Good morning, and thank you all for joining the call today. We are excited to present the top-line BROADWAY data. Today on the call, we have Michael Davidson, CEO of NewAmsterdam, and John Kastelein, our Chief Scientific Officer. Before we begin, we would like to direct everyone to slide two and remind everyone that the statements made on today's call will include forward-looking statements. Certain statements included in this presentation that are not historical facts are forward-looking statements for the purposes of the Safe Harbor Provisions under the United States Private Securities Litigation Reform Act of 1995. These statements are based on various assumptions, whether or not identified during this presentation, and on the current expectations of the company's management, and are not predictions of actual performance.
These forward-looking statements are provided for illustrative purposes only and are not intended to serve as and must not be relied on as a guarantee and assurance, a prediction, or a definitive statement of fact or probability. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are subject to a number of risks, which are described in more detail in our annual report on Form 10-K and subsequent quarterly reports on Form 10-Q. Forward-looking statements reflect NewAmsterdam's expectations, plans, and forecasts of future events and view as of the date of this presentation, and are not qualified in their entirety by reference to the cautionary statements herein. NewAmsterdam anticipates that subsequent events and developments will cause the company's assessments to change. Accordingly, undue reliance should not be placed upon the forward-looking statements.
Neither NewAmsterdam nor any of its affiliates undertake any obligation to update these forward-looking statements except as required by law. And now it is my great pleasure to hand the call over to Dr. Michael Davidson, CEO of NewAmsterdam. Michael.
Thanks, Matthew. As a cardiologist and longtime clinical trialist, this is an exciting day. We are thrilled to share positive top-line data from our phase 3 BROADWAY trial, the last of our three pivotal LDL trials, which we believe will support global registration. We initiated our phase 3 program with Obicetrapib back in 2021 with the hope that Obicetrapib will become the therapeutic option of choice to add to statins to further reduce residual CV risk. The goals of our phase 3 program, which confirmed the clinically transformative efficacy and promising safety profile we observed in phase 2, and most importantly, to support our hypothesis, that Obicetrapib's differentiated features position it to provide for MACE benefits in excess of what we might expect based solely on the impact of LDL-C lowering alone. We are further confirming this hypothesis through PREVAIL, which has been designed to test MACE benefit.
I expect that after today's presentation, you will agree with our belief that we have achieved these goals. This table highlights the change in central tendency for LDL-C compared to placebo, the primary endpoint across all three pivotal phase 3 trials. You can see that LDL-C was observed to decrease with median reductions of around 40% with Obicetrapib monotherapy and greater than 50% with ezetimibe combination. The primary endpoint analysis was the difference in LS mean change between OB and placebo, and you can see that the differences were highly statistically significant in each trial, p less than 0.0001. These trials confirmed our expectations that Obicetrapib and the FDC each have the potential to be the most efficacious oral add-on to statin therapy. Our phase 3 trial showed durability of the LDL-C reduction with Obicetrapib and a favorable safety and tolerability profile that exceeded our expectations.
In addition, we observed O bicetrapib to robustly lower LDL-A and small LDL particles, as well as improve glycemic measures that are linked to high CV risk, which potentially differentiates Obicetrapib clinically from other lipid-lowering therapies. We believe these additional benefits, combined with the potent LDL-C reductions, may explain the early separation of the Kaplan-Meier curve we saw in the BROADWAY trial, showing a 21% decrease in first four-point MACE at one year. As we look forward to PREVAIL, we are emboldened by the early four-point MACE signal and the robust and durable LDL-C observed in our pivotal phase 3 trials to date. Although the MACE data was exploratory, this gives us greater confidence that PREVAIL, our CVOT, will demonstrate a 20% or greater MACE reduction. Before we review the top-line BROADWAY data, I want to reinforce the urgency for bringing Obicetrapib to patients.
Only 10% of patients with high-risk ASCVD have LDL-C levels below the 55 milligrams per deciliter target, only 24% are below 70 milligrams per deciliter, and only 29% of patients with familial hypercholesterolemia have LDL-C levels below 100 milligrams per deciliter. We are proud to observe with our phase 3 data that Obicetrapib monotherapy and the fixed dose combination with ezetimibe have the potential to help a majority of these patients to reach their LDL-C goal, addressing a very important unmet medical need. I'm delighted to have Professor John Kastelein, our CSO, present the top-line BROADWAY data. John. Thank you very much, Michael.
Today is a very good day, a day that heralds the completion of our pivotal phase 3 lipid-lowering trial program and confirms many of the attributes of Obicetrapib that a treating physician may find of crucial importance in a cholesterol-lowering cardiometabolic drug, its effects on MACE, on LDL cholesterol goal attainment, and last but not least, on safety. And now let me take you through the data. Let me start by going over the design of the BROADWAY trial to tell you that we randomized more than 2,500 patients into a study that would last 52 weeks or a year. Randomization was two-to-one, two patients to Obicetrapib and one to placebo. The key inclusion criteria of this trial were ASCVD or heterozygous FH with an LDL above a certain level. What's very important to realize is that the primary endpoint was the LDL cholesterol value at 12 weeks.
Secondary endpoints included the normal run-of-the-mill other lipid parameters. And of course, safety endpoints included side effects, ambulatory blood pressure monitoring, and in addition, MACE was also an exploratory endpoint. When we move to the right hand of this slide, there's one thing that I would really like to emphasize, and that is that despite very intense lipid-lowering therapy as the background, this population still has an LDL cholesterol at baseline of around 100 milligrams per deciliter. And that is very important because I will talk about goal attainment later. And of course, goal attainment depends on the power of your drug, but also on the baseline level of the patient population. It is much harder to attain goals at a baseline of 100 milligrams per deciliter than at a baseline of around 80 milligrams per deciliter.
