Good morning, and welcome to the NewAmsterdam Pharma Phase III BROOKLYN Top Line Data Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. I will now hand the call over to Matt Philippe, Executive Vice President and Head of Investor Relations at NewAmsterdam .
Thank you. Good morning, and thank you to those joining us as we review the positive top-line data results from the Phase III BROOKLYN clinical trial. Before we begin, we would like to direct everyone to slide two and remind you that the statements made on today's conference call will include forward-looking statements. Certain statements, including in this presentation, that are not historical facts, are forward-looking statements for the purpose 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 in this presentation and on the current expectation 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, an assurance, a prediction, or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and may differ from assumptions. Forward-looking statements reflect NewAmsterdam's expectations, plans, and forecasts of future events in view of, of the date of this presentation and are 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 undertakes any obligation to update these forward-looking statements, except as required by law. On today's call, we have Dr. Michael Davidson, Chief Executive Officer of NewAmsterdam, and Dr. John Kastelein, Chief Scientific Officer of NewAmsterdam.
Ian Somaiya, our Chief Financial Officer, will also be available for Q&A following the presentation. With that, I'm excited to now turn the call over to Dr. Michael Davidson. Michael?
Thank you, Matt, and thank you to everyone joining us this morning. We are delighted to share the positive, statistically significant top-line results from the global pivotal Phase III BROOKLYN trial. As a reminder, BROOKLYN evaluated obicetrapib in adult patients with heterozygous familial hypercholesterolemia, or HeFH, we call it FH for short, whose LDL cholesterol is not adequately controlled despite being on maximally tolerated lipid-lowering therapy. BROOKLYN is the first of four ongoing pivotal Phase III studies in NewAmsterdam's clinical development program. Today's results mark a meaningful milestone for our company and for cardiovascular disease community more broadly. It remains a significant unmet need for new treatment options that are safe, convenient, and able to meaningfully improve LDL-C lowering effects, and we believe obicetrapib has the potential to solve this problem.
To present the top line of results is my great friend, a world-renowned expert on FH and Chief Scientific Officer at NewAmsterdam Pharma, Professor John Kastelein.
Michael, thank you very much for those kind words, and like you, I'm very proud to present the top-line efficacy data from BROOKLYN, which will show that obicetrapib has a substantial and rapid effect on LDL levels, and therefore, it will enable patients, even those who fail on maximally tolerated lipid-lowering therapy, to achieve their risk-based goals. Now, a little perspective for those on the call. I have devoted my career of over 30 years to the study of the treatment and diagnosis of familial hypercholesterolemia, a disease that has been difficult to break, so to speak, and for which many therapies have been developed. So the results of the BROOKLYN trial for me also herald a wonderful day in my history, so to speak.
If we can then move to slide number three, everything is put into perspective in terms of the disease that we're treating in BROOKLYN. Heterozygous familial hypercholesterolemia is by far the most prevalent autosomal dominant genetic disease in the world, and one in every 250 children has this disease, meaning there are tens of millions of these patients across the globe. When I started studying heterozygous FH, premature death at the age of 30 was not uncommon. We have learned since then that if we treat LDL cholesterol levels of FH patients to normal, these patients can actually have a normal lifespan. But if you start life with a very elevated LDL, you will need multiple therapies to lower that to normal levels. And it has been a very, very difficult journey to actually achieve that.
If we now move to slide number four, you will realize the study design and baseline characteristics that we have presented before. It's important to realize that the randomization was a 2 to 1 ratio, meaning that there are twice the number of patients on active therapy or obicetrapib in this trial as placebo. The key inclusion criteria were, of course, heterozygous FH and an LDL cholesterol level over 70 mg/dL while on maximally tolerated lipid-lowering therapy. The baseline lipids are a testimony as to how difficult these patients are to treat. The LDL was 123 mg/dL, and you can appreciate the other baseline lipids and lipoproteins. The demographics show that we have achieved gender equality because 53% of our patients were female.
They were somewhat younger than normal atherosclerotic cardiovascular disease populations, but one noteworthy aspect is the body mass index of 29. When I started, body mass index in FH patients was completely normal, and this shows you that even FH patients are getting more obese when time goes on, giving it an additional complexity in the treatment. 90% of patients were on a statin, and high-intensity statins were almost 80%. And not only that, half of the patients were on ezetimibe and 14% on PCSK9 inhibitors. There is no FH trial where a drug was tested on top of triple therapy, and in that sense, we are the first phase III study to do so in heterozygous FH. When we move from slide four to slide five , you can see the disposition of all randomized participants.
Now, Michael will later deal with the safety, but I think what's in the yellow box is a very important parameter of how a drug is tolerated and how safe it is. So the discontinuation rate, and please take a look at the number between brackets, because that's the percentage. The absolute numbers, because of the 2 to 1 randomization, are more difficult to interpret, but the percentages are, of course, the important number here. 7.6% of patients on obicetrapib discontinued treatment, while 14.4% discontinued, discontinued treatment while on placebo. That, of course, means that more patients on obicetrapib completed the study, and you can see that on the third line from the bottom. 95.8% of patients in the obicetrapib arm completed the study, versus the 93.2% in the placebo arm.
