NewAmsterdam Pharma Company N.V. (NAMS) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the NewAmsterdam Pharma TANDEM Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Mr. Matthew Philippe, Executive Vice President and Head of Investor Relations. Please go ahead.

Good morning, and thank you all for joining today. Before we begin, we would like to direct everyone to Slide 2 and remind everyone that the statements made on today's conference 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 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. With that, I would now like to turn the call over to Michael Davidson, CEO of NewAmsterdam. Michael?

Thank you, Matt, and thank you to everyone joining us this morning. Earlier this week, we announced additional topline data from our BROOKLYN pivotal Phase III study in individuals with heterozygous familial hypercholesterolemia. In this study, we saw a 36% and 41% reduction in LDL-C at days 84 and 365, respectively. We also announced Lp(a) reductions of 46% and 53% at the same time points and a decrease of 53% in total particles and 102% decrease in small LDL particles when compared to placebo. Today, we are delighted to share the positive statistically significant topline results from the pivotal Phase III TANDEM trial. As a reminder, TANDEM was designed to determine if the fixed-dose combination of obicetrapib 10 milligrams and ezetimibe 10 milligrams in patients whose LDL-C is not adequately controlled despite being on maximally tolerated lipid therapy is superior to each of the components for lowering LDL-C. As you see on Slide 4, goal attainment is still an issue for individuals with ASCVD or familial hypercholesterolemia. Even with therapies available today, only 25% of those individuals are achieving LDL-C less than 70 milligrams per deciliter and only 10% of high-risk patients are reaching the below 55 milligrams per deciliter target. Today's results mark a meaningful milestone for our company and for the cardiovascular disease community more broadly. We believe obicetrapib as a monotherapy or in a fixed-dose combination with ezetimibe provides clinicians the therapies to achieve LDL-C targets in the majority of high-risk patients on maximally tolerated statin therapy. We are pleased that the fixed-dose combination resulted in an approximately 50% reduction in LDL-C, which is clinically meaningful and statistically significant p<0.001 (sic) [ p<0.0001 ] to either obicetrapib or ezetimibe, thereby supporting global regulatory filings for this once-a-day oral therapy for patients with elevated LDL-C. To present the top line of results is my great friend, a world-renowned expert on lipid disorders and Chief Science Officer in NewAmsterdam Pharma, Professor John Kastelein.

Michael, thank you very much. I'm equally excited and honored to share the results of the TANDEM study today. On Slide #5, you can appreciate the study design and the baseline characteristics of the study population. The main purpose of this study was to investigate the fixed-dose combination of 10 milligrams of obicetrapib and 10 milligrams of ezetimibe, both in terms of efficacy and safety. The design of the TANDEM study is a simple parallel design with 4 arms of about 100 patients each. The key inclusion criteria included ASCVD or its risk equivalence and the fact that LDLs needed to be above 70-milligram per deciliter while, in fact, on maximally tolerated lipid-lowering therapy. What's very important to realize is that this study had 4 co-primary endpoints: the fixed-dose combination versus placebo, the fixed-dose combination versus ezetimibe alone versus obicetrapib alone and the difference between obicetrapib alone versus placebo. If we would miss a single co-primary endpoint, this study would have failed. When looking at the baseline lipids, you can appreciate that despite the fact that more than 70% of patients were on high-intensity statins, LDL was still 97-milligram per deciliter, indicating high residual risk. If we move to Slide 6, we see additional baseline details. As you can see, we had a very good proportion of females. Most of the patients were Caucasian, and body mass index was 32 kilograms per square meter, which in fact is typical of the North American population. Now moving to Slide #7. The primary endpoint of efficacy of obi 10 plus ezetimibe 10 versus placebo showed an approximately 50% LDL reduction with a range of 49% to 54%. The obicetrapib efficacy was consistent with previous trials, and so was, of course, the ezetimibe efficacy. These results are in line or better than expectations given the performance of each of the monotherapy arms, which I will discuss in a second. If we then move to the next slide and also to what is really important for patients and doctors, namely the waterfall plot on Slide #8. And again, appreciate that a waterfall plot is the most honest representation of what your drug does in the clinic. Every bar is a single patient, and it is depicting the movement in LDL-cholesterol from baseline after a certain period of time, in this case, after 12 weeks. 12 weeks is the usual time that you will see your patient back again in the clinic. And what you can appreciate from a waterfall plot is that this drug has a very robust response profile. And in fact, more than 61% of patients had a more than 50% LDL lowering and even about 40% of patients had a more than 60% LDL lowering. This shows you how robust and consistent the LDL response is for the fixed-dose combination. Now on to Slide #9, where we show the responder analysis. As you can see from the chart, we saw over 70% of all patients on the fixed-dose combination achieving an LDL level below 55 milligrams per deciliter. That is the most stringent guideline goal, both in Europe as well as in the United States. And even 80% of patients were below the 70-milligram per deciliter goal for ASCVD patients. This is quite impressive when looking at the ezetimibe only arm, and the obicetrapib mono arm was consistent with prior studies. When we go from Slide 9 to Slide 10. Both in our previous trials, OCEAN and ROSE2, we saw a synergistic effect of adding ezetimibe to obicetrapib, and this is clinically a very important point. Synergistic means that the cumulative effect size is larger than what you would expect on the basis of the 2 drugs alone. We observed exactly the same phenomenon in this trial, and we have done the math on the left-hand side of the slide. There, you can see that the ezetimibe monotherapy showed a 20.7% placebo-adjusted reduction, but the observed difference between obicetrapib monotherapy and the fixed-dose combination was almost 25%. That tells you that the efficacy is, in fact, 18.5% greater for the combination than the monotherapy, which is exactly what we also observed in our previous Phase II programs. Now this is important because at the same time, we have a lot of biology and preclinical work that makes us understand why this effect occurs. And on Slide 11, we have shown the observed effect across our Phase II and Phase III studies, which is the mean reduction in LDL cholesterol, which, as you can see, is very consistent. We have left off Phase I, but in fact, the efficacy, the observed reduction in LDL even in Phase I, Phase II and Phase III, now shows to be extremely consistent. Next on Slide 12, we present lipoprotein (a), which was again consistent with past studies or slightly higher in the TANDEM study with obicetrapib 10-milligram conferring an Lp(a) reduction of 56% and the fixed-dose arm showed a change of 63% when compared to placebo. Now moving to the last slide, safety, on Slide #13, was again uneventful as in all of our previous trials. The fixed-dose combination safety basically similar to placebo and nothing of any substance in any of the other 3 arms. And with that, I would like to really give the word back to Professor Michael Davidson, who will finish this presentation. Thank you very much.