If we then move to the next slide, the first important thing about a drug is to ask yourself whether it is well tolerated by patients. Lipid-lowering therapy is lifelong for ASCVD and heterozygous FH patients, and these patients need to stay on the drug for as long as possible. Discontinuation of treatment is a very good measure for projecting that in patients. The right-hand column reflects the disposition of patients in the Obicetrapib group. Because the trial was randomized two-to-one, please only look at the numbers between brackets, as those reflect percentages of patients in the group within each category adjusted for the randomization ratio. The point estimate, in fact, for discontinued treatment is 11.1 versus 12.4 in placebo, which is a trend that we also saw in both BROOKLYN and TANDEM.
Most of the numbers in the right-hand column, as a percentage of the group, are lower for Obicetrapib than placebo. When I say lower, I mean the point estimate, of course. None of this is statistically significant. If we then move to the next slide, you can see a more detailed breakdown of the demographics of the patients we randomized into this trial. Regulators in different countries are focused on making sure that trials have representation from various regions and ethnic groups. As you can see, not only is there a robust participation of North America, but also of Europe for the EMA, and of course, for Asia for the authorities both in Japan and in China. In terms of ethnicities, we had a good division over the respective ethnicities, which is now also mandated by many regulatory authorities.
Moving to the next slide, you will appreciate the very stringent background therapy. 90% of patients were on any statin, and approximately 70% were on high-intensity statins. And not only that, more than a quarter of patients were also taking ezetimibe. So a quarter of the patients have high-intensity statins as well as ezetimibe, and even a few percent had a PCSK9 inhibitor on board. Now, further confirming the modern background therapy in this trial, we also saw 6% of patients on a GLP-1 and actually more than 10% of patients on SGLT-2s. Let's move to the primary efficacy endpoint slide. As a gestalt, the LS mean and the median were very similar, around 33%-36% at day 84.
If we then look at the curve over time, what you can appreciate is this incredibly rapid drop of LDL cholesterol over time, with an almost 40% LDL lowering at day 30, and then a consistent mean change from baseline over time all the way until day 365 in both placebo and Obicetrapib groups. However, we believe that the next slide is a much more clinically relevant representation of what a drug does, and that is the waterfall plot. I was one of the first to publish waterfall plots on lipid-lowering trials a long time ago. Every bar is a single patient. It is the change from baseline that matters because this is what happens in the clinic. You see a patient in the outpatient clinic, you ask for a lipid profile, then you prescribe a drug, and you see the patient back after 12 weeks.
And what you see in the lipid profile after 12 weeks is the change from the baseline you saw on day zero. What you can appreciate, and which is, by the way, very similar to BROOKLYN, is that, again, the median LDL reduction from baseline at day 84 was approximately 40%, which is exactly where the star is in the figure. And a third of the patients actually had a more than 50% LDL reduction, again, very similar to the BROOKLYN trial. Now, next to the waterfall plot, which is the figure representation of the efficacy of a drug, the most important clinical question, in my view, as a treating clinician, is whether the patient has achieved his or her LDL goal.
Because patients come to me seeking specialized care when they're not at goal, and they go back to their GP, hopefully at goal, and therefore this is a very important clinical parameter. Remember that Michael told us that only 10% of ASCVD patients are currently at their strict less than 55 milligrams per deciliter goal, and this is completely compatible with our data in the placebo arm of BROADWAY. Look at the gray bars at day 84 and day 365 for the placebo arm. 10% and 8% of patients have an LDL less than 55, and so when you move to the Obicetrapib arm, you, in fact, see a 50% goal attainment. That is a five-fold increase in the Obicetrapib arm in the most strictest goal attainment category.
Now, the run-of-the-mill garden variety goal, almost everywhere in the world, is less than 70 milligrams per deciliter, and there, Obicetrapib gets over two-thirds of patients to goal. Remember, however, this is Obicetrapib monotherapy. We observed in the TANDEM study that with the Obicetrapib ezetimibe combination, this number actually was 80%. After achieving goals, what I would like to do is put this into perspective of our entire trial program. You can see there are small differences in LDL lowering when measured using a mean, an LS mean, and a median at the primary endpoint cutoff, but basically, over the entire clinical program, it is very consistent, which is also important for a clinician because he kind of knows that he can count on the drug when he or she goes from one patient population to another.
Now, let's move to the next slide and remind the audience, what did we hope for at the start of the study? What is the most important point for a large lipid-lowering registration trial? In fact, it is cardiovascular safety. What did we expect of this cardiovascular safety? We expected no difference in MACE or a hazard ratio of one. Because a hazard ratio of one between placebo and Obicetrapib would mean that OB would be, in cardiovascular terms, as safe as placebo, which would have been a great achievement. Furthermore, when we study the other two cardiovascular outcome trials of previous CETP inhibitors, evacetrapib and anacetrapib, the ACCELERATE and the REVEAL trials, you can, in fact, see that at month 12, which is, of course, similar to our 52-week trial, the Kaplan-Meier curves did not separate at all.
In fact, it took much longer for the curves to separate. This is also true for a non-CETP inhibitor trial, the simvastatin-ezetimibe fixed-dose combination Vytorin. So then, what have we seen in BROADWAY? And I'm thrilled to show you that all the hazard ratios, the point estimates for the hazard ratios were in favor of obicetrapib, which was truly a surprise given their magnitude. Now, first, look at the green box on the upper side of the slide and gives you the exploratory MACE endpoints just in BROADWAY alone. As you can see, all-cause mortality, hazard ratio of 0.83, CHD death, hazard ratio of 0.80, and then first four-point MACE, 0.79. And this is the internationally agreed outcome for basically any outcome trial that's currently running. That hazard ratio signifies a 21% difference in favor of obicetrapib compared to placebo.
