My name is Matt Hartwell. Welcome back. It's a pleasure to be here with Dr. Michael Davidson of NewAmsterdam Pharma. So thank you for coming.
Thanks, Matt. Yeah.
So let's just start off. It's an important year for the company, several important readouts. But before we get to that, can you just give us an overview of obicetrapib and kind of how it differentiates from the other CETP inhibitors that have been pursued by other ?
Sure. So obicetrapib is a much more potent CETP inhibitor. It's only 10 mg, and it lowers LDL in that 40%+ range, raises HDL 150%. And so the other benefits that this drug has are very differentiated from any other LDL-lowering drugs. So it's not just an LDL-lowering drug. It also lowers Lp(a), lowers the risk of diabetes, which mitigates the statin-related issues there, 'cause statins raise Lp(a), raise the risk of diabetes, and it also reduces the small particles by 90%, total particles by 50%. So it's got this very unique profile. Now, the other CETP inhibitors in the past, it has a very long... You know, I was involved with it as myself, as a researcher. I'm a cardiologist, lipidologist.
They all were focusing on HDL raising, and there was a rush to do that because the science said the association was a 1% increase in HDL reduced risk by 3%. So everyone was saying: Let's get HDL up. And then they rushed these drugs out the market, and unfortunately, they all were discontinued for different reasons. For torcetrapib being an off-target toxicity, which none of the other ones had. They've all been very safe since then. And then they all had very low LDL-lowering efficacy 'cause they were focusing on the HDL raising. And so they designed the studies for focusing on HDL. But the most important finding for us was the Merck one with anacetrapib.
They actually did power the study, 30,000 patients, and they went long enough to see an LDL-lowering benefit translate into cardiovascular outcomes. So that, for us, that was a eureka moment, where it's all about LDL lowering, and the genomics also supported that. And so when we had obicetrapib, you know, got that back from Amgen. And so now when you saw this data from REVEAL, the outcome study with anacetrapib from Merck, and all the genomic data shows all about LDL lowering. We have now had a much more potent LDL-lowering drug that we could then take forward into the Phase II and now Phase III trials. So it's an evolution of thinking about how to target this very important protein and how to make it effective in reducing cardiovascular risk.
Great, thanks. And we'll get back to some of the biomarkers in a bit, but, a number of important readouts for the company this year, and then, you know, subsequently into 2025 and 2026. So can you talk about kind of the top priorities for the company this year, heading into the Brooklyn and Broadway studies?
Sure. Well, I think from the trial perspective, we've really executed on all cylinders. I mean, we're a small company, but yet we enrolled all our trials either on schedule or ahead of schedule. And we also were able to start our outcome study, PREVAIL, at the same time as our LDL trials, and we fully enrolled that in April of this year, 9,500 patients. But our two pivotal LDL trials, you know, finished enrollment, and now we're getting to the end of the study's readouts. The Brooklyn's already finished, and we'll have the cleaning up the data, be ready to present that in the third quarter. And then Broadway is almost soon to complete, and then we'll have that data towards the end of this year. They're both pivotal LDL lowering trials.
One, Brooklyn, will be first. It's 350 patients, 2:1 randomization. All the patients have familial hypercholesterolemia, so the baseline LDL is quite high. And then Broadway is mostly atherosclerotic cardiovascular disease patients that will read out towards the end of this year, and that will be the larger of the two trials. So we're really on track for all our Phase III readouts for LDL lowering, and then the outcome study will follow. They're roughly the end of 2026.
And then you touched on kind of the biomarkers and the mechanism of action for Obi here. You know, what are your expectations for... Can you help set the stage for the expectations for both the Brooklyn and the Broadway readouts, in terms of biomarkers? What you expect to see, based on the compelling Phase II data that you had demonstrated so far?
Right. So in the lipid world, you know, we have what people focus on, the what's called the atherogenic burden, you know, what causes heart disease? It's LDL. The non-HDL might be a little bit better than LDL. Then we have ApoB, and we have LDL particles. People debate, you know, which one's the best, and we focus on LDL primarily clinically. It's the easiest, you know, to evaluate. But we're gonna look at all those parameters. Again, in Phase II, we were in that, you know, 43% for LDL, non-HDL, about 40%, ApoB, you know, close to 30%, LDL particles, 50%. Small particles is 90%. So we're across the board on all the different atherogenic lipoproteins. We do very well for all of them.
