Obicetrapib: Why There Is So Much Excitement Over The Release Of This Drug.

If you’ve been following my writing for a while, Obicetrapib is a name you’ve become familiar with.

In a previous post, I explained what CETP inhibition is and how it protects the brain and cardiovascular system. The biology is very intriguing - and while the cardiovascular benefits of CETP inhibition have been known for about 30 years - a successful drug development has remained elusive - until now!

In addition to astonishing improvements in cardiovascular risk biomarkers, the recent PREVAIL trial discovered something else - the possibility that manipulating cholesterol transport might have implications extending beyond cardiovascular disease and into Alzheimer’s disease, especially for those of us carrying APOE4.

Just 3 days ago, the European Commission approved Obicetrapib as Ubeslo®, as well as a fixed-dose combination of Obicetrapib plus Ezetimibe called Evlarco®. This is the first regulatory approval of Obicetrapib anywhere in the world.

The approval follows several Phase 3 trials showing substantial LDL cholesterol lowering on top of existing lipid-lowering therapy. But perhaps even more interesting for this community, we now also have peer-reviewed data suggesting an effect on Alzheimer’s biomarkers - and the strongest signal appeared in people carrying APOE4.

So rather than repeating what I’ve previously written regarding CETP, I want to look at where the evidence stands now.

And there is a lot to unpack.

First: What Exactly Is Obicetrapib?

Obicetrapib is a once-daily, oral CETP inhibitor.

CETP stands for cholesteryl ester transfer protein. It participates in the transfer of cholesterol esters and triglycerides between lipoproteins.

Blocking CETP produces a somewhat unusual lipid profile:

LDL-C falls. HDL-C rises—dramatically. ApoB falls. Lp(a) also falls.

That combination is part of what originally made CETP inhibition so attractive.

But there is a long and rather disastrous history behind this drug class - until now!

The Obicetrapib Trials

ROSE: An Early Hint That This Drug Was Different

The Phase 2 ROSE trial studied 120 people whose LDL-C remained at least 70 mg/dL despite high-intensity statin therapy.

Participants received either a placebo or 5 mg or 10 mg of Obicetrapib for eight weeks.

Those participants on a higher Obicetrapib dose, compared with placebo, saw reductions of approximately:

• LDL-C: 51%

• ApoB: 30%

• non-HDL-C: 44%

• Lp(a): 57%

HDL-C increased by as much as 165%.

Those numbers got people’s attention.

Although just a Phase 2 trial - the results certainly looked impressive!

BROADWAY: The Big Test

As a next step, the BROADWAY trial enrolled 2,530 patients at high cardiovascular risk who had established atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia.

Importantly, these weren’t untreated people.

They were already receiving maximally tolerated lipid-lowering therapy but still had LDL-C of at least 70 mg/dL.

Participants were randomized 2:1 to:

Obicetrapib 10 mg daily

or

a placebo

for one year.

Their average LDL-C at baseline was about 98 mg/dL.

At 84 days, LDL-C had fallen 29.9% from baseline in the Obicetrapib group, versus a 2.7% increase with placebo, a placebo-adjusted difference of 32.6 percentage points.

Adverse-event incidence was similar between groups. The results of the Broadway trial laid the foundation for the European approval this week!

But there was another trial that may be even more interesting!

TANDEM: Obicetrapib + Ezetimibe

Many readers here will already be familiar with Ezetimibe, which reduces intestinal cholesterol absorption through a completely different mechanism.

The TANDEM trial asked an obvious question:

What happens if we combine Obicetrapib and Ezetimibe?

The trial randomized 407 participants to:

• Obicetrapib 10 mg + Ezetimibe 10 mg

• Obicetrapib alone

• Ezetimibe alone

• Placebo

At 84 days, the combination produced approximately 49% greater LDL-C reduction than placebo.

It lowered LDL-C about 28% more than Ezetimibe alone and about 17% more than Obicetrapib alone.

