Obicetrapib: The First Oral Drug to Move Amyloid AND Tau in APOE4 Carriers

[0:00]A cholesterol drug just did something. No Alzheimer's drug has ever done in in APOE4 carriers In a pre-specified sub study of 1535 patients published this year in the Journal of Prevention of Alzheimer's Disease. p-tau217 the cleanest blood biomarker we have for Alzheimer's pathology dropped 7.81% on this drug, and it went up 12.67% on placebo.

[0:33]So that's a 20.48% placebo-adjusted difference in APOE4/4 homozygotes And the authors These are NEJM-level cardiologists not over claiming cheerleaders. And they wrote this these findings represent the first demonstration of a oral intervention capable of reducing both beta amyloid and tau pathology. Biomarkers in ApoE4 carriers. Hi my name is Doctor Kevin Tran.

[1:02]I'm a doctor of pharmacy and an APOE4/4 carrier I'm the founder of the Phoenix community for ApoE4 carriers to beat the odds. And every week I dissect new papers, new studies to find us ApoE4 carriers, new interventions to optimize our brain health and our longevity. So today I am going to walk you through the drug.

[1:25]It's called obicetrapib What the Broadway study actually showed and why other drugs in this class failed catastrophically, and why this one didn't, where the evidence is strong and where it's weak. And what ApoE4/4 carrier should actually do with this information right now. If you are an ApoE3/4 carrier, this is also very important for you.

[1:49]Even though those studies were done on ApoE4 Homozygotes. So what is obicetrapib obicetrapib is what is called a CETP inhibitor. CETP stands for cholesterol ester transfer protein. It's a oral drug. It's one pill that you take ten milligrams a day, and it's made by a company called New Amsterdam Pharma.

[2:12]Here is CETP in one sentence from the 2024 Current Atherosclerosis Reports review So CETP tend to result in a net mass transfer of cholesterol esters from HDL to VLDL and LDL and the net mass transfer of triglycerides from VLDL to LDL and HDL. Basically, the translation is CETP is a protein in your blood that shuttles cholesterol out of your good HDL particles and into your bad LDL and VLDL particles block it, and you do two things simultaneously.

[2:44]First, LDL goes down, second HDL goes way up. And here's the part that nobody talks about enough obicetrapib also raises ApoE and ApoA1 the apolipoproteins that sits on the surface of HDL particles. And I have a direct quote from the same review. LDL-C, non-HDL-C, ApoB, LDL particle concentration particularly small LDL particles and lipoprotein(a) (Lp(a)) and raises pre-beta HDL as well as mature HDL particles and ApoA-1 and ApoE All right. That's a lot of information.

[3:22]But basically hold that ApoE piece because we'll come back to it. It's the key to why this drug might matter specifically for us ApoE4 carriers. so mechanistically, obicetrapib sits in a completely different spot on the cholesterol pathway than your statins, than ezetimibe And we have another video on ezetimibe And compared to PCSK9 inhibitors because statins block the liver from making cholesterol Ezetimibe blocks your gut from absorbing it.

[3:49]And PCSK9 inhibitors make your liver pull more LDL out of the blood. obicetrapib blocks the trend first step in the blood stream itself. So all of those are different levers which means that you can stack them. And all of those are different targets. First let's look a little bit at history.

[4:07]Why other CETP drugs failed in the past and why is this one different? Because if you've been in this Alzheimer's ApoE4 space for a while, you might already be skeptical because CETP inhibitor has a body count. Three big drugs. Before this one, we had Torcetrapib Pfizer that blew up in 2006 because it increased cardiovascular events and death.

[4:31]We had Dalcetrapib from Roche with no benefits. We had Evacetrapib from Lilly, no benefit, who had Anacetrapib from Merck. It was technically positive, but tiny effect size and it built up in fat tissue forever. So that was pulled off What is interesting is the first one, the one that blew up in 2006 Torcetrapib is the one that matters for understanding obicetrapib because here's what went wrong with Torcetrapib from the same review.