Now, remember, in the BROOKLYN trial, we already saw an early positive trend, small numbers, of course, but any lipid-lowering drug reports cardiovascular safety for the entire phase 3 program. So when we pull the data for BROADWAY and BROOKLYN, both positive, you can see that the numbers even get a little better. But basically, the most important number today is in the yellow box, and that is the 0.79 hazard ratio for the first 4-point MACE in BROADWAY. And now, for me, this was a truly astounding finding. When we move to the next slide, you can see hot off the press, the Kaplan-Meier chart. And you can actually see that those curves overlap for the first 200 days, which is basically six months. And then they start to separate, and they separate more over time.
Now, this is very compatible with the biology of a drug like ours that lowers LDL and is also in line with what we've seen in preclinical data in a drug that stabilizes plaques. This is a Kaplan-Meier curve that is biologically very, very consistent with the mechanisms of action of Obicetrapib. How can we put all of this into perspective? We can compare ourselves to the CTT meta-regression line. Remember that this CTT regression line represents the expected relationship between a mean absolute reduction in LDL versus placebo and the predicted MACE benefits at different points in time. Based on prior outcome trials, if you only treat one year, you'll have less effect than when you treat two years, three years, or four years. Now, please look at these lines. There are four lines. The lowest represents a one-year treatment, then a two-year, three-year, and four-year treatment.
As you can see, the longer you treat, the better, and four years is kind of the optimum. Where are we? There was an absolute mean LDL difference in BROADWAY of about 30 milligrams per deciliter, and we are at the green diamond at a 21% difference. Look at what would have been expected for a one-year difference of 30 mg per deciliter on the CTT line. It is the dark blue dot, which is only a 9% difference. While BROADWAY was not designed to measure MACE, we now head to PREVAIL with really greater confidence. The green diamond is actually placed not just above the one-year line, but already above the four-year line. This is not entirely new for the class, however. Historically, there was another CETP inhibitor that also performed better than just based on the CTT meta-regression line, namely anacetrapib in the REVEAL trial.
And you can basically observe the same phenomenon here, although, of course, with the caveat that this is not statistically significant, but we believe it is an extremely positive trend. If we then move to the next slide, how can we bring all those data together in an overarching hypothesis? The hazard ratio difference in favor of obicetrapib is, in fact, much better than we expected. Now, we think and we hypothesize that this is because potent CETP reduction has many more effects on parameters related to atherosclerosis and heart disease than just lowering LDL cholesterol. In the middle, in the orange box, you can see that obicetrapib lowers LDL, non-HDL, apolipoprotein B, but also small dense LDL cholesterol. On the right-hand side of that, you'll see that this goes even a bit further. When you look at NMR profiling, LDL particles go down by 50% upon obicetrapib therapy.
Small LDL particles are basically eradicated. And since very recently, we also know that oxidized LDL is reduced. At the same time, on the left-hand side, we know that Lp(a) in our phase 2 and also in our phase 3 trials is actually reduced by 40%-50%. We still do not have definitive proof that lowering Lp(a) reduces heart attacks and strokes, but we are getting quite close. And all the genetics and the observational data point to that fact. So it might be that the Lp(a) lowering contributes to the MACE reduction too. And then on the extremes of this rainbow, you see the effect on diabetes, and I'll come back to that a little later. And on the left-hand side, you see the effect of ApoA1 and HDL, which recent data suggest that increasing HDL might also have benefit.
With that, I would now like to move from the cardiovascular safety to overall safety. And this is the kind of table that everyone wants to see after a large phase 3 program. And I'll tell you, this table in percentages is very similar to BROOKLYN. On the right-hand side, just look at the percentage points. Again, basically all lower for Obicetrapib than for placebo at whatever you look at. Now, besides the discontinuation rates, which indicate tolerability, there's also no difference from placebo. And I would like to take that one step further by looking at the events of special interest on the next slide. The top line is liver. The second line is liver again. The third line is muscle. Two effects that are very well known to the physicians that are prescribing lipid-lowering drugs. Nothing there for Obicetrapib.
Now, as you might know, previous CGP inhibitors also lowered the incidence of new-onset type 2 diabetes and improved measures of glycemic control. Now, if we take a closer look at all the parameters linked to those two effects, there is a 5% difference in favor of Obicetrapib, and that actually achieved statistical significance with a p-value of 0.015. Now, you might say, "5%, what does that mean? Well, it is a 5% absolute difference, which means one in 20 patients might derive a benefit from Obicetrapib treatment for diabetes-related parameters, and please realize that the background therapy of these patients is high-intensity statins, and high-intensity statins have a negative effect on type 2 diabetes, so despite that fact, Obicetrapib was able to drive a 5% absolute difference in the parameters of glycemic control and new-onset diabetes that I just talked to you about.
If you move from diabetes to renal function, you see that 7.5% versus 9.1% in favor of Obicetrapib. eGFR less than 30, etc., etc., etc. This difference just missed statistical significance at a p-value of 0.06. But to me, scientifically, this indicates that the HDL-raising part of this drug very likely not only affects glucose metabolism and the pancreatic beta cell, but could also potentially, in some way, positively relate to renal function. Overall, we are, of course, extremely pleased with the safety profile of Obicetrapib and the combination with ezetimibe that we have observed in our clinical trials. And with that, I'd like to give the word back to Michael.
Thank you very much. Thanks, John. The successful BROADWAY trial completes our three phase 3 trials that serves as the basis for global regulatory filings for the LDL-C lowering indication.