We can debate which one's better in predicting events. They're all good. We plan to show that data ultimately, you know, for the trials. Our first readout will be the LDL, which is the primary endpoint when we announce the data initially. But we also have very exciting data on Lp(a). I talked about that already, and diabetes prevention benefit that we may be able to see even that in our phase III trials, because it's one year. Usually, it might take a little bit longer to see the diabetes benefit really come to fruition, 'cause you're preventing diabetes with these drugs as well. It's been shown for all the CETP inhibitors.
And then on Lp, it's obviously becoming more of an interesting target, and people are more focused on it, from a biomarker perspective. Can you talk a little bit about what you've seen there, in the phase II studies and kind of, you know, how that-- what, what kind of role that plays, with OB? I, I don't-- I believe other CETP inhibitors have not seen that.
Well, all the CETP inhibitors actually did lower Lp(a), except for dalcetrapib, but again, much less potent. But anacetrapib and evacetrapib lowered it by about 20%. So about double, you know, we're double. We're in that, you know, as low as 40% in one trial, up to 57% in another. So we're in that range of Lp(a) lowering. But we-- we're not seeking indication for that. That will be the injectable therapies, RNAi and ASO approaches. They're going after, you know, much higher levels of Lp(a), which is... In my lipid clinic, which I still see patients, it's a very important unmet medical need for those very high Lp(a) patients who still have high risk despite being on statins.
But for us, the way we look at it is, it's a differentiating feature for patients that have high Lp that don't meet the threshold of where an injectable drug would be necessary, assuming their, the outcome data are positive for all the injectables, which will happen over the next few years. But we would, we would be for the patients that have the mild to moderate Lp lowering, net need for Lp lowering, which is the majority of patients that have high Lp. And we based on the data we know so far, it's a, it's a lower-is-better issue.
Even having mild elevation increases risk, and so we, we believe, again, this will be a, a differentiator that we could provide to clinicians, that they could utilize, obicetrapib, and then if they have really high Lp, then they go to the injectable drugs. A nd that would be where the indication would be for those therapies.
Then can you touch on the safety profile? You know, I know you haven't seen any issues with blood pressure in that blinded data, which is great. What else should folks be paying attention to from a safety perspective?
Well, there's a long list of lipid drug issues. One, liver enzymes, muscle enzymes, kidney function, blood pressure, and those are the things you look at the most, as far as safety. Diabetes, again, we think we'll have the other direction, but all the other lipid drugs, especially statins, have this diabetes increased risk signal. So those are all adverse events of special interest for us, and so we'll have that data when we fully release all the data in the upcoming medical meetings and publications.
That's great. And then as you think about the kind of registrational path here, I know you have the two LDL-lowering studies coming up this year. You'll get your outcome study, you said, I think, late 2026. Can you talk to me, talk to us about the registrational path here, how you think about filing for timing, assuming you do have positive LDL studies, and then where the outcomes piece plays in?
So we wanna launch with outcome data in hand, and so we will be able to meet with the regulators, the FDA. Europe is a little bit different path because they can file. We have already the green light to file based on LDL, and then the pricing would happen a year later, different countries. So the outcome data would be available at the time of pricing. For U.S., we wanna have outcome data in hand at launch, and so we can look at our event rates in PREVAIL and pretty accurately estimate when that study will finish. So we will file. The PDUFA period is 12 months, so assuming when we believe PREVAIL will finish, we could file the LDL indication, so it would read out during the PDUFA period.
That's how, that's how we're thinking about it right now.
Okay. And then can you talk about, you know, commercially, assuming a positive Brooklyn, Broadway, and then PREVAIL study? Can you? You know, you're in a unique position. You're, you're a KOL in the, in the, in the cardiology space and lipidology space, but you also happen to be the CEO of this company. So I think you're, you're in a unique position relative to other companies to, kind of understand the commercial opportunity. And can you talk about how you might use this in your clinic, and how you, your peers, you may, may use this, this product?