[5:00]Torcetrapib had structure-related off-target effects causing increased blood pressure, as well as increased aldosterone steroid, and endothelin-1 levels, and electrolyte abnormalities So basically it was a dirty molecule. It wasn't the CETP inhibition that killed it. It was all the off target junk that happened. Because when you unblinded the trial, the Torcetrapib patients had higher blood pressure, high aldosterone and higher cardiovascular death despite the gorgeous lipid profile.

[5:30]So the mechanism got blamed. The molecule was actually guilty. Obicetrapib was built specifically to avoid those off target effects. And here's what the Brooklyn Phase three trial published in Nature Medicine this year about safety. In the trial, Obicetrapib was observed to be well tolerated, with safety results comparable to placebo and no increase in blood pressure.

[5:50]The treatment is continuation rate for Obicetrapib arm was 7.6% versus 14.4% for placebo so no blood pressure signal lower discontinuation than placebo. This is a very, very clean molecule. That's the first thing you need to understand. The CETP target isn't cursed. It's mainly that the old drugs were Cursed All right.

[6:10]Let's look at Broadway, the study and the lipid story. Let's talk about what obicetrapib actually does to your lipids, the flagship trial is Broadway as I mentioned. So that was a phase three that was published in the New England Journal of Medicine in 2025 and 2530 patients with established cardiovascular disease of familial hypercholesterolemia already on maximally tolerated statin therapy randomized 2 to 1 to obicetrapib ten milligrams versus placebo.

[6:40]The primary endpoint Ldl-c change at day 84, so the least squares mean percentage change from baseline to day 84. In the LDL cholesterol level was minus almost 30% in the obicetrapib group, as compared with 2.7% in the placebo group. That's roughly a 32.6% point treatment difference versus placebo in LDL, on top of maximum those statins So the effect is durable through the whole year.

[7:10]It's flat. It doesn't fade. Now, if we zoom out to the meta analysis, this is the 2025 American Journal of Preventive Cardiology pooled analysis of all seven obicetrapib randomized trials. So we're looking at almost 3400 patients in total. So compared with placebo obicetrapib significantly reduced mean Ldl-c lipoprotein(a) and apolipoprotein B This is really cool because every trial went on the same direction the same magnitude.

[7:44]So that's extremely clean. And LDL went down by about 37% Lp(a) down about 37% as well. ApoB down about 25%. That's a almost boringly consistent drug, which in science is probably the best compliment you can pay. And notice a little thing here. We're talking about Lp(a) that normally is extremely, extremely difficult to change with any lifestyle interventions that you can do.

[8:15]Because typically when you see that you have Lp(a) that is relatively high, you can't do anything about it. And typically healthcare providers will tell you to test once in your life and not really look at it because you can't really change it. And these drug actually push it down by 37%, which I believe is insanely good news for those of us with a higher Lp(a) and we also had two more things from the meta analysis that you probably want to hear.

[8:39]So there were no significant differences in adverse events. That's pretty cool. And interestingly, Obicetrapib also reduce the incidence of new onset diabetes. So as you may know, statins slightly raised diabetes risk. Obicetrapib lowers it by about 12%. It's not the main story, but if you are ApoE4 and already watching your glucose and report should be, that's a meaningful like Like cherry on the cake, right?

[9:05]There's also an early cardiovascular events signal. Broadway was not designed as an outcome trial, but the offers did an exploratory analysis. So an exploratory analysis showed a 21% relative reduction in major adverse cardiovascular events. So mass and Pooled with BROOKLYN The rate of coronary heart disease, death, myocardial infection, ischemic stroke, or coronary revascularization was lower with obicetrapib with a risk reduction in the second six months.

[9:34]So that pattern the no separation in the first six months, then the curves diverge. That's exactly what you would expect from any LDL lowering drug, because it takes a lot of time for the plaques to know you change the numbers. This is not an outcome trial. I want to be clear.

[9:50]The confirming outcome trial is PREVAIL That's close to 10,000 patients and the readout is expected late 2026. So very excited about that one. So until PREVAIL result the honest statement is the biomarkers look outstanding. The direction of cardiovascular signal is encouraging. But we do not yet have definitive proof that obicetrapib reduces heart attack or cardiovascular death.