Thanks, John. We will report out other secondary endpoints such as non-HDL, ApoB and LDL particles at upcoming scientific conferences. But I can assure you that these results are comparable to our previous clinical trials. As previously announced, we plan to release the BROADWAY Phase III trial results before the end of the year. The recently presented BROOKLYN trial results and the BROADWAY trial with over 2,500 patients treated for 365 days will serve as the basis for obicetrapib's global filings for LDL-C reduction in patients with ASCVD or HeFH on maximally tolerated statin therapy with residual LDL-C elevation. The successful TANDEM trial, by demonstrating the ability of the FDC to cut the LDL-C in half and superior to each of the components of obicetrapib and ezetimibe alone will also provide the basis for global regulatory filings. The positive results from TANDEM give us confidence in the ongoing REMBRANDT trial, which is evaluating the impact of obicetrapib plus ezetimibe on non-calcified plaque volume. This will potentially enhance the evidence for the synergistic clinical benefits of the 2 drugs combined in an oral well-tolerated medication. As we look forward to regulatory filings for both obicetrapib and the fixed-dose combination with ezetimibe, we are encouraged by the marked growth in the prescriptions of both generic ezetimibe and the branded lipid-lowering drugs. Based on new evidence, there is renewed enthusiasm for clinicians to add therapies to statins to further lower elevated LDL-C. We believe that clinicians are seeking oral agents such as obicetrapib alone or in a fixed-dose combination with ezetimibe that can provide the efficacy, tolerability and safety that can more effectively achieve the desired LDL-C targets. We look forward to presenting additional data at an upcoming medical conference. I thank you for listening. I'd like to turn it over for questions from you, the audience.

[Operator Instructions] We will take our first question. And your first question comes from the line of Tyler Van Buren from TD Cowen.

Congrats on the results. It's encouraging to see the LDL reductions in line with PCSK9s and the synergistic benefit of obi on top of ezetimibe. But can you help us understand the difference between mean and LS mean specifically? And what might be causing the slight delta? And related to that first question, my second question would be just the obicetrapib monotherapy results here. Do they adjust your assumptions as you think about the potential outcomes for the PREVAIL trial that's ongoing?