Right. I think the biggest issue for treatment is, is inertia, and treatment inertia, where physicians have, at this point, limited options. They have, you know, two oral add-on to statins, ezetimibe and bempedoic acid, lower LDL in the 15%-20% range. One is generic, and it actually is growing well. It's 20% annual growth, so it's, it's easy to use. It's a generic pill, you just add on. It's safe, well-tolerated, so it's growing. Bempedoic acid, also efficacy, generally well-tolerated, but does have some side effects. It's, it's branded, you know, and has that, that, that hurdle of getting the payer authorization and so forth. Then you have injectables, which are very effective, generally well-tolerated, but expensive and, and injections. And so what physicians need-...
This is, again, speaking from my own clinical experience, if we can just give you one little pill to take that's well-tolerated, and we have, again, no headaches, you know, no, no side effects. Everyone gets the goal, which is what our data shows. If you remember, we're also doing a fixed-dose combination with ezetimibe. And roughly, in our studies, 50% are on ezetimibe already in Brooklyn, and in Broadway, it's 20%, PREVAIL 25%. So we're talking about if we can just have the fixed monotherapy or the FDC combination, that's all they need to do. In fact, our data would suggest, based on our modeling, that almost everybody with those two options get the goal, and you're done. So there's very few drugs like that in practice.
Even the diabetes drugs, you're thinking, "Okay, I got, I got a little bit more A1C lowering. I'm at another third drug or fourth drug to get that A1C below seven." In our situation, just one simple, well-tolerated oral therapy, and you're done. I think that's to be very appealing to the primary care doctors out there, and we're doing all the work, hopefully ahead of time, to, to maximize access, so we can get them great access at the time of launch. And, and, and part of that is having the outcome data in hand at the, at the time of launch.
Is there anything you can learn from kind of prior precedent, launches in PCSK9 or bempedoic acid, you mentioned?
Well, yeah, I think key is, again, outcome data in hand is important for the payers. And then, of course, you know, pricing it where you get the maximum amount of access, which doesn't mean... fortunately, doesn't necessarily mean lower price, but a price where the payers can get their their rebates, so they can get broad access without, you know, without many, too many prior authorization requirements. And then, of course, the overall profile of the drug. At the end of the day, it comes from patient demand, clinical demand to get the payers to move. And so we believe with this type of profile, the efficacy on LDL, but all the other benefits, the demand itself, we believe, that can be created, will get, you know, payers to get on board as well.
That, that's our focus, so we have enough lead time. We hired this BJ Jones, who ran the commercial Chief Commercial Officer at Biohaven. He's brought many of his former teammates on to help us lead this commercial effort. But we want to prepare the market well, for we believe is a very ... We can make in the market ahead of time.
Can you remind us how big the market opportunity you think this could be?
Well, if you look at, I mean, the one, the one analogy I like to talk about, it's historical, is ezetimibe when it was 15% on add the statins, with a $4 billion market, and it had another $2 billion of Vytorin. Again, easy to use, safe, well-tolerated, modest efficacy. So that was a market that was, I think, a good benchmark for us. Now, we actually believe the market could be even bigger because back then, the goal was 70, and maybe not even a hard 70. Now, the goal is 55 or less. And so the unmet need is actually greater. And so we, again, with a simple-to-use, oral, efficacious, well-tolerated drug, you're getting almost everybody below 55 with one add-on treatment.
We think the market could even be larger than what they saw with the ezetimibe.
Great. And you mentioned ezetimibe. You are running a fixed-dose combination study with ezetimibe. Can you talk a little bit about that study, kind of who you're enrolling into that study, and how you see that expanding the opportunity here or enhancing the opportunity?
Yeah. That's the TANDEM trial. It's a pretty standard formulation study where you get placebo, and then you have each drug individually, then the fixed-dose combination. And you want to try to show added efficacy of the combo versus each of the components, versus placebo. And so, Nexletol and Nexlizet did that, and I think that's probably the more successful of the two options, because it does have the greater efficacy. We want to try to follow that same kind of regulatory path. But we have something special about the two drugs that's enhancing the science behind it. Because CETP inhibition actually improves removal of cholesterol through the intestine. It's called TICE, transintestinal cholesterol efflux.