Now, I'm very proud to actually move to slide number six, where we show you additional baseline details of all randomized patients. Again, when I go through this, mean age was about 57 years, almost the same number of men and women, a slight preponderance of females. I think, the important point that I made on body mass index is shown in the bottom. A body mass index of 29 is, of course, somewhat elevated, which, by definition, will lead to other abnormalities that make treatment even more difficult. What's also important is that the patients were diagnosed with FH, almost 72% had a genotyping confirmed diagnosis of heterozygous FH, or a very definite diagnosis according to the Dutch lipid criteria or to the Simon Broome Register.
So this is truly a completely definite heterozygous FH population that, in fact, had maximally tolerated lipid-lowering therapy. Even 14% of patients were on triple therapy. Now, moving to slide number seven, I think this is even more intricately explicated. Again, statin treatment at high dose, 78.8% in the obicetrapib arm and 67.8% in placebo. And the ezetimibe use is, as far as I know, the highest that I've ever seen in an FH trial, 53.8% for obicetrapib and 50% for ezetimibe. Again, denoting that these patients are very difficult to treat.
So despite the fact that these numbers, almost 80% of patients on high-dose statins, 50% on ezetimibe, and 14% also on PCSK9 inhibitors, despite that, baseline LDLs were above 120 mg/dL, which kind of denotes the difficulty in treating these patients and getting them to goal. Now, moving from slide seven to slide eight , you will see the primary efficacy endpoint. So at day 84, the placebo-corrected LDL difference was 36.3%, and the secondary endpoint at day 365, the placebo-corrected LDL lowering was 41.5%. But I think what is more important here is to look at the graph on the right-hand side of the slide.
The first measured LDL difference between placebo and treatment was at day 30, and you can see that that actually gets close to a 43.5% lowering of LDL cholesterol. So this is achieved at day 30, a very rapid decrease, and then it's, in fact, maintained over the entire course of the year, where at the end of the year, the placebo-corrected difference is 41.5%. And those two lines, the placebo line and the treatment line, are actually parallel over time, denoting that the drug is capable of actually maintaining that treatment difference of around 40% over the space of a full year.
And again, what is most important here is that, that placebo-corrected difference at one year is, of course, the important difference for the patients, because that will determine the efficacy in terms of MACE reduction in our cardiovascular outcomes trial PREVAIL. So I hope you are as excited as I am about these numbers and about this, efficacy that we've shown now, over the course of an entire 52 weeks. And with that, I would like to move, to slide number nine to further dive into the efficacy data. What's very important is in the treatment of heterozygous FH, is to achieve guideline-directed treatment goals.
And as you can see, moving from left to right, is that in the obicetrapib arm, 24% of patients achieved less than 50 mg/dL, which was in the beginning, when I started treatment trials with FH, completely unheard of. Then when you move one bar to the right, you'll see that obicetrapib 10 mg was able to get 51% of patients down to less than 70 mg/dL, compared to only 11% in the placebo arm. And by the way, all of these differences are highly statistically significant. Now, of course, for FH patients that do not yet have atherosclerotic cardiovascular disease, there is a goal of less than 100 mg/dL, and in the obicetrapib arm, this was achieved by 77% of patients versus 40% of patients in the placebo arm.
This actually tells you that when you add obicetrapib to this wide armamentarium of drugs, then in fact, you are capable of achieving the guideline-directed LDL goal of less than 100 milligrams in almost 80% of patients. Now, as I always like to say, is that there is nothing more honest than a waterfall plot, and this is an LDL-C responder analysis in the obicetrapib 10 milligram arm. What you can appreciate from this waterfall plot is that the vast majority of patients actually have a significant LDL lowering with adding obicetrapib to their maximally tolerated lipid-lowering therapy. But in fact, a third of patients actually had a more than 50% LDL reduction, which is those patients that achieve an LDL bar that gets below the red line.
On the right-hand side, there are so-called non-responders, which are typical of FH trials, common and seen with other therapies. Now, how do these data that we share with you today, these exciting data, how do they kind of compare and stack up to our phase II program? When we look at LS means for our Japan phase II study, our ROSE study, and our ROSE II study, and when we compare that to the primary endpoint in BROOKLYN at day 84, and the secondary endpoint in BROOKLYN at day 365, you can see that this is very consistent with prior clinical trials that we have reported and have actually published in peer-reviewed journals.
That actually tells you that this is now the translation from our phase II program into our phase III program, in terms of efficacy, is very, very consistent, which of course makes us both very well for our future. With that, I would like to now ask Michael to, in fact, go deeper into the safety data of this drug. Please, Michael.
Thank you, John. I'm thrilled to present the safety results of the trial. On slide 12, treatment-emergent adverse events were 70.3% on placebo, 63.7% on obicetrapib. Any study drug-related adverse event was 6.8% on placebo versus 4.3% on obicetrapib. None of these adverse events were considered severe. As far as any adverse event leading to death, it was 1.7% on placebo and 1.3% on obicetrapib. Slide 13 highlights non-serious treatment-emergent AEs, seeing in greater than 5% in either arm, a total of 44.1% on placebo and 40.6% on obicetrapib. The most common events were as expected, things such as influenza, COVID-19, hypertension, and nasopharyngitis.