Yes. Thanks, Tyler, for the question. This is Michael. So yes, we're obviously very pleased with the efficacy of the fixed-dose combination, cut the LDL in half. And as you said, very well, that it's very comparable to the injectables as an oral therapy. So we're excited about that we have this pill option that's very safe and well tolerated for lowering LDL-C and getting more patients to goal, if that's the objective. So regarding the LDL on the monotherapy, we show the mean and the medians on purpose because in all our trials, as John showed, is the mean and medians are extremely consistent across all the trials. And so when you do an LS mean, you have to impute the dropouts, and therefore, you get this different result. Now, sometimes it works in your favor, sometimes it works against you. And the main endpoint here is though when you look at the CTTC line for [indiscernible] based on mean and median is not on LS mean, so we have no need to adjust our consumptions for the PREVAIL trial. So again, if you look across all our trials, that 35% to 40% LDL lowering for the monotherapy, it's unbelievably consistent. I just want to make 1 point, and then, I'll turn it over to John to elaborate, too, is that we look at patients on drug, which we've done in these trials, so we have PK measurements. The LDL efficacy is 43% median for the mono and 57% for the combination. So it's all about the drug works extremely well when they take it and they don't change their other meds around. And so it's not a drug issue per se, that drug obicetrapib has performed beautifully in all our trials. It's really about the patient population. And in a study with 100 patients, you get a few dropouts, it can affect your LS mean to this degree. Again, very modestly, but the bottom line for clinicians is it's the mean and medians that they look at. And I'll let John elaborate more because we purposely show the waterfall plot so people get the actual true -- the true view of what's happening in each patient. So, John, do you want to add to that?

Yes. Tyler, this is John. So indeed -- I mean, for a clinician sitting in an office with a patient, the waterfall plot is important because that shows you the reduction from baseline. And if you can draw a line through a waterfall plot, let's say, the 50% line, and you see that 61% of patients have a more than 50% reduction, you immediately realize that if you take the mean from that or the median, if it's abnormally distributed, that you would end up with a number that's higher than 50%. And so what the drug really does is most shown, actually, in the waterfall plot, and then, you deduce from the waterfall plot, you go to goal attainment. And so the goal attainment is, of course, what's important for the doctor and the patient in terms of, am I there where I want to be? And again, that is a function of the median change from baseline and not so much from the LS mean, where there are things imputed. Now you want to have a real number, the real movement from baseline to 12 weeks later in the goal attainment that the numbers are extremely robust. So going back to Michael's comment, if you read the 2 papers, the Lancet papers in 2005 and 2016, and the REVEAL paper. And if you look at the CTT meta-regression line for LDL or for non-HDL, it's all based on either means or median, and it's the weighted mean difference between placebo and active treatment arm, most of the time, in fact, the mean at year 1. So what they've done in this, in the CTT meta-regression is to take a look at the year 1 mean difference. And sometimes, even like with clear outcomes, bempedoic acid, they've taken the 6-month mean difference. And so we have those data right now, basically, from our trials if you look at [indiscernible] difference. And so we do not have to change anything in terms of our prospects versus PREVAIL. I think we stay with what we've said. It is so incredibly consistent that we don't need to change anything. Is that adequate, Tyler? Did that...

Yes, that's great.

Your next question comes from the line of Dennis Ding from Jefferies.

This is Anthea on for Dennis. Congrats on the data. I just wanted to ask on Lp(a). Can you comment on if Lp(a) reduction was in line with the prior data sets and if you saw any synergies with the combo versus the 2 mono arms there as well? And then just a quick one on BROOKLYN Lp(a). Just curious on the 52-week data, and why that didn't hit ad stat sig and if you could provide some more color there?

Yes. Yes. Okay. So I'll start with the last question. So stat sig, it was not a study that was enrolled on -- based on high Lp(a)., so a lot of variability. So the right analysis is what's called Hodges-Lehmann on the median data. We have that. We wanted to present it at the AHA. We somehow didn't get into the presentation. But the Hodges-Lehmann, the p-value is less than 0.001 for significance. It's highly significant when you use the Hodges-Lehmann, which is the correct method, when you have a very heterogeneous data like Lp(a). So we're very encouraged by that, that efficacy for Lp(a). And for TANDEM, it's in line. I mean, we saw greater numerical numbers. But when you -- again, when you think about the outliers and so forth, it's extremely consistent Lp(a) lowering, which is our added value, we believe, and key differentiator from any other LDL-lowering drug, especially in oral Lp(a) lowering -- any other LDL lowering and statins raise Lp(a). So it makes it the great addition to statins to not only mitigate the elevation of the Lp(a), but bring it down significantly further. And whether that translates into any outcome benefit, we're not making that assumption for PREVAIL. But if we talk to folks and we think about it, it could be something that could provide extra clinical benefit, but we have to wait and see how that plays out.