The ezetimibe is an inhibitor of intestinal cholesterol absorption, so it kind of like opens up the faucet and then also opens up the drain. So you turn on the faucet more powerfully, open up the drain, you get a lot more flushing out of cholesterol. We believe that that has not just LDL-lowering synergy, which we showed in our phase two trials, but also we believe that could have an impact on atherosclerosis, and we also now launched an imaging study with CT angiography as the biomarker of non-calcified plaque volume, which is a growing target of many imaging modalities to look at plaque. I believe as a cardiologist, lipidologist, that's the future. We're gonna look at plaque now, and before people have events, determine that we've turned off the plaque progression.
I think, with those tools, and we apply them effectively, you know, no one should get to the point where they get heart disease. You know, it would be. We want to treat it before it actually becomes a clinical event. And these plaque analyses are very helpful. Even if people that already have events—we can then treat them till we know we've turned off the plaque progression with these type of modalities. So we're using that, this new technology, to enhance the change in that parameter, in the, what's called the REMBRANDT trial, which will read out slightly after PREVAIL, actually.
That's great. So the totality of the data coming out over the next couple years is gonna be really, really cool to watch. Can you talk about kind of, you know, the rest of the portfolio, the strategy here? I know you guys raised some money earlier this year, and, you know, kind of what you're thinking in terms of, you know, what, what else you'd like to do with, with Obi or, you know, other, other strategy around the portfolio?
Well, it is, in some ways, a pipeline in a pill because we have the mono, we have the fixed-dose combination. We also have an exciting, just proof of concept Alzheimer's trial. This. Even the Alzheimer's Disease Discovery Foundation wrote a full report on CETP inhibition on Alzheimer's disease because there's a lot of scientific rationale for it. What we decided to do was to, with this proof of concept study, showing we do modify cholesterol metabolism in the brain of people that have APOE4, which is a lipid gene, and it's the most prominent gene for developing Alzheimer's. Because they. Our theory is they can't transport cholesterol out effectively. We showed that we did get cholesterol out of the brain with our proof of concept study.
We're now in Broadway, which is a 12-month study, 2,500 patients. We will have a large subset with APOE4, and we're gonna look at tau and amyloid biomarkers. If we see a positive signal, then we could, we may decide to move forward with a separate Alzheimer's program. But that would be ex- You know, that's a upside, very large upside opportunity that we'll... You know, again, we're not banking on that. It's not part of our main investment thesis right now, but if we do show that, it would be a very big upside for the company.
That's great. And then I got one more for me, and then open up to folks that, if anyone else has any other questions. But, so I think there, there's been some recent kind of in FDA label expansions or extensions for marketed products for, like, use. We saw this with bempedoic acid. How do you think about that as a potential tailwind for this, for the space? And kind of, you know, what does that imply the FDA's, you know, thinking around about this space?
Well, actually, there's a couple of tailwinds. One is that the FDA, I think, recognizing that payers were using labeling to restrict access. So they had. They first had this label where you can use the drug on top of maximum statins in certain high-risk groups, ASCVD or FH, atherosclerotic cardiovascular disease or familial hypercholesterolemia, because the levels are still too high. And they didn't. They didn't define what exactly too high means, and they also required statin background therapy. So now the new label doesn't. It takes away the statin background or the ASCVD FH requirement. So they're basically giving the indication across the board for anybody that needs LDL lowering, including primary prevention, secondary prevention. And so those are, those then should no longer affect. They, they no longer. Payers can't use that, the label, to restrict care.
That's so that helps. And then secondly, the guidelines have shifted back to targets again. There was a period of time where goals were taken away. That was 2013. It's a very unfortunate period of time where there was no data showing that on top of statins, there was benefit. Now there's substantial data showing there is benefit, and so the guidelines have now moved back to goals again, and now the goal shifted even lower to 55. So those two tailwinds are gonna help us even more so when we hopefully have a great drug available for launch.
Any questions from anyone else in attendance?
Thank you so much. I'll probably a quick questions regarding people are kind of wondering the correlations between, the lowering down, like, like LDL-C, around, like, 30%-40%, compared with, the percentage of the MACE reductions, the MACE event rates that happened. So I think what we see, like, in the past history, that, if you zero, like, 20% of the lowering downs of LDL-C, my trigger is around, like, lower than 10% of the MACE.