The events of interest, and I especially look for as a clinician, are some of the GI side effects. Diarrhea, 6.8% on placebo versus 3.8% on obicetrapib. Back pain, 5.1% on placebo versus 3% on obicetrapib. Fatigue, 5.9% on placebo, 0.9% on obicetrapib. Slide 14 highlights our pre-specified adverse events of special interest. These include elevated liver enzymes, more than three times the upper limit of normal for ALT and AST. We had zero on placebo, zero on obicetrapib. Bilirubin greater than 2x the upper limit of normal, 2 patients on placebo, or 1.7%, zero on obicetrapib. Muscle enzymes greater than 5x the upper limit of normal, 3.4% on placebo versus 1.3% on obicetrapib.
New-onset diabetes mellitus or worsening of glycemic control, 22% on placebo, 20.5% on obicetrapib. eGFR <30, a measurement of severe renal function or a decrease in 25% in renal function from baseline, 8.5% on placebo, 4.3% on obicetrapib. Another measurement of kidney function, serum creatinine increasing by >0.3 from baseline, 7.6% on placebo, 2.1% on obicetrapib. And then age-associated macular degeneration, 0 cases on placebo or 0 cases on obicetrapib. Moving to slide 15. In conclusion, BROOKLYN met its primary endpoint of LS mean reduction at day 84 of 36.3%, P<0.0001. This was consistent with the safety results from our previous phase II ROSE, ROSE II in Japan, phase II trials.
The LDL reduction at one year of 41.5%, again, less than 0.001, supports the consistency and durability of our LDL-C lowering over a one-year period of time. 77% of patients receiving obicetrapib had an LDL below 100 mg/dL, and 51% below 70 mg/dL, and 24% below 50 mg/dL, which are goals established for this very high-risk patient population. 34% of patients in the treatment arm achieved greater than 50% reduction from baseline and LDL at day 84. These benefits were seen regardless of background therapy or number of therapies. As I mentioned, as a clinician, I'm especially pleased with the observed safety results compared to placebo, with no increase in blood pressure or any difference from placebo, looking at liver enzymes, hs-CRP, a measurement of inflammation or renal function.
We intend to report other secondary endpoints, such as non-HDL, ApoB, and Lp(a), and additional safety data at upcoming scientific conferences. These results are also consistent with data observed in our previous phase II studies. Moving to slide 16. The BROOKLYN trial represents the first of our phase III trials, with BROADWAY, our second pivotal phase III trial for the LDL lowering indication. In this study, we have patients with established cardiovascular disease, predominantly with LDLs over 55, with additional risk factors, or LDL above 100 mg/dL without additional risk factors, on maximally tolerated lipid-lowering therapy. As reported previously, the baseline mean LDL-C is 98 mg/dL.
The mean baseline characteristics of BROADWAY participants are as follows: high-intensity statin therapy is 65%, ezetimibe is 24%, PCSK9 therapy is 4%, which again represents the standard of care throughout the world where we're conducting this trial. We expect to report top-line data from BROADWAY towards the end of this year, and the trial's enrolled over 2,500 patients. The BROADWAY trial inclusion criteria are generally consistent with the PREVAIL trial, with a 95,441-patient trial comparing obicetrapib to placebo, looking at cardiovascular outcomes. This patient population has ASCVD with LDLs over 55 mg/dL with other risk factors. The baseline mean LDL is 103 mg/dL, and similar to BROADWAY, the majority, 70%, are on high-intensity statins, and many are also on ezetimibe and have their LDL levels controlled as best possible. Moving to slide 17.
We continue to expect top-line results from BROADWAY in the fourth quarter of 2024 and for PREVAIL in 2026. We're also developing a fixed-dose combination with ezetimibe, and a fixed-dose combination trial is underway, fully enrolled in July this year, called TANDEM. We anticipate releasing top-line data in the first quarter of 2025. We expect that these results, BROOKLYN, BROADWAY, and TANDEM, if favorable, will be the basis of our filings for the monotherapy obicetrapib, as well as the fixed-dose combination with ezetimibe, for potential regulatory approval throughout the world. BROOKLYN is another exciting milestone for the company and provides us with another mark of potential efficacy over 12 months in a challenging patient population. This trial also gives us optimism regarding potential benefits of PREVAIL as our large cardiovascular outcome trial.
On slide 18, we have modeled the BROOKLYN results compared to the baseline data from PREVAIL. The 36% LS mean difference at day 84 provides a 37 milligram per dose drop in LDL, which suggests a hypothetical estimated MACE benefit of 22% based on the well-established CTTC regression line. Especially notable for BROOKLYN is the 365 data. This is the time point generally used to calculate the difference in LDL from outcome studies, showing an LDL-C lowering of 41%. This will result in a 43 milligram per dose drop in LDL-C, which suggests a hypothetical 25% MACE benefit. BROOKLYN continues to write us with optimism about our ability to achieve the benefits of obicetrapib in our ongoing outcome trial, PREVAIL. I want to thank you very much for your attention.