Yes. So the fact that the fixed-dose combination had an absolute larger reduction than obicetrapib monotherapy is something that we take at this moment for granted. This is what we've observed. But we don't think that we can speak of any synergy in that regard. In fact, it is more likely that the 2 things are very similar and that there is still some variation. The data in essence, going all the way from early Phase II now to late Phase III, are very, very consistent. And Michael tells it exactly right, we are modest and conservative in our expectations. There are many KOLs who think that our Lp(a) reduction in PREVAIL is going to help with our endpoint, but we are not taking it into account at the current time. We're just banking simply only on the mean LDL difference driving the benefit in PREVAIL.

Your next question comes from the line of Yasmeen Rahimi from Piper Sandler.

Congrats on the data. A few questions. Maybe first one was, could you maybe comment on what the absolute changes were in placebo across ezetimibe, obi and combo arm? That could be helpful. That's question one. And then question two is, have you had the opportunity to look within the different subpopulation in the TANDEM study, whether what the responses were consistent, whether we looked in patients with HeFH versus ASCVD versus the high-risk group? If you could comment on that, that could be very helpful. And then maybe one last mini one if I could sneak in there.

Yasmeen, we have the data since very, very recent, and we've not been able to exactly understand who completed the study or who did not complete the study, who did not take the study drug. But in general, there were -- I mean, it was only a few patients who discontinued study drug. We don't -- sorry, we are very sorry, but we don't have the data yet. We will have the data soon, but we won't have the data yet to precisely understand whether there was a disbalance between either ASCVD, ASCVD risk equivalent or heterozygous FH in terms of their persistence with therapy. And I think that looking around the table, we also do not have absolute numbers yet. Did I understand correctly that you wanted absolute differences in the different arms?

Yes. Yes, in the placebo and what the placebo was, yes.

Well, we do have baseline LDL Levels. And so it's very easy if you know the mean difference in each arm, which we gave you in the table, then you can basically rapidly do your own absolute difference. In the placebo, it was basically negligible.

Yes. I think it was a 2% to 3% increase, if I'm not mistaken. Yes.

Yes, the 2% to 3% increase, Yasmeen, which is tiny.

In the placebo arm.

97-milligram per deciliter. So that is like 1.8 or something. Very tiny difference in the placebo. But just -- because I kind of gather where your question comes from, just to put your mind at ease, this was not a result that was driven by large changes in the placebo arm. This result was driven by large changes in the 3 treatment arms.

Perfect. That's exactly what we wanted to ask. That's very helpful. And maybe one last question is, I think investors have the tendency when the data comes in to always extrapolate into BROOKLYN, which is expected any minute. Obviously, these are completely 2 different studies to very different populations. I think the stock reaction this morning just reflected this, looking at the LS mean of 32. Could you maybe educate us again, like again, not for investors to draw any incorrect conclusion? But -- purpose of TANDEM -- yes, that would be helpful.

Yes, let me take the opportunity to again emphasize what Michael already said, the LS mean does not matter in this regard. It's a mean difference in PREVAIL that will drive the benefit. And so it is the mean difference in TANDEM, the mean difference in BROOKLYN, the mean difference in ROSE2 and ROSE, and it will also be the mean difference in BROADWAY. And so the number that everybody needs to focus on is the actual mean difference that we gave in the table. That is the consistent and that is the clinically relevant. And that is also on which all lipid-lowering trials are based that are taken up in the CTT meta-regression analysis. That LS mean number has a lot of artificiality in it with imputation that -- and it sometimes helps you in trials and it sometimes does not help you. But fortunately, we do have median numbers and mean numbers, and those are the numbers that are relevant going into BROADWAY and that are relevant going into PREVAIL.

And I just think it all comes down to outcomes, yes. And I think, like we said, we presented at the American Heart the BROOKLYN data, the outcomes were in the right direction. We'll have to see what happens in BROADWAY. But if you can match that type of outcome benefit from an outcome perspective, I think the LDL lowering is going to be important to drive that. But at the end of the day, it's all about outcomes, and we believe we have a very well-tolerated, effective drug. We know it's a drug. I mean it's going to be available to patients based on we have BROADWAY yet to come. We checked [indiscernible], BROOKLYN and now TANDEM for the fixed-dose combination. BROADWAY is going to come relatively soon. And I think what we're trying to say is the efficacy on LDL lowering is so consistent on the mean and medians across every trial, and so the LS mean, it's going to be what it is, but the actual drug effect is unbelievably consistent across all the trials.

And also, this is a trial for the fixed-dose combination, not for the obi mono.

Your next question comes from the line of Debjit Chattopadhyay from Guggenheim.