And it does this in one oral tablet.

That combination has now been approved in Europe as Evlarco®.

For people who cannot achieve their LDL goals with statins—or cannot tolerate sufficient statin doses, this potentially creates another potent oral option before moving to injectable therapies.

BROOKLYN: Familial Hypercholesterolemia

The BROOKLYN trial tested Obicetrapib in 354 people with heterozygous familial hypercholesterolemia whose LDL remained elevated despite existing treatment.

The mean starting LDL-C was 122 mg/dL.

At day 84, compared with placebo, Obicetrapib produced:

LDL-C: −36.3%

ApoB: −24.4%

non-HDL-C: −34.5%

Lp(a): −45.9%

and an extraordinary:

HDL-C: +138.7%

Again, the drug was generally well tolerated.

But LDL-C Isn’t the Entire Story

LDL-C, LDL particle number and ApoB don’t necessarily change by identical percentages with CETP inhibition.

ApoB represents the number of circulating atherogenic particles. Every LDL, VLDL remnant, IDL and Lp(a) particle carries one ApoB molecule.

So when LDL-C falls 35–40% but ApoB falls perhaps 20–30%, we should not simply assume cardiovascular risk has fallen by the LDL-C percentage.

CETP inhibition changes the composition of the particles themselves.

For those of us who follow ApoB rather than relying exclusively on LDL-C, this is an important distinction.

It is also one reason the next trial matters so much.

PREVAIL: Does Obicetrapib Actually Prevent Heart Attacks and Strokes?

Lower LDL is encouraging.

Lower ApoB is encouraging.

But ultimately we want to know whether people experience fewer cardiovascular events.

That is what the PREVAIL study is designed to answer.

More than 9,500 patients with established ASCVD and inadequately controlled LDL-C have been enrolled.

The primary question is whether adding Obicetrapib reduces major adverse cardiovascular events.

Until those results are available, we should distinguish between two statements:

Obicetrapib has convincingly demonstrated substantial lipid lowering.

and

Obicetrapib has independently demonstrated that it reduces cardiovascular events.

We have evidence for the first.

PREVAIL is intended to answer the second.

And now we get to the part that I suspect most readers of this newsletter are waiting for.

What Does Any of This Have to Do With Alzheimer’s?

Potentially quite a lot.

APOE isn’t just an Alzheimer’s gene.

APOE is fundamentally a lipid-transport gene.

And the brain is an extraordinarily lipid-rich organ.

Because circulating cholesterol does not simply cross the intact blood-brain barrier in meaningful quantities, the brain largely manages its own cholesterol economy.

Astrocytes manufacture cholesterol and package lipids into APOE-containing particles that distribute them to neurons and other cells.

APOE4 appears to perform some of these jobs differently from APOE3.

Research increasingly implicates APOE4 in altered lipid handling, cholesterol accumulation, oxidative stress, inflammation, impaired amyloid clearance and blood-brain-barrier dysfunction.

Which raises an intriguing possibility:

Could modifying CETP activity improve the lipid environment of the APOE4 brain?

There have been clues for years that it might.

Certain genetic variants associated with reduced CETP activity have been associated with longevity and slower cognitive decline, and some studies suggest that CETP genetics can modify APOE4-associated memory decline.

But genetics and biological plausibility alone are insufficient - now we have some data to back it up.

The Surprise Inside the BROADWAY study

The BROADWAY trial was a cardiovascular trial.

But forward-thinking investigators had prespecified an Alzheimer’s biomarker substudy.

Of the 2,530 BROADWAY participants, 1,535 had known APOE status and plasma p-tau217 measurements at both baseline and 12 months.

And this is where things become exciting!

Across the entire substudy population, plasma p-tau217 increased 4.94% with placebo but only 2.09% with Obicetrapib.

That difference was statistically significant.

Not an enormous effect - until researchers separated participants by APOE genotype!