[10:15]Write that on the inside of your eyelids. But for now, biomarker results. That's already fantastic. All right. The ApoE4 bombshell. So looking at the Broadway substudy because this is why you're here. This is why I am here hidden inside Broadway. This is a pre-specified not fished was a sub study.

[10:35]We had 1535 patients who had the ApoE genotype and the baseline and 12 months p-tau217 blood measured. That's a massive Alzheimer's biomarker cohort and published separately in December 2025. So very recently in the Journal of Prevention of Alzheimer's Disease. Here's the opening line of the abstract. obicetrapib significantly slowed as disease biomarker progression over 12 months In participants with ASCVD with the greatest effects in ApoE4 carriers.

[11:09]I love to hear that greatest effect in ApoE4 carriers, it matters most drugs. If you remember the infusion, the monoclonal antibodies lecanemab, donanemab and so on, they work less well in ApoE4 carriers and cause more side effects. This one goes the other direction. So finally, some good news for us, right?

[11:30]So now the specific number here is among ApoE4/4 participants. There was a 7.81 adjusted mean decrease in p-tau217 with obicetrapib compared to a 12.67 increase with placebo. That represent in total, when you mix it representing a 20.48% treatment difference. So look at that figure. The effect scales with genetic risk.

[11:53]The non carriers small effect ApoE3/4 heterozygotes bigger effect ApoE4/4 homozygotes Largest effect of any subgroup in the study. And we're not just looking at p-tau217 Look at the full biomarker panel in if e4 patients ApoE4/4 participants showed consistent improvement across multiple alzheimer's disease biomarkers compared to placebo treatment with placebo addressing benefits ranging from 13.67% to 22.65%.

[12:25]So p-tau217, Abeta42/40 ratio p-tau217 and Abeta ratio GFAP by the way. That's a marker of astrocyte activation and neuroinflammation NFL, which is neurofilament light a marker of neurodegeneration All of those markers, all five moved in the right direction specifically on GFAP So among ApoE4/4 participants, obicetrapib demonstrated significant effects on GFAP That's a 15 point gap on the marker of brain inflammation in ApoE4/4 patients in 12 months from a daily oral pill that was designed to lower LDL.

[13:04]And now the key quote, Davidson and colleagues write this in that discussion, and these are conservative cardiologists and lipidologists I want to remind you, they are not like, you know, like neuro-maximalists, right. So this finding represents the first demonstration of a oral intervention capable of reducing both beta amyloid and tau pathology biomarkers in ApoE4 carriers offering a potential preventive strategy for these high risk population who currently have no effective prevention options.

[13:32]So I would love you to reread that again, because if you are an ApoE4/4 carrier and you've been listening to the field tell you that you know for 20 years that genetics is destiny, blah, blah, blah, this one sentence is the first time a peer reviewed phase three substudy has contradicted that.

[13:48]So as an ApoE4 carrier watching this data come out in real time, I kind of got really excited and this is a great moment for us Now, I also want to mention three caveats because if I don't talk about them, I don't think I'm doing my job. So yes, we're excited, but there are caveats First, this is a biomarker outcome, not a cognitive outcome.

[14:13]So normally has measured, you know, MMSE or CDR-SB on real world dementia incidence on obicetrapib p-tau217 is arguably the best surrogate or the best proxy we have for AD pathology but surrogate get a proxy. It's an operative word. What we want to see is not only biomarkers improvement, even though those are already great.

[14:35]It's also like actual functional health afterwards. Right? The second is the number the ApoE4/4 subgroup. While it was pre-specified, which is great, is a small slice of 1535 total. So we would love to see more replication. But for me that number is big enough to definitely take the drug.

[14:56]Third, and it needs confirming because again, it's an independent data set. A larger overlapping analysis showed concordant result which is great in ApoE4 carriers. So obicetrapib stabilized p-tau We had 0% increase versus 5.7% increase with placebo. That was with an AAIC abstract from Davidson. And the p-tau217/Abeta42:Abeta40 ratio rose only by 2.1% on obicetrapib versus 10.2% on placebo.

[15:26]So that is a really reassuring internal consistency. But it's still the same clinical problem, not a different trial. Right. So the honest synthesis is this is the strongest oral drug ad biomarker signal we have ever seen with ApoE4 carriers. It's not yet proof of dementia prevention. So for that we would want to prospective randomized native endpoint trial.