We believe today's results support the ability of obicetrapib to significantly reduce LDL-C, enabling patients, even those who fail on maximum tolerated lipid-lowering therapy, to achieve their risk-based goals. These data reinforce our optimism and the opportunity for obicetrapib to overcome limitations of prior CETP inhibitors and to provide patients with better care. We're excited about the results presented today for BROOKLYN, our first phase III trial, and are encouraged by the consistent safety data generated for obicetrapib across multiple clinical trials. We look forward to building on today's results with top-line data from BROADWAY in the fourth quarter of 2024, and from TANDEM in the first quarter of 2025, and presenting full data for BROOKLYN in the coming months. I thank you for listening. I'd like to turn it over for questions from you, the audience.
Thank you. To ask a question, please press star one, one on your telephone and wait for your name to be announced. To withdraw your question, please press star one and one again. We will now take the first question. From the line of Dennis Ding from Jefferies. Please go ahead.
Hi, good morning. Thanks for taking our questions, and congrats on the data. Just one question from me. Can you just talk about, you know, your thoughts on, how the percent reduction in LDL changed from week 12 to week 52? I appreciate that it got better over time, but I'm just wondering, should that be people's expectations going into the BROADWAY data in Q4? And then perhaps as a follow-up, what does that mean as to your overall confidence level for the PREVAIL study? Thank you very much.
Yeah. Yeah, thanks, Dennis. I'll turn it over to John to answer the question.
Thanks, Michael. Yeah, Dennis, so in all placebo-controlled randomized trials of lipid-lowering drugs, and especially in trials with heterozygous FH, the reason to include a placebo is because, by definition, people will be less adherent to everything they do in life, starting at about one month of the beginning of the trial till, you know, about one year. And so the important thing is, and that's also, by the way, why the FDA has stipulated that LS means placebo-corrected is the right measure to look at.
So when you look at the efficacy in the obicetrapib arm at day 30, and then you look further along the time to day 365, and you do the same for the placebo, you see that these two lines are parallel because the trial is placebo-controlled and blinded, so patients don't know whether they are on either obicetrapib or placebo, which, by the way, is not true if the drug has a lot of side effects. So this also shows you patients are not aware of their treatment randomization, and so they will, in equal manner, change their behavior over the space of this year, which means they are less adherent to diet. They sometimes forget a tablet of statin. They sometimes forget a little bit of their ezetimibe, et cetera, et cetera.
You will, by definition, have at one year, when you only look at baseline, you'll have less efficacy in both the treatment arm of obicetrapib, but also in the treatment arm of placebo. The most important thing here is to look over time at the parallel nature of the lines. As you can see, these lines are completely parallel. They indicate a 40%-42% LDL lowering as a difference over time from day 30 onwards. That is, if you look at the LS means that we have reported for our phase II program, that is spot on. That is the efficacy of the drug in a real-life setting when you take LS means as the primary endpoint.
Now, of course, this gives us great hope that the rest of our phase III program will show similar results, including the PREVAIL trial, and we have done our kind of, you know, theoretical exercise by using the CTT meta-analysis line. Then you can see that whether you take the day 84 or the day 365, and listen, it's my personal conviction that day 365 is much more relevant because that is the long-term kind of outlook of obicetrapib, that you end up, you always end up with a MACE reduction over 20%, and that is ignoring the potential other non-lipid benefits of the drug, such as those possibly on diabetes.
And so that is our feeling going, going further with our phase III program, which, again, is a, is a strong confirmation of the LS means efficacy we saw in phase II. But even more importantly, and I hope that everyone, everyone appreciates that, the safety of this drug is, as far as I'm concerned, really, really impressive. And that, of course, is always very important because it's safety that breaks drugs in phase III.
Great. Thank you so much.
You're welcome, Dennis.
Thank you. We will now take the next question from the line of Roanna Ruiz from Leerink. Please go ahead.
Yep, morning, everyone. So wanted to ask a little bit about the observation that OB had about half of the discontinuation rate compared to the placebo arm. How significant is that in clinical practice, and how do you expect it to impact physician prescribing of obicetrapib down the road, you know, trying to get patients to goal, et cetera?
Yeah, thanks, Roanna. Yeah, I'll, I'll take this on as my, you know, clinician hat. Yeah, so we rarely see drugs like this in practice where, you know, the side effect profile based on the BROOKLYN data is really comparable to placebo. And so I can tell you that every time you have a discussion with a patient about any LDL lowering drug, it's all about safety. And we know that ezetimibe, when it first was launched, it had a 15% LDL lowering, but was very safe, and it, you know, it sold $4 billion-plus a year alone, $6 billion with, you know, Vytorin as the combo pill. So safety, in many ways, is far more important for, you know, primary care doctors and for patients than efficacy.