We anticipate a label for Obicetrapib that includes LDL-C lowering of 36% and 33% based on Brooklyn and BROADWAY trials and the fixed-dose combinations with ezetimibe of 49% based on TANDEM. We believe that the safety profile of Obicetrapib is exceptional. Treatment-associated adverse events overall were comparable to placebo. There was no increase in blood pressure in the trials, including a 200-patient, 24-hour ambulatory blood pressure sub-study in BROADWAY. There were no adverse effects on hs-CRP, liver or muscle enzymes, and renal endpoints. Importantly for patients, we observed statistically significant reductions in glycemic adverse events compared to placebo. As we conclude our phase 3 LDL-C program, we shift focus to our cardiovascular outcomes trial. The BROADWAY and Brooklyn data give us great cause for optimism that PREVAIL will achieve a greater than 20% MACE reduction. Thank you.
Thank you.
As a reminder to ask a question, you will need to press star one and one on your telephone and wait for your name to be announced. To withdraw your question, please press star one and one again. Please stand by while we compile the Q&A roster. We will take our first question. And the first question comes from the line of Tyler Van Buren from TD Cowen. Please go ahead. Your line is open.
Hey, guys. Congrats on the unprecedented MACE and outcomes data. Since this is such a surprising result, can you compare and contrast these data a bit more with what was observed in the historical REVEAL study data and when REVEAL separated? And then the second question is just, did you see a similar benefit on all four points of the 4-point MACE?
Does this change any assumptions in the ongoing PREVAIL outcomes trial based upon this comprehensive data set?
Yeah, thanks. Thanks, Tyler. Really appreciate the question. So let's go back just to put in perspective. When John and I founded NewAmsterdam, the REVEAL study was extremely important for de-risking the clinical benefits of a CETP inhibitor like Obicetrapib on outcomes. So we actually designed our outcome study PREVAIL based on the REVEAL population. And what we did was looked at the REVEAL and saw that patients responded better when they had higher baseline LDLs, higher triglycerides, low HDL, high Lp(a). So we designed PREVAIL accordingly. Then BROADWAY was therefore designed to de-risk PREVAIL even more so. And we actually tried to pretty much adopt those types of inclusion criteria. So higher baseline LDL achieved that with 98 milligrams per deciliter.
And then, of course, enriched the study with patients that had a better response, high Lp(a), low HDL, high triglycerides, diabetes, etc. So we're very, very excited about the MACE benefit that we saw in the BROADWAY trial. So in the REVEAL endpoint for BROADWAY, which is the CHD death, non-fatal MI, and total revascularization, we actually saw a 0.72 first-time MACE benefit, first event. But we also pulled that 0.68 hazard ratio with a p-value of less than 0.05. So it hits that sig for the REVEAL endpoint. So what we're going to do with REVEAL is, sorry, we're going to do with PREVAIL is we're going to look at our events at the one-year mark, which is roughly April of next year, and think about that endpoint. We'll make that decision at that time. But we're very, very excited about our overall MACE benefit across the board.
As we showed you, we shared with you the mortality benefit, CHD mortality, total mortality. But it was across the board the benefits for that four-point MACE with the BROADWAY trial. So it was a consistent benefit across multiple endpoints.
Thank you. We will take our next question. Your next question comes from the line of Dennis Ding from Jefferies. Please go ahead.
Your line is open. Hi, good morning. Congrats on the data. If I can ask two questions. Number one, just on PREVAIL, I'm just curious how confident are you on the translatability of the BROADWAY data to PREVAIL and with regards to your confidence that this can be reproduced? And then number two, when you kind of extrapolate the expected 30% LDL reduction on the CTT line, that gets you to around 18%-19% MACE benefit. And that's over multiple years.
But you're showing 21% at only year one, which should theoretically widen with longer follow-up. If your math on slide 16 is correct, then PREVAIL could show something north of 30% or maybe even 40% MACE benefit. So my question is, how do you reconcile the 18%-19% that's predicted versus the implied 30%-40% from your slide 16? And how much do you think Lp(a) is driving that delta? Thank you so much.
Yeah. John, I'll let John answer that question. Yes.
Dennis, first of all, when you see a MACE difference in favor of a drug in a phase 3 program that is basically not powered for showing a difference, then you have to do what Michael just did for Tyler Van Buren, and that is to see whether the benefit is across CHD death, CV death, all-cause mortality, etc., and the different components of the endpoint. And that is the case. The second thing you do is you look at the Kaplan-Meier curves. Because the Kaplan-Meier curves, sometimes in trials, they widen and then they go back again. And then it was just a fluke of time. Well, as you've seen on the Kaplan-Meier, this is a consistent effect.
They open up at six months, which is very compatible, and then they open up further, which is, again, compatible with the biology we saw in the relevant mice models where Obicetrapib stabilizes plaques by lowering inflammation and, of course, lessening the influx of atherogenic lipoproteins. So all of that is very consistent. Now, normally, in year one of any outcome trial, you see about half of the effect. Now, if 21% is half of the effect you see at four years, then I think we are getting into the realm of numbers that might not be that realistic. I think a much better way of looking at this is the fact that Obicetrapib is really not only an LDL-lowering drug. It has a wealth of effects on the HDL side of the spectrum. It has a potent effect on lipoprotein(a). It lowers oxidized LDL.
It lowers small dense LDL cholesterol, and so all of those effects combine, and it raises lipophilic antioxidants, for example, both in the circulation as well as in the HDL fraction, so everything combined clearly yielded an effect that was larger than we expected, and so I think the only thing that we can truly safely say at this time is that if at one year and the patients are very similar between BROADWAY and PREVAIL, if at one year we are 21%, then we will definitely above 20% at the year four mark in PREVAIL. I think that, I mean, you can never be sure about the future, but I think that that is a kind of axiom that we can position here, but actually, to now calculate and then double, I think that would be taking it one step too far.
