magnitude of LDL/ApoB reduction puts the oral pill in the same tier as the injectable PCSK9 inhibitors.
Beyond LDL-C, the oral PCSK9 inhibitor trials demonstrate reductions in apolipoprotein B (~47–50%), non-HDL-C (~49–55%), triglycerides (~13%), and lipoprotein(a) (~23–25%).
What This Means Moving Forward
This mechanism isn't new. PCSK9 inhibitors aren't new. The delivery is.
Who would qualify for PCSK9 inhibitors:
Patients who have maxed out statin therapy
Patients with FH (familial hypercholesterolemia)
Patients with established ASCVD
I'd expect a few things to follow from here:
More patients reaching guideline LDL targets, simply because adherence tends to be easier with a pill than a syringe.
PCSK9 inhibition moving earlier in the treatment algorithm for high-risk patients, rather than being reserved as a last resort after statins and ezetimibe.
Competitive pressure on price and access, especially with AstraZeneca's own oral PCSK9 candidate still in the pipeline behind this one.
This isn't a replacement for statins, and it isn't a reason to skip the diet and exercise conversation — the approval itself is explicit that it's an adjunct to both. But for patients who've hit a wall with LDL despite doing everything right, an effective oral option is a meaningful expansion of the toolkit.
The final question mark is outcome data - does this pill truly reduce cardiovascular events?
The CORALreef Outcomes trial is ongoing with a projected completion date of December 2029 and will determine whether the LDL-C reductions translate into reduced major adverse cardiovascular events (MACE).
Based on past PCSK9 inhibitor data, I feel confident that outcomes will be favorable.
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