So we saw here, you know, confirmation of this great safety we saw in phase II. And I think when you talk about, you know, what do people worry about? You know, they worried about, you know, the in statins, in particular, the diabetes risk, you know, the muscle aches and pains, and liver enzyme elevations, muscle enzyme elevations, all the things that you think about for lipid drugs. We saw none of this with obicetrapib. And so it's gonna be a again, holds up throughout phase III, which we have a lot of confidence it will, you know, based on this trial, you know, one year and 350 patients in the study. This will be, I believe, a very well received by the medical community.
We see this as a very important part of the whole commercial strategy of the drug. It's very, very efficacious on top of statins or other lipid drugs, and it has a very excellent safety profile.
Got it. Helpful. And a quick follow-up. Are you able to tell at this point, did any of the background lipid-lowering therapies drive higher discontinuation rates in the placebo arm? And could you elaborate, like, if it was balanced between the active and the placebo arm?
It was... You know, obviously, there was more discontinuation rates on placebo. We haven't looked at that question exactly yet, Roanna. But, but I think that, you know, our expectation from all the other trials that John and I have conducted, that you do, you do see people dropping off over time for, for various reasons in these trials. And, and this is kind of the expectation. Now, we were really gratified that, that at the end of the day, this was a very high-quality trial. 95% completed the trial. That means they came for the visits at the end and got their labs measured. And so this was a, this was a very high-quality trial. We know that, based on PK measurements, you know, the people that were randomized to the drug took the drug.
So we feel really good about the quality of the data and how this will translate into, you know, future trials, you know, for the company.
Got it. Thanks.
Thank you. We will now take the next question. The next question is from the line of Debjit Chattopadhyay from Guggenheim. Please go ahead.
Hi, good morning, all. This is Robert, for Debjit. Congrats on the data, and thanks for taking our question. One from us today, and I'll ask on the potential trend in new-onset diabetes during the trial. It appears to be slightly favorable towards OB. I'm wondering if that's a trend or too early to tell. Thank you.
Yeah, thanks. Yeah, it looks encouraging. Well, we have more data to follow on this. We'll present at upcoming meetings, but just to say we're encouraged by that data. BROADWAY will, of course, be a better study to look at this. And so, we'll, you know, stay tuned on that because, you know, we feel this is gonna be a very important part of our program for establishing the benefit of obicetrapib, you know, for treating elevated LDL. But more to come in the months ahead, and especially when we have our BROADWAY data.
Thanks. And on BROADWAY, I'll squeeze one more in. Given that BROADWAY is a mix of both HFH patients and ASCVD, do you expect similar or better absolute reduction in LDL-C compared to a sole HFH population?
Yeah, I'll have John take that question.
Hi, thanks for the question. Well, I would like to turn that question around a bit. Heterozygous FH, especially if they're all maxed out on therapy, which these patients are, you do realize that many of these sites that participated in BROOKLYN were academic sites, and to get there, you have to be already quite a complicated FH patient. Then they treat you with, you know, statins, then they add ezetimibe, and in 15%, 14%-15% of patients, they add a PCSK9, and still these people were not at goal, and so then they end up in our trial. And by definition, these are difficult to treat patients, no doubt about it. Even then, we saw, as I just described, these two lines parallel over 365 days.
So I don't think at this time it is correct to have all sorts of predictions into the future, but the patients in BROADWAY are definitely not as hard to treat as the patients in BROOKLYN. So I think I would like to leave it at that and just really focus on the fact how amazing it is that in a trial where 15% of patients have triple therapy, that we still have achieved such LDL lowering.
Thank you. We will now take the next question from the line of Tyler Van Buren from TD Cowen. Please go ahead.
Hey, guys. Good morning. Thanks for taking the questions. I have a couple for you. The first one is, can you help us understand how the percent of patients on high-dose statins and ezetimibe at baseline compares to the PCSK9 trials in HeFH, as we think about comparing the magnitude of LDL lowering across the trials, and if this could have had an impact? And the second question is just, given these data, do you believe that the phase III BROADWAY data next quarter will likely look similar, higher, or lower on LDL lowering?
Yeah, John, I'll have you take that also.
Tyler, good morning. This is John. So, I think that we, in BROOKLYN, have pretty similar patient numbers on high-intensity statins than most recent trials, and then I'm talking about bempedoic acid and inclisiran, for example. I don't think that there are fundamental differences. What is a fundamental difference is that 14% of patients in BROOKLYN actually were also on a PCSK9 inhibitor, which of course by definition means triple therapy. So I think that... And also what is interesting, if you look, and I'm gonna have to name two other trial. When you look at inclisiran and bempedoic acid, for example, they also I mean, they showed efficacy numbers in their heterozygous FH trials that were lowest of all their trials.
ORION-9 had definitely lower LDL lowering numbers than ORION-10 and ORION-11 . So you can, I think, very well compare these trials, and the same actually is true for bempedoic acid. But again, I think it's always dangerous to try to predict the future. The only remark I can make is that in BROADWAY, we'll have a percentage, but it's not a large percentage of patients that have heterozygous FH. The vast majority of patients are straightforward ASCVD patients, and those patients are usually easier to treat and have less stringent background therapy on average than the average heterozygous FH patient.
Very helpful. Thanks.
You're welcome, Tyler.