But I can definitely say that based on all the biology and everything that we observe in BROADWAY and the similarity of the BROADWAY patient to the PREVAIL patient, we can be very confident in the PREVAIL result.
Got it. Thanks.
Thank you. We will take our next question. Your next question comes from the line of Roanna Ruiz from Leerink Partners. Please go ahead. Your line is open.
Hi. Morning, everyone. So regarding the events of special interest, I was curious if you could talk about the clinical meaningfulness of OB's differentiation from placebo on both level of new-onset diabetes and also the directionally favorable difference in renal function worsening. How will clinicians think about these differences?
Yeah. Thanks, Roanna. And again, as a clinician, I still see patients at the University of Chicago.
So I can tell you that the diabetes issue with statins is well recognized by clinicians and patients. To see this reduction in adverse glycemic indices is really exciting. We see with other CETP inhibitors over time, but to see it in one year was, again, a magnitude that was unexpected. What this means, of course, John said, is that one in 20 patients have less of a worsening of diabetes over time. It was across the board, the new-onset diabetes, A1C less than 6.5 going to greater than 6.5, more than two glucose levels greater than 126, reduction of diabetes, no addition of new diabetes meds. You can think about just the cost-benefit of that on other drugs that patients are taking. That's clearly there. But more importantly, it's about the relationship between diabetes and cardiovascular risk.
To have a drug that can not just be neutral on diabetes or like statins worsen diabetes, something that improves diabetes is truly a very exciting attribute of Obicetrapib that we're going to explore further as we go in other future trials as well, especially PREVAIL. We'll have longer-term follow-up in that study and link that to outcomes potentially. The renal endpoints are also interesting. John brought this up because we saw this in BROOKLYN as well. This was a surprising finding. It all links to HDL going up, we believe. Because HDL increases has been known to protect against diabetes as well as protect the kidney from deterioration, renal dysfunction over time. These are, again, unique benefits of Obicetrapib that we're going to explore further. Ultimately, it comes down to recognizing this benefit for patients.
Clinicians will obviously be aware of that when they think about what drug to choose for a specific patient.
Maybe if I could add something, Michael. This is a point that John made earlier when describing the study design. We had upwards of two-thirds of patients on high-intensity statin dose. As we're seeing in published literature, there is a marked increase in the rate of new-onset diabetes with high-intensity dose of statins. It's upwards of 36%. What you're seeing in our trial is not only a 5% absolute reduction. It's a 5% absolute reduction with taking into account the effect that the high doses of statins are having in our trial population.
Interesting. Super helpful. The second question for me, I was curious, could you just recap your plans and regulatory next steps for OB in the U.S., Europe, and other global regions?
Particularly when potentially talking to the FDA about the BROADWAY results and MACE signal, what do you think they'll focus on most in that type of discussion? Thank you.
I think at this point, our guidance on regulatory is the same. We will have our plans to file in Europe. We have, obviously, we have the global capability to file in Japan and China as well based on the LDL lowering efficacy and remarkable safety. For the FDA, our plan is to meet with them in the next few months and discuss our filing plans and so forth. Our guidance remains the same that we plan to file so that the outcome study from PREVAIL will be available prior to the launch of the drug.
However, I mean, in light of this fantastic MACE data in BROADWAY, I think we're going to obviously give great reassurance to all the regulators about what this drug can provide beyond just LDL lowering. And so that's something we're going to think about as we go into 2025. It will be a year of a number of regulatory interactions with the company.
Understood. Thanks.
Thank you. We will take our next question. Your next question comes from the line of Rai Forseth from Guggenheim Securities. Please go ahead. Your line is open.
Hi. This is Rye Forseth from Guggenheim team. Given the ApoB data from prior studies and MACE benefit in BROADWAY, are we correct in our assumption that risk reduction in PREVAIL could be 17% on the lower end as well as 20% on the upper end in the best case?
I'll let John take that question.
Yes.
So the actual ApoB hypothesis has never been tested prospectively yet. This is all based, of course, on epidemiology and post-hoc analysis of large lipid-lowering trials in which both LDL, non-HDL, and ApoB was measured. We think that just looking at ApoB underserves the power of Obicetrapib to reduce MACE. In our phase 2 and also in our phase 3 program, when we look at NMR-based determinations of LDL particles and especially of small LDL particles, we see much larger reductions of NMR-measured LDL particles than on the basis of the ApoB reduction. The reason for this discrepancy until now is unknown, but we are looking deeply into it with some of the leading scientists in the United States. We have seen a number of studies where LDL particles and ApoB were compared as to their predictive ability for risk.
A number of these studies actually yielded information that LDL particles were more accurately predicting risk than ApoB levels. Now, at this point in time, we do not have enough evidence, but it's very clear that the mechanism of CETP inhibition is crucial for making small particles disappear. CETP activity per se is absolutely necessary for the formation of small dense LDL particles. When you, like obicetrapib, does inhibit CETP by 97%-98%, you basically stop the CETP mechanism and thereby making it impossible for these tiny dense particles that are easily oxidized to form. We think that might be for CETP inhibitors like obicetrapib, that is a more accurate measure of what they do to atherosclerosis.
We are supported in that belief by our preclinical work in relevant mice models where we have seen that both Obicetrapib alone as well as Obicetrapib plus ezetimibe basically eradicates atherosclerosis, especially the more advanced plaques. We still are very confident on the basis of the BROADWAY results that we will see a more than 20% reduction in MACE at the four-year mark in PREVAIL. We also have, I think, sufficient evidence to suggest that Obicetrapib does more than just lower LDL cholesterol and that it has a plethora of effects that are all important in fighting the residual risk of the current ASCVD patients in the United States and elsewhere.