[15:49]And till then we treat this as a major hypothesis with unusually strong backing evidence. And in any case I'm super excited about it personally. One more thing from the figure, the effect was biggest in other patients. Our median member age in the Phoenix communities around like 58. I'm guessing if you're watching this video, you should be in the same type of cohort.

[16:10]So you have to know that this age clearly sitting right inside the window where the effect was largest. So keep that in your head, because it means this drug might be perfect for you. So the obvious question why would a drug that was designed to adjust blood lipids touch brain pathology?

[16:28]I always love to understand the mechanistic side behind it because this one is beautiful. So ApoE is a protein. Your ApoE4 gene is coding for the ApoE gene. Basically the E4 version of your gene produces a protein toward ApoE that doesn't traffic cholesterol as efficiently in the brain.

[16:48]In your brain, cholesterol is carried around on HDL-like particles that have ApoE sitting on them. Those particles are supposed to help clear beta-amyloid which is, again, the stuff that clumps up into Alzheimer's disease plaques out of the tiny vessels in your brain. But when you block CETP, which is again, what obicetrapib does, you raise HDL particle and you raise the ApoE riding on those particles from the mechanistic review in Journal of Cardiology and Cardiovascular Science.

[17:15]This year, they said in mice genetic and pharmacological studies have shown that HDL levels are highly associated with CAA, and that peripheral injection of synthetic HDL particles stimulates clearance of both Abeta42 and Abeta40 from the brain. So CAA stands for cerebral amyloid angiopathy amyloid buildup in the small vessels of the brain which is a huge deal for us ApoE4 carriers.

[17:39]So the mechanism obicetrapib leads to more HDL-ApoE particles which leads to better amyloid clearance in the brain vasculature which leads to less pathology accumulation, which leads to biomarker improvement. That's a very coherent story. It's not in our hand wave. And every step is actually independently supported, which is great.

[17:59]Now let's talk a little bit about things that led to this outcome, how we could have predicted that. And I want to talk a little bit about Mendelian randomization, which you might have heard several times on this channel already, because we basically should have seen this coming from genetics years ago.

[18:17]And maybe the scientists who developed obicetrapib actually saw that so that's why they actually dive into building this molecule, because this technique called Mendelian randomization, the short version of it is it uses genetic variants as a natural experiments because they are randomly distributed at conception. Let's say if you have a genetic variant that lowers CETP for life, you are essentially in a 60 year randomized trial of CETP inhibition Right?

[18:44]Because all of that and that's the idea of the Mendelian randomization is you can't really say, let's say if we take an example with statins, let's say we say statins reduces risk of cardiovascular risk. And you're looking at people who take statins versus people who don't take statins.

[19:00]The problem with doing that and observational study is that you would end up with tons of confounding factors if you are looking at the general population. Why? Because it means that people who take statins, they are also the people who tend to go to the doctor because that's why they are prescribed statins.

[19:15]Maybe they also in a higher social economic class, because they have money to afford the drug and money to afford to go to the doctor and what it means. It also might mean that their diet is also cleaner, or they tend to exercise more because they have more money, more hobbies or whatever. Right?

[19:31]So you realize very fast that these observational study tend to have a lot of confounding factors that is very, very difficult to account for. And that's why looking at Mendelian randomization which means like looking at people with just a genetic mutation that leads to the same pathway. That's the best way, because everything else is equal, because it's not just a random gene.

[19:53]Right. So going back to that Mendelian randomization for CETP. So Schmidt and colleagues in 2024, in Alzheimer's research and Therapy run exactly that analysis. And here's what they found APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE4 positive patients compared to ApoE4 negative patients, which is ApoE3 and ApoE2 patients.

[20:14]LBD here refers to Lewy body dementia, the kind that Robin Williams had and the effect is 39% lower risk which is very high right in ApoE4 carriers with genetically lower CETP versus only 11% lower risk in non-carrier and the interaction p value is. Really statistically significant. So the drug benefit should be concentrated in ApoE4 carriers.