APOE4 Changed the Picture

Among APOE4 carriers:

Placebo: p-tau217 +6.91%

Obicetrapib: +1.92%

Again, a significant difference.

But among the small group of APOE4 homozygotes, the signal became considerably larger.

The placebo group experienced a:

+12.67% increase in p-tau217

while the Obicetrapib group experienced a:

−7.81% decrease.

The treatment difference was:

20.48%

with P=0.010.

As an APOE4/4 carrier myself, that number is the most exciting thing I’ve read about APOE4 in the last decade.

But there is an important caveat.

There were only 29 APOE4 homozygotes in this analysis.

Twenty-nine.

So however exciting that result looks, and I do think it is very exciting - it needs replication in a much larger APOE4/4 population study.

And It Wasn’t Only p-tau217

This is perhaps the part of the study that makes the result harder simply to dismiss as noise.

Researchers also examined:

• p-tau181

• GFAP

• neurofilament light (NfL)

• Aβ42:40

• p-tau217/Aβ42:40

Across the full population, Obicetrapib significantly limited the increase in the p-tau217/Aβ42:40 ratio.

And among APOE4/4 participants, researchers reported significant favorable effects on several additional biomarkers.

For example:

GFAP

Obicetrapib: −6.39%

Placebo: +8.85%

and:

NfL

Obicetrapib: −10.49%

Placebo: +6.82%

The biomarker directions therefore weren’t confined to one isolated measurement.

That is encouraging.

But I want to put a large caveat next to the word encouraging.

Biomarkers Are Not Alzheimer’s Disease

This distinction is essential.

Obicetrapib has not been shown to prevent Alzheimer’s disease.

It has not been shown to prevent cognitive decline.

And this substudy was conducted in cardiovascular patients - not in cognitively normal APOE4 carriers selected specifically for Alzheimer’s prevention.

What it showed was that over one year, several blood biomarkers associated with Alzheimer’s pathology progressed differently in people taking Obicetrapib.

Even the investigators conclude that dedicated prevention trials are needed to determine whether these biomarker changes translate into clinical benefit.

Why Might APOE4/4 Respond More Strongly?

This may be the most fascinating question of all.

If the result holds up, the increasing treatment effect with increasing APOE4 burden could be telling us something about mechanism.

APOE4 is associated with dysfunctional lipid transport in the brain.

Astrocytes carrying APOE4 can accumulate cholesterol esters and lipid droplets. Lipid trafficking and cholesterol efflux may become impaired. Oxidative stress and inflammatory signaling can increase.

HDL-like particles within the central nervous system participate in moving cholesterol between cells.

CETP may influence that system.

So one hypothesis is that CETP inhibition improves cholesterol transport and HDL-particle function in a brain whose lipid-handling machinery is particularly impaired by APOE4.

The more impaired the starting system - in theory - the greater the opportunity for improvement.

That would offer one possible explanation for why the biomarker signal appeared progressively stronger from the overall population from APOE4 carriers to APOE4 homozygotes.

Again, this is hypothesis only!

We don’t yet know that this is the mechanism responsible for the BROADWAY findings.

Does Obicetrapib Have to Cross the Blood-Brain Barrier?

This is another fascinating wrinkle.

The simplistic model would be:

Drug enters brain → inhibits brain CETP → improves Alzheimer’s pathology.

But biology may be more complicated.

Peripheral lipoprotein metabolism can influence vascular function, inflammation and blood-brain-barrier integrity without requiring large concentrations of a drug to enter the brain.

At the same time, an earlier proof-of-concept study specifically investigated Obicetrapib in APOE4 carriers with early Alzheimer’s disease and examined cerebrospinal-fluid lipoproteins and cholesterol-efflux capacity.

So researchers are actively investigating both peripheral and CNS mechanisms.

This is an area where I expect we will learn considerably more.

The Cardiovascular/Alzheimer’s Intersection

This is also why I think Obicetrapib is especially interesting for APOE4 carriers.