Roanna, I just want to add your report several months ago that showed the REVEAL predicted benefit on LDL and that what was actually observed was greater than expected.
So that, obviously, that's based on ApoB and LDL non-HDL. You did a really nice job laying that out. And so for us, again, with BROADWAY, as John has really well elucidated, we have these other benefits beyond LDL. LDL alone, yes, gets us close to that 20%. But then you look at this rapid benefit within 12 months. Like I said, it hits that SIG with the REVEAL endpoint pooled with BROADWAY, 0.68, P less than 0.05. So it hits that SIG at the 12-month part for your pooled phase 3 data is really exciting for us. And again, really emphasize the confidence that we're going to get more than 20% with the PREVAIL ongoing study.
But your analysis was actually helpful to us to understand as well that REVEAL does show this added benefit already with the anacetrapib, but we're seeing it even more so with Obicetrapib being a more potent CETP inhibitor.
Thanks for the input.
Thank you. We will take our next question. Your next question comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead. Your line is open.
Good morning, team. Just want to say thank you for the very nice early Christmas gift with really outstanding data. So a few questions. I think the first question that people are wondering is, given this spectacular data, are you planning to take an interim look at one year at PREVAIL and come back to the street and to confirm the data that you just saw? That's question one.
Question two is, given this data also, is there an opportunity that PREVAIL could actually read out earlier? I think the original guidance was in 2026. So given this data, could that move the timelines into an earlier time point? And then the last question is for Michael and John. Have there been in the history of CVOT studies or any phase 3 studies that we have observed a four-point MACE reduction at year one? I think you've beautifully put that together with the CTT analysis that no other CETP inhibitor has done that. But if you could just talk to us if there's any agent that has ever seen that, that would be helpful. And thank you for my multi-part question and congratulations.
Yeah. Yeah. Yeah. Thanks. I'll start with the first couple of questions and then turn over to John about the unprecedented MACE separation at year one.
But regarding the interim analysis, we don't have an interim analysis plan as of yet with PREVAIL. The FDA discouraged us from doing that. Ultimately, what we want to do is we want to also not just look at 4-point MACE, but also coronary artery disease death, mortality benefits. So that may take as long as we have predicted to go forward. Now, obviously, we see these signals of mortality benefit already in our pooled data in particular. But also, we're excited about the fact that even evacetrapib in the ACCELERATE trial had a statistically significant mortality benefit at two years. So there's something about CETP inhibitors that seem to have at least the ones that have been the ones that don't have effect on blood pressure, which is clearly the case with obicetrapib.
We see this overall mortality benefit that we want to try to run PREVAIL as long as we need to to try to see that benefit, of course, which I think would be very exciting for clinicians to see a mortality benefit for an LDL-lowering trial, which hasn't been seen recently, so I will let John answer the other part of the question.
Yes. Hi, Yasmeen. Yeah, so this was a Christmas gift for us too, as you can imagine, so in the more recent trial programs, and then I'll say alirocumab, evolocumab, and inclisiran, after the phase 3 lipid-lowering programs of these trials, there were differences in terms of an exploratory atherosclerosis endpoint. And actually, those differences were there, but this was not represented as Kaplan-Meier curves nor as first four-point MACE, so there were differences in revascs and MIs.
They suggested, like you would expect, that in fact, for example, for Inclisiran, the trials were not 12 months, but 18 months. And so there was a beneficial difference in the atherosclerosis events in ORION-10 and ORION-11. And the same was true as far as I can remember for both the Evolocumab trials and the Alirocumab trials. But I have never, ever seen a benefit like this at the 12-month mark and definitely not represented in a Kaplan-Meier curve that actually shows the biology of what's happening, namely overlapping curves till six months and then separation of the Kaplan-Meier curves that are widening while the trial progresses. So in that sense, this is for us a very reassuring finding, as I said before, that we think will translate into a benefit in PREVAIL that is better than the benefit that we currently saw after one year in BROADW AY.
Amazing.
Thank you. I'll jump back in the queue. Thank you. We will take our next question. Your next question comes from the line of Matt Phipps from William Blair. Please go ahead. Your line is open.
Morning. Congrats. Especially Michael and John on this great outcome here. It's great to see such a strong separation. Just maybe on timelines to when you will meet with FDA as far as discussing these results and kind of confirming your plans for filing timelines. And then can you just remind us on the method of imputation for LDL measurements to how it accounts for discontinuations and particularly how that impacts the LS mean?
So timelines, we're not going to be public with those at this time. We have a lot of work to be done to get ready for these meetings. We want to meet as soon as feasible with the FDA.
Like I said, we want to time anyway to the PREVAIL readout. So we're not in a huge rush, but we want to meet with the FDA, get their feedback. And I think they're going to obviously really appreciate the safety data we generated from our clinical trial program. Remember, BROADWAY was set up to pull as many patients as we could at one single trial, which gives us a lot more power. It's purposely designed that way, which I think is, again, gives us the excitement around the MACE benefit in a single trial for that benefit. So that's, again, something we'll get more public on that as we get more along with our we just have the data now, so we're going to talk about that in future upcoming presentations to the investor community.
Regarding the imputation, so just to point out, as John showed you, we have amazing consistency across all our trials, phase 2, phase 3, for meeting medians in that high 30s, low 40s % range. And if you think about on treatment, it's above 40% across all the trials. So it's really the drug itself. We know clearly what the efficacy is for that. And then imputation at the day 84, we saw the effect when you do LS mean differences. Even LS mean differences across all the trials are very, very similar across all the studies. So you impute retained dropouts into your treatment, into your placebo. For the day 84, the primary endpoint we showed you, that's the 33% LS mean difference from placebo imputed. We have that in the table. Show how that works. Day 365, again, we imputed about 10% of patients had missing data.