And we are kind of trying to forecast that we have around 30%-40% of the LDL-C lowering, and it could be, like, higher than 25% of the MACE. So, what is the forecast that for your, in your forecast about ApoB too? And we're also seeing the discrepancy around in, like, PCSK9, and butting up, like, previous trials. The correlation seems a little bit off the line compared to statins in the future, and how you're kind of explaining why PCSK9 was not reflecting the same, on the front, a nd how does that compare to our own trials? Thank you.
Right. Right. So yes, there's a well-established relationship between absolute LDL lowering and event reduction, but it's also time-based. You know, you have to take the time to get there because the first year or two, the benefits are very modest. And so, for the PCSK9 inhibitors, the issue there was that they had, yes, they had a profound LDL lowering of, you know, 40, 50 mg per deciliter. However, they only went 2.3 years and median, and then they had over 10,000 patients that had only nine months of exposure in that trial, which dilute out the overall benefit.
If you just did an analysis where you take anyone who'd been on the drug for only a year, a minimum of a year, the relative risk reduction went from 15% to 20%. So when you model the LDL lowering efficacy by time, it's right on the line for PCSK9 inhibitors, for what you saw with statins. So time is the other factor that never-- everyone has to adjust for time. And so an absolute LDL lowering is really the key, not percent LDL lowering. And so what we've done in our trial to maximize both, is we have a much higher baseline LDL. I think we, we came out with our baseline LDL at the, our R&D day a few weeks ago. Our baseline LDL is around 100 mg per deciliter.
The outcome studies that were done with REVEAL and center field with the LDL, the baseline was 61 mg per deciliter. If you went to the higher tertile, the baseline LDL was a little over 70. It was a 17% relative risk reduction. So baseline makes a big difference in that trial in particular. So we want to maximize both the baseline being higher, the absolute magnitude of LDL lowering and the time horizon. And so I put that two and after a minimum follow-up in there. So in our modeling, and we show this, we're over 20% relative risk reduction with our modeling for our drug.
However, you got to account for drop-in, drop-outs, which are always more challenging as trials go on because you got, you know, the people go on other drugs. There's other drugs available, so we, you have to adjust for that. But so far, we feel really good about the drop-in, drop-out rates in all our trials. So far, so good, and we hope to continue that. And I think part of the reason for that is that we started the trials, people are already on maximal drugs, what they already could take. And so we wanted to make sure that the standard of care was well achieved, but we were able to get the patients that were at the higher baseline LDL into the trial, and then already on maximal therapy, that helps prevent the drop-ins and the drop-outs.
Just following up on that, do you expect to see many, you know, PCSK9 drop-ins?
We might see some, but most of the patients are in Eastern Europe, China. About 2,000 of the 9,500 are in the U.S. But in these other countries, the access to the PCSK9 are just not there right now. So again, we're seeing very little drop-ins right now. And so now we're, you know, we got another, you know, roughly two years to go, you know, so we hope to hold steady with that.
Anything else from anyone else in the audience?
Thank you. So when you took a look at the blinded data for blood pressure, what exactly did you have access to? Did you look at the average, median, the range?
Everything.
Did you have a sense of outliers? What was the highest elevation seen?
All that, yes. All, all the above, yes. We looked at mean, median, those who had to go on other blood pressure medicines, who had their dose, her dose of medication changed. We saw, again, mean and median, no effect at all on blood pressure. We saw very, very little changes in blood pressure medicine during the trial. So, so that's what we're seeing blinded, in a blinded way.
And what's the highest elevation in blood pressure you saw in a blinded manner, of course?
Yeah, I can't tell you what that is, because, you know, that happens in every trial. We see sometimes people go off their meds, and they come in. We have not— But we're seeing, again, nothing surprisingly... Well, like I said, I've done a lot of trials. I've never— We see blood pressure completely flat in the trial overall. And this is two-to-one randomization in the studies.
Okay, thank you.
Anyone else? With that, thank you, Michael.
Okay.
Appreciate it.
Sure.
Pleasure to have you here, and look forward to the studies reading out later this year.
Yeah, thank you. Thank you, Matt. Thank you.