Thank you. We will now take the next question from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead.
Thank you, team. First of all, congratulations on the data, and thank you so much for sharing your comprehensive results, especially around the safety of the drug, which was the goal of the BROOKLYN study. A few questions for you, team. I guess the first question is, you commented on quite a bit, this BROOKLYN study was one of the most challenging HeFH patients with ezetimibe use, as high as 50% and high statins of 80+. And as you could tell, everybody's trying to predict BROADWAY based on BROOKLYN. I guess, how should we think about the differential uses of ezetimibe and high statin between these two studies? Like, how much does that impact the LDL-C reduction? That's sort of bucket one question.
Bucket two, it looks like you guys did a really nice job on managing placebo in BROOKLYN versus other HeFH studies. If you could kindly talk about, you know, what do you hope to see in BROADWAY and what strategies are in place? And then my third question for you is, if you could just broadly comment on the other lipids. And I know you're saving the presentation, I know you're saving the presentation for another scientific conference, but given the LDL-C reduction came so consistent based on previous studies, I was wondering if you could comment around other lipid markers. I'm so sorry for so many questions.
Yeah.
I'd appreciate if you could provide color on all of them.
Yeah, thanks, Yaz. I'll take the last one first. So yeah, so I, there might be some confusion. Our HDL went up, as expected, you know, over, well over 100%. I mean, so that we'll present that at the upcoming American Heart. And our LPLA data and non-HDL ApoB all look, you know, very consistent what we saw in phase II. I can assure you that I think when the data is presented, you'll see, you know, how excited we are to present that data as well, you're coming up at the American Heart Meeting.
But we, you know, had a really, as expected, a very nice, robust effect on HDL and the LDL, LPLA, non-HDL, and ApoB benefits were, again, very consistent with our, you know, with our data in phase II. And, I think one other... Just highlight one more point. I think people have asked, too, about, you know, this was the beta- quant method that we used, the gold standard, and we did look at Friedewald and Martin Hopkins, and they’re very similar. You know, in fact, Friedewald was, it was 44% at 365. So very similar to the 41.5 that we saw in the beta- quant.
So we're seeing a very, very consistent effects of LDL lowering without the issues with how we measure the LDL. So we're doing all those analyses. We'll present those at the American Heart Meeting coming up. But again, very consistent benefits across the board on all the other lipid parameters. The other question, I'll turn it over to John to address the first two questions. John, do you remember the questions? I think we can-
Yes, yes, I do.
Yeah.
Yeah, yeah. So, as you know, people with heterozygous FH, by definition, have a single LDL receptor gene that works. And statins and ezetimibe basically work by upregulation of that gene, and therefore, the protein, which is also the mechanism of action of obicetrapib, and we have shown those data at the R&D day. So we have now proof that the MOA of a CETP inhibitor is basically extremely similar to that of ezetimibe, bempedoic acid, and statins, and also PCSK9 inhibitors. Simply, you have more LDL receptors at the surface. But if you only have 50% of the gene available to you, by definition, it gets harder and harder when you stack one therapy on another, to actually squeeze the last LDL receptors out of the gene, so to speak.
So if you have two functional LDL receptor genes, as is true for the vast majority of BROADWAY patients, it is easier to upregulate them, and therefore, it's easier to treat them than heterozygous FH. So that is the biological underpinning of our trust and our feeling moving into the rest of the phase III program, that we've had our most difficult-to-treat patient population first, and that we are now moving into more run-of-the-mill ASCVD patients, either in BROADWAY or, of course, in TANDEM, where we treat patients with a combination of obicetrapib and ezetimibe in a fixed-dose combination pill.
So that is the biology you have to realize behind our kind of, yeah, I would say, confidence that we will see at least equal results in our next phase III trials. Did you have another question, Yaz? Because I see-
Yes.
I think that I forgot number two.
Number two was on placebo. You guys did a nice job managing placebo versus other HeFH studies. Would love to think about, you know, how we should be thinking about placebo and BROADWAY.
It'll be, it'll be exactly the same. So, yeah, I am personally, when I look at the placebo discontinuation rate and I look at the obi discontinuation rate, and I know you can never do statistic on this, so you can't say it's really different because there is no p-value associated with it, and you're not allowed to do this with safety readouts. But it's very comforting and reassuring that patients on obicetrapib have actually better adherence rates than patients on placebo. And that is, that is a thing that will not be different between heterozygous FH and ASCVD patients, because those are subjective feelings of a patient towards a drug. Do I get muscle pains and aches?
Do I get-- I mean, is there anything my, my primary care doctor tells me about my liver enzymes or my renal function, or do I have other, yeah, subjective side effects? Obviously, those side effects were not there. If they're not there in heterozygous FH, it's extremely unlikely that they will be there in a very large ASCVD population. That's why I think that the placebo arm in the larger trials will behave exactly as the placebo arm in this trial. That is something that I think we can assume, go moving into the future.
Thank you so much. I'll jump back in the queue.
Thanks, Yaz.
Thank you. We will now take the next question from the line of Matthew P. Phipps from William Blair. Please go ahead.