About 3% are retained dropouts. So we had a minus 2% imputed effect in that day 365 LS mean difference. So it's a statistical view, but again, consistency across all the trials and meeting medians is what we really have shown across all our phase 2, phase 3 trials. And that's where you derive the MACE benefits. And think about the MACE benefit at day 365. The delta of 80 milligrams per deciliter is what we plotted for the MACE benefit on that figure we showed you. And that's what we feel really excited about, that difference and how that translates in the MACE already at year one for the BROADWAY trial.
Good. Thanks again and congrats.
Thank you. We will take our next question. Your next question comes from the line of Leonid Timashev from RBC. Please go ahead. Your line is open.
Thanks, guys.
Congratulations on the great data. I want to ask, from your perspective as clinicians, how the patient population compares to sort of what you see in the clinic and the initial patients you think that are going to receive Obicetrapib? I mean, just because initial physician experience with the drug is quite important. I mean, do you think that this sort of mirrors the patients that would initially receive Obicetrapib? Do you think they're actually more difficult? Does it mean they have a better experience? And sort of from the patient side of things, how the dropout rate in the trial compares to real-world adherence over time on lipid-lowering therapies? Just curious of your thoughts. Thanks.
Yeah. Thanks. So again, speaking as a clinician, what's most important is the safety profile.
People don't realize that's actually far more important than anything else when it comes to how clinicians and patients think about drugs. So here, I think we made the point that we have a very simple oral, extremely well-tolerated drug that can get almost everybody to goal, either alone or in the fixed dose combination with ezetimibe. So I see it really as the go-to next drug for the majority of patients. They're already on a statin. They're on high-intensity or moderate-intensity or no statin. You add Obicetrapib or the FDC, and basically everyone gets to goal. So we see it as the drug of choice for that drug to get the LDL targets. But as we said, what's really exciting is the other attributes of Obicetrapib: the diabetes benefit, the LDL-lowering, the small-dense particles. Those all are going to drive greater utilization for those subsets of patients.
Those that have prediabetes or diabetes would represent 80% of patients on a statin. High LDL represents 20%-25% of the patients today in the lipid clinics in particular. And so I believe it's the safety tolerability. And then the other attributes that's going to make this, highly confidently, in my view, going to be the next drug to consider for any patient to get their LDL levels to target. And the oral well-tolerability is really the key to drive that utilization with clinicians. And as you can tell, the unmet need is tremendous. The market is large, and it's growing, and new guidelines are coming. And so we see all those things really emphasizing for us a great future for obicetrapib once it's available for patients in the coming years. I think we're at the end of the hour, right? Heidi, is it? Is that the last question?
We do have further questions. Matthew, Ian, do we keep going, or do we?
Yes. We can continue for ano
ther few questions, Heidi. Okay. Of course. Please stand by for the next question. Your next question comes from the line of Sebastiaan van der Schrier from VLK. Please go ahead. Your line is open.
Thank you. Hey, guys. Congrats on the excellent data set. I'm just wondering if you can talk a little bit more about the narrowing of the LS Mean from day 84 to year one. And then I was wondering whether you can give some insight on when you expect to publish the full results. Thank you.
Yes. So as I mentioned, the means don't change from 84 to the end of the trial. The means don't change either. On treatment, it stays the same. So it's not a drug issue.
The imputation, so just to put it in perspective, last observation carried forward was the standard. In 2021, the FDA asked for this imputation to occur. So you're imputing retained dropouts, which is about 3% of the patients, a minus 2 into the 10% of patients with missing data. That's where the LSM difference comes in. It's not a change in the drug's efficacy. It's all about this imputation. So we're not statisticians. We can walk you through that. But the main point is not about the drug. It's about how the statistical handling of these missing data is factored into the trial. Again, the primary endpoint is day 84, not day 365.
But the curve we showed you, the lines over time is what's going to be in the label with the 33% as the primary endpoint for the efficacy from the BROADWAY data and 36% from the BROOKLYN trial. And maybe, if it helps to walk you through some of the numbers, what you saw at day 30, it's not an LS mean value, but it's a mean value of roughly 40% LDL reduction. What we saw at day 84 was a 33% LS mean value. As you get to the end of the study, as you look at imputing the patients that dropped out, the number that we utilized for the imputation was minus 2%. That's the LDL value we're assigning for the 10% of patients that were on Obicetrapib but no longer took the study drug. And that's why you see that effect in the LS mean calculation.
And it is simply a calculation, but not representative of the drug effect. You can see from the waterfall plot. You can see from the responder analysis. And now, most importantly, you can see from the observed MACE trend that what matters most to a clinician and the benefit that patients are deriving from therapy is best represented by mean and median.
Great. Thank you, guys.
Thank you. We will take our next question. Your next question comes from the line of George Farmer from Scotiabank. Please go ahead. Your line is open.
Hi. Good morning. This is Chloe Yong for George. Thanks for squeezing us in. I'd like to add our congratulations to the data as well.
I'd like to play devil's advocate here for a second and ask for your perspective on why you think the magnitude of LDL reduction in BROADWAY wasn't any higher than what was captured in the BROOKLYN trial. Comparing these two phase 3, I mean, the compliance looked very similar and consistent, but the placebo and the Obicetrapib arm in BROADWAY don't look as perfectly parallel as they did in BROOKLYN. Maybe that could have contributed. We'd love to get your thoughts on that.