I have a couple here. So as you -- if you see the BROADWAY study, how confident are you potential noncompliance or dropouts will not again affect the mean versus the LS Mean, which is what people are focused or fixated on for the BROADWAY readout? And then number two, can you talk to the ApoB reductions in TANDEM and how it compares to the BROOKLYN study? And if you noted any decoupling between LDL-C and ApoB and what that might actually mean for the PREVAIL study? I appreciate it.

Sure. Well, the ApoB was -- I think we said it was basically the same as BROOKLYN, almost identical, ApoB reduction. But of course, more so in the fixed-dose combination. So we got a nice ApoB. You can expect that to come out at our upcoming medical conferences. So that's, again, very consistent with what we saw in our other trials. So as far as BROADWAY goes, all we can say at this stage is we had a really very well conducted trial. I think our dropout rate was low. We had over 90% complete the trial, which is great, very good quality metrics. We monitor drop-in and drop-outs. But as far as metrics of quality of a study, we match any other trial by far out there in the lipid world. So we're very proud of the data quality that we're going to have when BROADWAY gets, hopefully, released soon because we have the data -- winding up the data analysis now. So we hope to have that before the end of the year.

And personally, I would concentrate on events for BROADWAY and not so much on LDL because that's actually what is, for us, by far the most important thing.

Your next question comes from the line of Roanna Ruiz from Leerink Partners.

So with TANDEM data in hand, I was curious if the future outcomes data for obi in PREVAIL shows robust risk reduction on top of standard of care. Would you be able to make an argument that obi could be and the fixed-dose combo could be used in earlier line treatment considering management of ASCVD or hyperlipidemia? Just curious how clinicians might interpret the data altogether if all trials end up being positive.

Sure. Thanks, Roanna. So yes, I mean, ezetimibe is now well-established to have outcome benefits. And you can see, I think, the growth of ezetimibe recently, 20% annually, is a reflection of that kind of turn the corner for -- it was great. When we started using it, it was widely used, and then, outcome concerns were raised and stopped being used. Improvement came out. It's taken time. But ezetimibe is very well established now for outcome benefits. So obicetrapib having, hopefully, outcome benefits as well, but the 2 drugs will be seen as a great tandem drugs that TANDEM, that's why we had the name, that used together to maximize LDL lowering in practice, where again, we feel that for most patients who need that 50% LDL lowering, the FDC is there. And those already on ezetimibe, which is a growing number of patients, the FDC is there. So we see the FDC as being a really important part of our utilization of obicetrapib, obicetrapib in combination with ezetimibe that in the end of the day, for me, speaking as a clinician, you are on a statin, you have obicetrapib alone or obicetrapib with ezetimibe, you're basically done. Most patients are at goal, and you don't need to do anything else for those patients. And the Lp(a) lowering is a real benefit on top of that. And of course, the other benefits we hope to see is the -- all the small dense LDL reduction, which we believe is a very important factor on risk reduction, and of course, the diabetes prevention. So this is not just about LDL lowering, but the entire profile of the drug that we hope to demonstrate it is clearly linked to improve outcomes for patients.

Got it. That's helpful. And secondly, I wanted to ask a follow-up question about the Lp(a) reduction for the FDC. What are your thoughts on how this positions the FDC product against possible future competitors? I know there are other products like siRNAs that directly target Lp(a). Curious how you think the FDC would fit in that treatment paradigm as well?

Thanks, Roanna. This is John. So the siRNAs and the ASOs against Lp(a) and also the oral agents are actually positioned at the 90th percentile of that distribution or higher, which in practice comes down to about 8% of the entire Lp(a) population. And these are people that have Lp(a)s above 250 or even higher. Now there is a very large proportion of patients that are in the middle portion of that distribution, let's say, between 125 and 50 nanomoles per liter, where it is unlikely that you will need an siRNA agent to drop down your Lp(a) by 90% because you will, in fact, end up at very, very low levels. And theoretically, there is a diabetes risk that still needs to be further investigated. But you probably also from a risk perspective doesn't need that. And there, a drug that lowers Lp(a) by about 50% could be very beneficial, especially because it also lowers LDL. So that is kind of the vision we have for the positioning of obicetrapib, either monotherapy or the fixed-dose combination in that elevated lipoprotein (a) field.

Your next question comes from the line of Matthew Phipps from William Blair.

Congrats on the positive results today. I know you said that the safety was really nothing of substance, but maybe you can just -- is there any comments you can make on the discontinuations in the obicetrapib arm? I know the FDC looked less than placebo, but anything you can comment on the monotherapy arm there?

Yes, that's -- I mean, this is really small numbers, Matt. And also, of course, we haven't gone into the deepest detail of exactly the entire safety database. But everything we have seen so far, there is absolutely nothing eventful in any of the safety items here. So please remember that, of course, this is a much smaller trial than, for example, BROOKLYN, and I think this is all chance.