Hey, thanks for taking my questions and providing this, comprehensive update today. Just do you have a sense of compliance rates in this BROOKLYN trial, as far as taking the medication, how you're tracking that? And I assume that we'll, be able to monitor that in BROADWAY as well. And then I guess, you know, I can kinda estimate from the graph. I'm wondering if a sense of the median LDL reduction, something you guys have also reported in some of your other recent studies.
Yeah. Thanks, Matt. So yeah, the compliance was excellent. We actually measured PK on all the main visits at day 84, day 365, and compliance was excellent on the drug. And so we can reassure everyone that, you know, this drug was very well tolerated, and people were taking the drug, you know, during the trial. So, the median was 40%, you know, right on line with what we saw in our phase II trial. So the median of 40% at day 84. We don't have the medians at the end. It's not how we do the analysis. We just have LS means at the 41.3%. The median was 40% at day 84.
Thanks, Michael. Last question, maybe if you can just remind us on the powering for the PREVAIL study. Question I've gotten just as far as the powering able to detect risk reduction.
So we're well-powered, you know, for this 20% MACE benefit with our, you know, 9,500 plus patients. And again, we have a 2.5-year minimum follow-up to allow enough time for the curves to separate effectively. And, you know, when we officially publish our baseline paper, we'll go into more about the details about the powering and the specific MACE events we'll be reporting, you know, during the trial as the primary endpoint.
Good. Thanks, Michael. Look forward to this whole data.
Okay. Thank you.
Thank you. We will now take the next question from the line of Leonid Timashev from RBC Capital Markets. Please go ahead.
Hey, guys. Thanks for taking my question, and, congratulations on the data. I had two from me. So I guess, first of all, we can see that at day 365, sort of the LDL-C reduction is trending lower over time, and, you know, we've talked about some of the reasons for that. But I guess, as we think about PREVAIL and the 2.5-year follow-up there, I mean, should we expect that to continue to trend down, or do you think that would sort of stabilize it maybe at the place that it is at one year?
Then my second question is, I guess, are there any differences in how patients behave in patients who are in the secondary CVD versus the HeFH in terms of compliance with drug, lifestyle modifications that might affect you know how we should think about LDL lowering over time in this group versus what we'll expect to see from PREVAIL and from the other studies?
Well, well, I'll turn it over to John, 'cause John has been involved with just about every CVOT, so I'll have John answer that question.
Yeah. Good morning again, Matt. So what's very important is what Michael just answered, is that the PK data. So we have measurement of drug data in this trial, and they were really good. By definition, that means that the upward trend in the obicetrapib arm of LDL has nothing to do with obicetrapib, but has everything to do with how these patients basically deal with their environment and the other, and the other drugs that they're taking. That's why you put in a placebo arm, because these patients do exactly the same. As you can see, the difference between the two stays basically the same over a year. Now, it is very unlikely that after a year, this will go down further.
So usually, and that's also why always, the use of a drug and the, I would say, the disadherence to a drug is reported at year one, because that's when most drugs stabilize, at least if there are not too many side effects, of course. That is also the number that is always used from phase III to actually predict the efficacy in a MACE outcome trial.
So in that sense, I do expect that that difference between placebo and obicetrapib, which is about 42%, will carry on over the entire 3.5-4 years that we're gonna need for PREVAIL in order to have our maximum MACE reduction over time, which is now, you know, kind of calculated to be somewhere between 22%-25%, depending on which time point you take, but it's over 20%. And so this is what we always do when we look for the results of a MACE CVOT. It's the day 300, the day 365 time point, because if patients would actually lose a little of their adherence more over the next three years or so. The same would happen to the placebo arm, and so the difference basically would stay the same.
It's the difference that determines the MACE outcome, not the change from baseline into the active treatment arm. So that is, yeah, simple trial math. Yeah.
Thank you. We will now take the next question from the line of George Farmer from Scotiabank. Please go ahead.
Hi, good morning. Thanks for taking my questions. Couple from me. Wondering if you could inform us as to whether there were any cardiovascular events in the trial and if maybe there was some imbalance there. Also, kind of along with, aligned with safety, you know, is there anything that you might be worried that FDA might poke on, you know, as they start to scrutinize this data, you know, kind of like a surprising gotcha moment that you could maybe prepare us for? And then finally, I noticed that you launched this clinical trial combining with Repatha and obicetrapib. Can you talk about how that fits into your regulatory strategy? Thanks.
Yeah, sure. So thanks for the question. So there weren't a lot of cardiovascular events, but they were in favor of obicetrapib, but we will again present those at the American Heart Meeting. But there was a trend in the right direction. Obviously, more will come, you know, with BROADWAY, and of course, PREVAIL. That's why we're doing PREVAIL. But what we saw was a favorable trend in MACE events in BROOKLYN even. So that was also encouraging. So you know, so the FDA, you know, they obviously, you know, you have to be honest, the class history is there. But and as I mentioned, this is why to us, this data is so exciting on the safety, because we saw no effect on blood pressure.