Yeah. I think the thing is, you look at BROOKLYN and BROADWAY, and the medians, they're almost identical at day 365. You see imputation that you're talking about. You imputed a +10% in the BROOKLYN trial, made it 41% versus what we saw in the BROADWAY trial imputation.
So again, as Ian pointed out, it's all about this imputation, which is a statistical factor, not about the efficacy of the drug. If you look at the waterfall plots for BROOKLYN and BROADWAY, they're almost identically superimposable. The drug is working the same in both studies. The LSM imputation is really a statistical artifact. It doesn't impact the overall mean and medians that we see at the end of the trials, including those that have dropped out of the trial. The mean and medians are pretty much the same as you saw at the day 84 time point. As we keep bringing back, it all comes down to outcomes and MACE. And we see that at day 365, the 30 milligram per deciliter drop and absolute drop in LDL, which will translate into that similar drop in PREVAIL, is linked to a 21% MACE benefit.
We're very excited about the persistency of the drug and how well it works. The tolerability, as you can tell, is comparable to placebo. I think that was one question I didn't quite answer before. Typically, if you look at the real world, statin compliance is not the greatest. Even though statins are well tolerated, at least a third stop within a year. In our study, we had 10%, both placebo and obicetrapib, stop the drug, which we think is an excellent type of quality metrics and comparable to a lot of other trials, including inclisiran, where you're mandating the drug for the patients with injection. We feel really good about the study quality and then emphasizing, again, how well tolerated obicetrapib was compared to placebo with less overall dropouts, less adverse events in placebo numerically.
And so this, again, is an extremely well-tolerated drug, which should then translate into better compliance for patients in the real world. I also want to emphasize no liver monitoring, no muscle monitoring, of course, the diabetes thing. This is going to be a really remarkable drug for clinicians when it comes to the patients, hopefully, in the next few years.
Definitely, we agree. But the benefit that you saw in a broader ASCVD secondary prevention setting, is that something that were you expecting it to be different at all from just a 100% FH solution?
Well, FH still have a lot of events. And they didn't have quite as number of high events as the ASCVD population. But we saw this 50% MACE benefit in BROOKLYN, smaller numbers, of course, only about 11 events.
But here, with BROADWAY, a much larger number of events, we see, again, this very exciting 21% first MACE benefit. So the event rates we're tracking as kind of what we expected. And so again, in PREVAIL, we're seeing the same thing. We're seeing the event rates tracking as expected. So we feel really good about PREVAIL now, of course. A similar population as BROADWAY, events that are tracking as expected. And as we talked about earlier, the PREVAIL endpoint, the REVEAL endpoint of three-point MACE, CHD death, non-fatal MI, and coronary revascularization, a 0.68 hazard ratio, P < 0.05. We're really excited about what that means for PREVAIL. And we'll think about that endpoint as we get more events documented in the PREVAIL trial at roughly the one-year mark, which is roughly April of next year.
Okay. Got it. Thank you.
Thanks for your big compliment.
And I think we have time for one more question.
One moment, please. Please stand by. Your next question comes from the line of Serge Belanger from Needham. Please go ahead. Your line is open.
Good morning. Thanks for squeezing in, guys. Congrats on the data. First one on MACE reduction. Since this is an event-driven endpoint, can you just talk about the rate of MACE events and whether it was in line with what you were expecting? And if that changes your outlook for the duration of the PREVAIL trial? And then regarding the CTT regression line, at one year, you're already off the chart here. Just curious if we should expect additional separation going forward over the next three years. Thank you.
Yes. I think we're right on line with expectations with events.
Remember, BROADWAY was. I tried to make the point. BROADWAY was set up as a very large trial just for this reason to have more exploratory MACE events as a safety endpoint in one 2,500-patient trial, which is kind of a mini outcome study in some respects, and have that population be almost identical to the PREVAIL population, so we purposely set it up this way to try to further de-risk PREVAIL going forward, and so the events we're tracking as expected. The event rates in BROADWAY were as expected. Again, seeing the MACE benefit this early doesn't change our guidance because we believe that ultimately, with our two-and-a-half-year minimum follow-up, we want to try to get to the CV, CHD mortality benefit to be established, which would be a game changer in the lipid world, and so that's kind of our objective with PREVAIL.
It's not just the 3-point, 4-point MACE. It's also getting to a mortality benefit, which we'd like to see, hopefully, with that trial. And so we're going to let it—we're going to give it the time it's due to achieve those endpoints. And that's just kind of how we have set it up. And we're extremely encouraged by what we have so far. And again, tracking safety in PREVAIL has been really remarkable as well. The DSMBs have met multiple times and give us the green light on the safety aspects of the drug. So we feel that, again, that's 9,500 patients approaching all patients on almost one year of therapy. So that gives us even more enhanced confidence about translating the BROADWAY data then into the PREVAIL endpoint in the future. So anything else, John, you wanted to add to some of those comments?
No, Michael, I think you said it all. I don't want to repeat you.
Okay. I think we really appreciate all the questions. And very much, as you can tell, we're extremely excited about the BROADWAY data. In fact, our entire phase 3 program could not have been better. We exceeded our expectations in many ways and showed a lot of benefits that we just couldn't hope for across the board. And so now we look forward to the year ahead and the regulatory interactions and so forth, again, preparing for building the team out for launching the drug or working with our European partner, Menarini. So we're really excited about that partnership. And so this is a great day for us. And we want to wish everyone happy holidays and look forward to continuing to get more data out there, upcoming medical meetings.
That's our plans, both TANDEM and BROADWAY, to be presented at upcoming medical meetings in 2025. So again, thank you very much, and wishing everyone a happy, healthy holiday and healthy and happy 2025. Thank you very much.