Yes. Okay. And then looking at Slide 11, your on-treatment analysis, for TANDEM there. I was wondering is that just removing the patients who discontinued or is that also removing patients who you did PK analysis on and saw maybe mid levels of obi? And if so, just maybe what was the end for that analysis of the 39.8% mean change in TANDEM?

So first of all, this is as it was defined in ROSE2 and also defined in all other programs, this is a PK analysis. So we have done pharmacokinetics of obicetrapib in all of our trials. And when you are 3 standard deviations below the mean, which basically means 0, then you do an on-treatment, you do an on-treatment analysis. But the numbers of patients, 87, so 87 for -- the on-treatment arm was 87. So that means starting with, I think, 102, and then, you can do your math, that's 15 patients less than the original ITT analysis. And that's the kind of number we also offered in our other -- same percentage that we had in our other trials.

Great. And I know you recently added the obi mono as a co-primary here to maybe get it on label. I guess would that be -- I know you've talked before about maybe FDA willing to accept on-treatment analysis, is that something -- is that what you expect here? Or would you look at the overall LS mean number?

Yes. I think -- I mean we could get that mono on our label. It will be in the label for the FDC. But I think we already have a 41% on BROOKLYN. That will be in our label. So that, as you know, how marketing works. I mean, you could use all your trials and you can point out the 41% to clinicians as an efficacy marker. So we'll have that establish that. But as far as on-treatment, not in this situation. The one we had before was a patient misconduct issue. We could take -- legitimately take patients out. But in this situation, we knew patients were off the drug. One had to go to the dentist. They had to get a tooth extract. So things like that, that we just -- we knew they're off the drug. And so that we can't take out and use analysis. But nevertheless, we'll have -- we have what we have. It's a range of the BROOKLYN data, 36% to 41%; the TANDEM will have 49% in the label for the fixed-dose combination. And then we'll see what happens with BROADWAY. But this is a -- as you know, it's double any other oral therapy pretty much. And you had to fix those combination together, were as good as the injectables. So when it comes to efficacy, we have a drug that all patients -- that all doctors and patients need to get the goal. That's the bottom line. Whether it's 36% or 37% or whatever, it doesn't matter, it is just getting the goal that matters, and these 2 drugs can do it for the vast majority of patients.

Your next question comes from the line of Leonid Timashev from RBC Capital Markets.

Congrats on the data. I just wanted to maybe ask you to put the data somewhat in context with PCSK9. I mean you mentioned at the start of the call that it's comparable. So I guess I'm curious what's the difference in LDL that physicians would find meaningful? And how would they think about using the fixed-dose combo versus the PCSK9, if you're just looking at LDL? And then similar maybe question for the fixed-dose versus the monotherapy arm given that in BROOKLYN you showed, call it, 37% and here you're at 48%. I mean I think is that a difference that physicians would think is meaningful if they're just looking at the labeled numbers. I mean, how would they think about going to the monotherapy versus switching to the combo with ezetimibe?

I think Michael can answer certain part of the questions. But before that, from a Gestalt point of view, if you lower something by 45% from a certain baseline and next to it is something that lowers it from a baseline 48%, that last 3% difference is in absolute terms tiny. And so it is much more important to understand what percentage of patients you get to goal because that is where a physician will stop. If you have a 70% -- 70-milligram per deciliter goal and you are at 68, you will stop. And it doesn't matter whether you're actually at 68 or 64 because that 4-milligram per deciliter difference makes a tiny difference for your risk. So in the end, it is always getting to goal. Now the last PCSK9 injectable that we've seen trials of is inclisiran. And if you look, for example, in the FH trial, ORION-9 for inclisiran was 48-point something, which is exactly the same basically as our fixed-dose combination. So you can -- the last data we have on the PCSK9 injectables show very similar efficacy to the fixed-dose combination. Michael?

Yes. Yes. I think the difference is if you look at PCSK9 inhibitors, they lower LDL, Repatha has a 60% in their label, but the majority of trials are in that 40% to 50%, actually, on efficacy. So we're right in line with our FDC. What they do also, which I just -- it's a side note being seeing as clinically is they can lower the LDL down to 0 sometimes. And most doctors get really concerned about that, and they stop the PCSK9s for that reason. It's not necessary to do that. We try to tell doctors not to. But in our drug, it's all about getting the goal in a safe way and everybody getting below 55%, so effectively with the fixed-dose combination in particular, I see -- the doctor is going to prefer that rather than having an LDL down to low 10, which is what you get with the extra injection sometimes. So overall, I think when [indiscernible] profile of our drug with oral, safety, Lp(a) reduction, small particles, it's going to be well received by health, especially PCPs, who want safety and ease of use more than anything else, will be very competitive with any other lipid-lowering drug out there.