That's what they look at the most because of the obicetrapib history. You know, blood pressure actually went down 1.4 millimeters over the entire 12 months of the trial. So, you know, it went down over time. No increase in blood pressure. You know, CRP, which has gone up, and other CETP inhibitors actually went, you know, down. And we'll again, we'll go into more details about that as we present data coming up. No, no, you know, macular degeneration, which has been, unfortunate. We really think this is a drug that might help AMD in the long term because of, of its mechanism. So we, we feel those are the key things the FDA would be focusing on.
They looked at, you know, they asked us about, you know, renal function and liver enzymes, and this drug looks exceptionally safe based on the BROOKLYN data that we have so far. So this is, I think, one of the, you know, really the best aspect of BROOKLYN. We confirmed the LDL lowering efficacy that we saw in phase II. But now we have, you know, a very much larger safety data set, especially going out for 12 months, and we're seeing really no signals of any issues that would be of concern. In fact, we see favorable trends in a number of aspects of this drug that we hope to see, you know, further delineated with our BROADWAY data.
So this is a very exciting time for us with data in [BROOKLYN]. So the other thing about the PCSK9 combo, the small pilot study, you know, we are, we're gonna have data, as you see, from some patients on PCSK9 inhibitors in our trials. But we do want to see the combination of these two drugs together. And we're looking at all aspects of that LDL lowering in combination and also the LP lowering of both drugs together, because they both... Obviously, our drug will have our data to present, but we're very excited about the LP lowering benefit. You know, PCSK9 lowers LP by about 15%-20%. So we think if they're additive to each other, then that could be a really nice additional thing to consider, you know, for future development.
That's our plan with that pilot study, to look at that combination and see how we can go forward with that, maybe with other trials in the future.
Okay, great. Thanks very much.
Yeah.
Thank you. We will now take the last question from the line of Sebastian van der Schoot from Van Lanschot Kempen. Please go ahead.
Hi, team. Thank you for taking my questions, and congrats on the results. Two quick questions from our side. Could you maybe provide some insight on whether the baseline therapy influenced the adherence rate, so being ezetimibe or PCSK9 inhibitors? And then looking a little bit forward at the academic presentation, I was wondering whether you could provide some color on whether the trajectory for the Lp(a) lowering was also similar, specifically in the previous trials, and what you think is the importance of this specific biomarker. Thank you.
Yeah. Yeah, so just to answer your second question—yeah, like, we're very happy with the LP lowering, and okay, we'll present that at the, hopefully at the American Heart meeting coming up in November. So, in your first question, again, I'm sorry, what was the first question one more time? Like, trying to be-
It was regarding the influence of the baseline therapy.
Oh, oh, right. Right. Yeah, so, yeah, so the baseline therapies, they were, they were similar, in, both the placebo and the obicetrapib arm, and we, at least so far, we haven't looked at this extremely carefully yet, but in our first analysis, we saw no difference. I think I made a comment, but we saw no difference in efficacy, whether they're on other drugs or not. Again, we looked at the subset of people on ezetimibe and those without ezetimibe, and we see similar benefits. I think it was asked earlier, too, I think the question is the efficacy of ezetimibe in combination, that'll be tested in TANDEM much more specifically, because that's a parallel design of obicetrapib alone, obicetrapib plus ezetimibe, ezetimibe alone.
So we'll be able to see the, we believe, the synergy much more clearly. When you talk about a population that's put on ezetimibe, they are by nature more refractory to treatment. And so you don't really get a good signal of what the synergy might be, because these are more challenging patients to begin with when they're on ezetimibe. So the same thing, too, for PCSK9 inhibitors, that they're on a PCSK9 inhibitor for a specific reason. They've been refractory. And so that's why we're doing the actual proof of concept of the two drugs together study as well. But by and large, we saw no difference in efficacy across those that had different concomitant drugs during the trial.
Great. Thank you so much.
Thank you. There are no further questions at this time. I would now like to turn the conference back to Michael Davidson for closing remarks.
Yes, thank you very much to all of you for listening, and we really, really appreciate the questions, and we're extremely excited about the data from BROOKLYN. We're thrilled by the efficacy, confirming the phase II benefits across the board, especially that it got, you know, better over time compared to placebo, the 41.3% beta quant LDL measurement. And I say stay tuned to further updates on our data as they come out. We have, I think, more exciting data to share with you at the American Heart Meeting, as we get more into the safety data and to the things we talked about, the MACE outcomes and so forth.
You know, this was a very, very well-tolerated drug, and that to me, at the end of the day, is gonna be a big part of our story for clinicians and for patients. And BROOKLYN is our first of our phase III trials to show this combined benefit of efficacy and safety together in an oral option for patients to get them to their goals of treatment to reduce cardiovascular risk.
So thank you all very much, and we look forward to continue to update you on our progress as we have an exciting several months ahead to present to you the rest of our two pivotal phase III trials on LDL lowering and then continue to update on the progress that we had with PREVAIL, now fully enrolled, and we'll make progress on getting that study completed towards the end of 2026. So thank you again, and we hope to be in touch as time goes on. Thank you.
This concludes today's conference call. Thank you for participating. You may now disconnect.