[20:39]So the geneticists told us that in 2024 and Obicetrapib delivered it in 2025. The authors conclusion there is that these results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect in ApoE4 carriers, which is us, which is great. in ApoE4 carriers, which is us, which is great.

[20:58]And there's even older genetic data, which I like, because you really want to have as much data as possible that are confirming all these mechanistical actions, right? So Nir Barzilai I hope I'm not mispronouncing the name. You might know him from the longevity world studied Ashkenazi centenarians in 2006.

[21:16]He found a striking association between CETP VV genotype, which is basically genotype that naturally lowers CETP activity and preserve cognition. So subjects with MMSE about 25 were twice as likely to have the CETP VV genotype, and those with the VV genotype were more likely to have an MMSE of above 25.

[21:36]So basically, people with the lower CETP variant were more likely to keep the cognition into extreme old age, and the CETP gene tracked with both exceptional longevity and preserve cognitive function If you have your gene sequence, I suggest you look into that because maybe you have this gene variant, and maybe you basically have already lowered CETP.

[21:56]We also had several other studies that were interesting. The 2015 Cache County Study were around 4500 people, followed for up to 12 years, confirmed it. Analysis revealed an average 0.6% decrease per year in the rate of cognitive decline for each additional valine We conclude that CTP I405V is associated with preserved condition over time, but is not associated with low status.

[22:20]So the worth noting the Cache County didn't find the link between CETP I405V and the clinical Alzheimer's diagnosis itself just a slower rate of cognitive decline But that's already very good. So this is a cognitive trajectory signal, not a confirmed disease prevention signal. So two decades of genetics a causal-inference MR analysis pointing toward an ApoE4 specific effect, a coherent HDL-ApoE-amyloid mechanism and now a phase three biomarker without.

[22:48]So these are all pointing to the same direction. The conversion is what makes this story very different from most promising early signal noise that you can hear in the space. And that's why I'm so excited about So I want to go a little bit on And that's why I'm so excited about So I want to go a little bit on Lp-little-a because I believe we don't talk about enough.

[23:06]So Lp-little-a is mostly genetically determined LDL like particle that independently raise your cardiovascular risk, your stroke risk. And and this matters a lot your vascular contribution to dementia risks. It's ApoE independent. So those two genes are completely independent. You inherit your Lp-little-a level. It basically doesn't change with diet or exercise.

[23:27]That's why I know a lot of people freak out about this when it's high. And until very recently, there were no approved drug that meaningfully lowers it you had a few Lp-little-a targeted drug in development right now, like pelacarsen, lepodisiran, olpasiran, muvalaplin but none are FDA-approved yet And what is insane is obicetrapib drops Lp(a) by about 36 to 46% in Brooklyn studies Specifically, treatment with Obicetrapib resulted in a placebo adjusted reduction in apolipoprotein B of -25%, approximately non-HDL cholesterol of -34.5% and lipoprotein(a) of -45.9% as well as a placebo adjusted increase in high density lipoprotein cholesterol of 138%.

[24:16]So a 46% of Lp(a) reduction from a oral drug not in infusion. It's not as headline grabbing like the p-tau217 story, But for us, ApoE4 carriers that Lp(a) affect is huge and we have very few other tools for this right now. This is the part of the Obicetrapib story that even cardiologists keep underselling, and that I found really fascinating.

[24:43]So now that we are only cited about it, can we get access to Obicetrapib So the short answer is no, because it's not FDA approved yet. So you can't pick it up in your local pharmacy. But what you can do is the study prevailed, is active, and fortunately it's not recruiting.

[25:03]So the spots are full, but they are a small phase two pilot in early Alzheimer's disease. ApoE4 carriers. Those are completed, but you have more and more that are popping up right now. So we are keeping track of these in the dashboard in the Phoenix community about all the clinical trials and most importantly in the Amsterdam, the pharma company behind it, had signaled intent to file with the after PREVAIL So the timing and approval is kind of speculative.

[25:30]You can't really take dates from that, but it might take a little while. So if you're in a hurry, the best bet first I just look at your whole genome sequence. Because maybe you already have the gene that lowers your CETP naturally, and then it's jackpot for you.