Your next question comes from the line of Sebastiaan van der Schoot from VLK.

Congrats on another great data set. I was hoping that you could maybe expand on the Lp(a) data from BROOKLYN and TANDEM and whether there is any correlation between the high baseline levels and then the depth of Lp(a) reduction? And then I have a follow-up.

Until now, we have -- of course, I have asked this also for our Phase II. And there is no strong correlation between the base defined Lp(a) level and its reduction. So it seems that obicetrapib 10-milligram lowers Lp(a) across the board. Now we don't have a trial where baselines are very high yet, of course. But for the baseline distribution that we've seen so far, there is no difference. Also, I think that the data in BROOKLYN are, of course, 365 data and day 84 data in a larger patient population than in the arms of TANDEM, which were only 12 weeks and 100 patients. So I think that you can -- when you do a helicopter view of all the data, you can say that the Lp(a) lowering across our trials, Phase II to Phase III, is until now very consistent.

Okay. Got it. And then could you remind us of how you will be using this data set for your regulatory process in both the U.S. and in Europe?

Yes. So it's the basis of approval. It's a single trial. And obviously, obicetrapib and the combo will go together in a filing -- 2 separate filings, but at the same time basically, so we plan on having both drugs available to launch at the same time. So that's -- again, that's our plan because we believe having both available at the same time is going to be to our advantage because we can be very competitive against any other drug out there when this drug gets launched, the 2 drugs get launched together.

And just as a reminder, from a timing standpoint, the European filing will be second half of next year, 2025. In the U.S., we're continuing to obviously guide to a filing where the outcomes data would be -- would become available during the regulatory review period.

Your next question comes from the line of George Farmer from Scotiabank.

A couple for me. I was wondering thinking about this data within the context of treatment in the real-world setting. Can you comment on just how many patients may already be on ezetimibe in combination with statins for their efforts to reach their goal and really how relevant, therefore, is this data? And then number two, regarding the outcomes -- sorry, the events that you saw in BROOKLYN, you reported just a few of them. Can you mention anything about those patients? Were they first-time events? Or were they repeat events?

Well, they are first-time events, just let you know that. That's how we think about -- we look at total events also. So broadly, we'll have a much larger number of first events and total events. So we'll look at both. Yes, we'll look at both when we have the data available. So the first question was about the...

Yes, just thinking about the relevance of this data in total given that a lot of patients may already...

Yes. In BROADWAY, I think we had talked about this already, about 25% are on ezetimibe, as in PREVAIL also, 25% are on ezetimibe. 50% on ezetimibe in the BROOKLYN trial, which makes sense because they have FH. And -- but again, everyone had to be on ezetimibe and statin and had LDL still too high, so it represents kind of the real-world scenario to a large degree. But I think, overall, right now, I think there's about 10% of patients on ezetimibe -- 45 million on ezetimibe. And so that's still a very big number, and most of them are not at goal. So -- yes, that's just the U.S. So we have a lot of opportunity to maybe swap out ezetimibe for our FDC as a single pill, and that will be all the patients need again to get to goal the vast majority of the time. So it's already got a boost to us to have -- to even target ezetimibe prescribed patients to go right to the FDC. We see that as a real opportunity for us.

And -- sorry -- then the combination with ezetimibe on top of statins versus a combination with ezetimibe in the FDC. Is that kind of equivalent do you see? Is that -- these are very different mechanisms of actions all these drugs have, but is it -- does it look kind of similar to how -- what one would expect just by adding ezetimibe on top of a statin as far as the doctor is concerned?

No, that was -- I think that was the point John tried to make. You get a 15% to 20% efficacy of ezetimibe on top of a statin. Here, we get 25% efficacy. So it's a boost. I mean -- and I said the boost is meaningful. It's about a 20% added efficacy as you can -- if you do the math. But more importantly, we need to do a lot more work around this. But in our preclinical models, we have shown this already, and we're going to show this more. But when you add ezetimibe and obicetrapib, you wipe out atherosclerosis in animal models, completely wipe it out. So that's why we're doing the trial to try to do a human study to show in the noncalcified plaque volume. There's a good scientific rationale for that. When you use obicetrapib, you basically funnel more cholesterol into the intestines it's, called TICE. You're moving more -- it's called transintestinal cholesterol efflux, getting a lot more [indiscernible]. Ezetimibe is there to basically flush it out, block it from being reabsorbed. So there's a lot of biologic rationale for this combo. So we've seen this synergy on LDL now 3 times, 3 different trials. We've seen the great benefits in animal models for atheros, and now, we're moving forward with our human trial within REMBRANDT. It [indiscernible] about the same time as PREVAIL. So when we have PREVAIL, we will also have REMBRANDT as an imaging study for the combo. It becomes the combo's own outcome study in some ways. That's how we think about it. And so that's how we're going to look at it from a commercial perspective as well.