We tend to talk about cardiovascular disease and Alzheimer’s disease as separate problems.

Biologically, they overlap far more than that separation suggests.

APOE4 increases Alzheimer’s risk.

It also adversely affects lipid metabolism and cardiovascular risk.

Vascular dysfunction can affect cerebral perfusion.

Blood-brain-barrier dysfunction may facilitate neuroinflammation.

Lipid dysregulation influences both atherosclerosis and brain biology.

And many of the things we do to protect our cardiovascular system - exercise, blood-pressure control, metabolic health, avoiding smoking and managing atherogenic lipoproteins - also appear relevant to maintaining brain health.

Obicetrapib is unusual because the same molecular target may potentially influence both sides of this equation.

A Particularly Interesting Attia Interview

If you want to understand the history and reasoning behind all of this, I highly recommend Peter Attia’s recent conversation with Dr. Michael Davidson, founding CEO of New Amsterdam Pharma, the company that developed Obicetrapib. Bookmark it and do listen - it’s absolutely worth the time!

Davidson is both a cardiologist/lipidologist and developed this medication as a result of his own familial experience with cardiovascular disease.

When I first wrote about CETP inhibition, I regarded it as one of the more intriguing emerging targets for APOE4 - and I still do.

But we have moved beyond pure speculation. We now have large randomized Phase 3 cardiovascular trials showing substantial LDL-C lowering, reductions in ApoB and Lp(a).

We have European regulatory approval.

We have a large cardiovascular outcomes trial underway.

And, perhaps most intriguing for this community, we now have a prespecified, peer-reviewed Alzheimer’s biomarker analysis involving more than 1,500 people, showing a modest effect in the overall population but a progressively larger signal in APOE4 carriers - and a striking result in the small APOE4/4 subgroup.

For those of us carrying APOE4, the idea that an oral drug could simultaneously improve cardiovascular risk factors while potentially influencing pathways involved in Alzheimer’s pathology is difficult to ignore.

And Next Comes SPINOZA

Perhaps the most important next chapter will be SPINOZA, NewAmsterdam’s planned Phase 2b trial designed specifically around Alzheimer’s prevention.

More information on this clinical trial can be found here: https://clinicaltrials.gov/study/NCT07794670

Unlike BROADWAY, which enrolled people for cardiovascular disease risk and discovered the Alzheimer biomarker signal in a prespecified substudy, SPINOZA is being designed to test that signal prospectively in people with preclinical Alzheimer’s disease. The randomized, double-blind, placebo-controlled study is expected to enroll up to 400 participants, including at least 100 APOE4/4 carriers, along with approximately 125–150 APOE3/4 and 125–150 APOE3/3 participants. The primary endpoint will be the change in plasma p-tau217 at 52 weeks, with additional Alzheimer biomarkers and cognition, using the PACC5 cognitive composite, also being followed.

That deliberate enrollment of a much larger APOE4/4 group is particularly important. The remarkable BROADWAY result in APOE4 homozygotes came from only 29 people. SPINOZA should give us a much better opportunity to determine whether that striking APOE4 gene-dose signal was real—and whether CETP inhibition can actually alter the trajectory of Alzheimer’s pathology before cognitive symptoms appear.

For me, this is where the Obicetrapib story becomes particularly exciting. We are no longer talking only about lowering LDL-C, ApoB and Lp(a), nor are we simply speculating from genetics about what CETP inhibition might do in the APOE4 brain. We now have a signal in humans and a trial being designed specifically to test it.

If SPINOZA confirms what BROADWAY unexpectedly uncovered - particularly in APOE4/4 carriers - we may be looking at something much bigger than a new cholesterol medication. We may be looking at an entirely new approach to Alzheimer’s prevention: targeting lipid biology years before the disease becomes symptomatic.

We aren’t there yet. But this is one trial we should all be watching very closely.