[25:45]Congratulations! I don't have it, fortunately. Otherwise, like, we'll keep track in the Phoenix community about all the different trials there and you can know how to apply for them. Also, reach out to Big Pharma to build these clinical trials with them. And I'm actually currently actively talking with a few of them, and I'm actually currently reaching out to new Amsterdam to see how we could help recruit for more ApoE4 patients, because our goal at the Phoenix community is really to give you access to those clinical trials as fast as possible.

[26:15]And as a patient group, we want to show big pharma that we can help them recruit, so it makes the allies as well easier. So if you are from New Amsterdam Pharma watching this like please reach out to me. You can find me at Kevin at the Phoenix Community.

[26:31]please reach out to me. You can find me on LinkedIn or by email. I would really love to have a chat with you. We have 500 plus members right now at the time of recording of this video of ApoE4 carriers who really want to get on Obicetrapib and we have 4000 plus ApoE4 carriers in our newsletter that also would love to get onto it so we can help.

[26:54]Please reach out. All right. That was my bottle in the sea. Hopefully it can reach people at New Amsterdam Pharma because I really would love to have a chat with you guys. All right, before we finish this video, I want to be completely honest about what we know and what we don't know, because I don't want you to walk away from this video with your false level of certainty.

[27:14]Let's start with what we do not have. We do not have cognitive outcomes. Trial on Obicetrapib So typically with MMSE or CDR-SB all of those were not measured. We do not have an ApoE4 prevention trial. We do not have long term safety data beyond the trial duration, which is one year.

[27:33]We do not have confirmed cardiovascular mortality benefit and we do not have FDA approval or pricing information. However, what we have is three positive phase three trials on lipid endpoints, which is, I believe, great. We have a poor mass signal that looks real and appears after six months.

[27:53]We have a pre-specified ApoE4 biomarker sub study with the strongest oral drug signal on record. We have an independent confirming analysis, and we have two decades of genetics predicting the same direction with Mendelian randomization. We also have a very coherent mechanism and we have a clean safety profile.

[28:14]So for me that's really unusual that we have such strong evidence for a drug that is not approved yet. It could still disappoint. You know, sometimes science does that. But if you ask me, what's the most exciting drug you are watching for ApoE4 in 2026 and 2027? This is the one All right.

[28:31]If any of these matters to you, and if you are still here watching the video, it probably does. Here's how the Phoenix community fits in. We built Phoenix specifically for people like us for ApoE4 carriers high family risk folks, people who want to navigate this stuff with scientific rigor without getting crushed by aloneness.

[28:48]What we do inside Phoenix community is blood work tracking with ApoE4 specific reference ranges, because normal for the population, for the general population isn't the same as optimal for an ApoE4 carrier. So when you are looking at drugs like Obicetrapib and everything else, your lipid panel your ApoB target is extremely different compared to the normal populations Target your Lp(a) target matters even more.

[29:11]We build all the tooling for that to show you what is the optimal value for you as an ApoE4 carriers, and which interventions you should follow based on what works for people in our community which are genetically similar to you, which means they are like ApoE4 carriers, because what works for people similar to you has a higher chance to work for you as well.

[29:30]We also have this clinical trial dashboard where we are always monitoring the latest clinical trials, and we help our members get into them or connect with them. We also have monthly pods where you connect with other ApoE4 carriers to talk about your monthly targets. So then you can feel that you get understood by people because as you know, like probably your friends or your family don't really understand the way that you carry with ApoE4 And it's way easier to discuss it with people who are very, very aware of it because they are in the same journey as you.

[30:02]We also have tons of different experiments that are pre-built on your guinea fat inside our app for you to run to find which interventions works for you specifically, not just based on studies. I really believe you should not navigate this alone when I realize I carry ApoE4 I really hope that something like that existed.

[30:19]It didn't, so I built it All right, that's it for today. It didn't, so I built it All right, that's it for today. Thank you so much for watching. If this was useful, subscribe to this YouTube channel. I release that this type of video every week or so.

[30:32]The link to the Phoenix community is here on your screen or below in the description, and all the citations are in the description of the video. Take care of yourselves and see you in the next video. Bye!