And, George, really important question here because if you look at the market data, 90% of patients are not able to get to an LDL below 55. And what our data clearly shows is we can get well over 70% to that goal.

Your next question comes from the line of Serge Belanger from Needham.

A couple of questions for us. The first one, I think you mentioned that 71% of the patients enrolled in TANDEM were on high-intensity statins. Curious if you had any patients that were on PCSK9 inhibitors or if they were excluded from this trough? And secondly, we can clearly see the synergistic effect of the combination on the LDL-C reduction. Curious if we should expect a similar synergy on some of the other lipoproteins like Lp(a), ApoB and the other ones you'll be monitoring?

So if you see a synergy on LDL cholesterol, you automatically, and that we've seen that, you see synergy on non-HDL cholesterol and you see synergy on ApoB. So to that, the answer is yes. Lp(a) is somewhat more elusive. You might call it a coincidence that our LDL lowering and our Lp(a) lowering is quite in sync, but we have not seen a correlation between the 2. So it is not true that in those with the largest LDL reductions, we also see the largest Lp(a) reduction. So it seems that in a single patient, the 2 reductions are, in fact, independent from one another. And so you cannot speak of synergy in the Lp(a) lowering. The PCSK9 -- yes, so PCSK9 numbers are, I think, between 300,000 and 400,000 in United States patients. And so the numbers of patients that are treated with PCSK9s are very small. We, of course, allowed PCSK9 therapy in BROOKLYN, as we have just presented the day before yesterday. In fact, about 20% of our patients were on PCSK9s. And that meant that in that trial, BROOKLYN, we had high intensity 7s, 50% ezetimibe, 20% PCSK9s. So there were lots of patients who were on triple therapy, which, by the way, was the first time ever that a drug was tested on triple therapy. So we were then the fourth drug. There was no difference between just testing it on statins versus testing it on statins plus ezetimibe or testing it on statins plus ezetimibe plus PCSK9 inhibitors. So, again, the response, the LDL lowering response of obicetrapib 10-milligram does not depend on whether you have 1, 2 or 3 other drugs at baseline. Was that an adequate answer because I didn't entirely hear your question?

That sounds adequate. And then one last one. I think you kind of surprised everybody this morning with an earlier-than-expected timing of these TANDEM results. Just curious if that changes the potential timing of a BROADWAY readout.

No. No, it doesn't. The BROADWAY trial is still on schedule for the fourth quarter. As we have mentioned fairly recently, we do not want to release the data in the second -- the last weeks of December. So that would push the data into early January at the latest.

And your next question comes from the line of Debjit Chattopadhyay from Guggenheim.

John, I wanted to clarify your comment on BROADWAY. You said the focus should be on events. The primary endpoint is LS Mean. Just trying to sort of tie the ends there. And -- are you sort of suggesting there is a clear delta in events even at month 12?

No, I'm not suggesting anything. I thought -- I think the word focus, yes, you can explain that in multiple ways. Of course, there's a primary endpoint. And the primary endpoint is going to be LDL, LS mean as always. But, again, I think it's very important for [indiscernible] that you do not only look at LS means, but also at means and medians as we've just explained for TANDEM. And so these results are very -- what I tried to convey is that the exploratory endpoint of CV events is important for us because it will denote safety, and it's a safety endpoint. And that's what I meant.

Yes. So, Debjit, I mean, I think what we're hoping for, obviously, in the hazard ratio around 1, I mean that's the -- that would mean safety -- I mean, for MACE in the first year -- I mean, we look at all the different trials, the lines don't separate, maybe 0.91 is what you see overall for the lipid trials, so 1 would be a great outcome for us for safety in every trial.

This concludes today's question-and-answer session. I'll now hand the call back to Michael Davidson for closing remarks.

Okay. I just want to thank everyone. Great questions. I'd say we're excited about the data because TANDEM is a pivotal trial for the fixed-dose combination. We hit all our endpoints, which enables the regulatory filing, which is really important. We realize that if we would have missed one of those p-values the study would have been not available for file and we had to redo them. So we're excited about the results, what it means for patients, and look forward to the BROADWAY data relatively soon.

This concludes today's conference call. Thank you for participating. You may now disconnect.