Good day, and thank you for standing by. Welcome to the NewAmsterdam Pharma TANDEM 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. To ask a question during the session, you will need to press star one and one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one and one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, 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 two 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, an 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 top-line 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 a 102% decrease in small LDL particles when compared to placebo. Today, we are delighted to share the positive, statistically significant top-line results from the pivotal phase III TANDEM trial. As a reminder, TANDEM was designed to determine if the fixed-dose combination of obicetrapib 10 mg and ezetimibe 10 mg 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 four, 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 mg/dL, and only 10% of high-risk patients are reaching the below 55 mg/dL 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 less than 0.001 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 Scientific 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 number five, 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 mg of obicetrapib and 10 mg of ezetimibe, both in terms of efficacy and safety. The design of the TANDEM study is a simple parallel design with four arms of about 100 patients each. The key inclusion criteria included ASCVD or its risk equivalents and the fact that LDLs needed to be above 70 mg/dL while in fact on maximally tolerated lipid-lowering therapy.
What's very important to realize is that this study had four 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 mg/dL, indicating high residual risk. If we move to slide six, 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 kg per square meter, which in fact is typical of the North American population.
Now, moving to slide number seven, the primary endpoint of efficacy of OB 10 mg plus ezetimibe 10 mg versus placebo showed an approximately 50% LDL reduction with a range of 49%-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 number eight, 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, onto slide number nine, 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 mg/dL. 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 mg/dL goal for ASCVD patients.
This is quite impressive when looking at the ezetimibe-only arm, and the obicetrapib monoarm was consistent with prior studies. When we go from slide nine to slide 10, both in our previous trials, OCEAN and ROSE II, 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 two 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 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 of 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 mg 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 number 13 was again uneventful, as in all of our previous trials. The fixed-dose combination safety was basically similar to placebo, and nothing of any substance in any of the other three 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 two 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.
Thank you. As a reminder to ask a question, you will need to press star one and one on your telephone and wait for your name to be announced. To withdraw your question, please press star one and one again. We will take our first question, and your first question comes from the line of Tyler Van Buren from TD Cowen. Please go ahead. Your line is open.
Hey, guys. Congrats on the results. It's encouraging to see the LDL reductions in line with PCSK9s and the synergistic benefit of OB 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?
Yeah. Hi, thanks, Tyler, for the question. This is Michael. So yeah, we're obviously very pleased with the efficacy of the fixed-dose combination, cut the LDL-C in half, and as you said very well, it's very comparable to the injectables as an oral therapy. So we're excited about that we have this option that's very safe and well-tolerated for lowering LDL-C and getting more patients to goal. That's the objective. So regarding the LDL-C on the monotherapy, we show the mean and the medians on purpose because in all our trials, as John showed, 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.
The main point here is that when you look at the CTT line for production, it's based on mean and medians, not an LS mean. We have no need to adjust our assumptions for the PREVAIL trial. Again, if you look across all our trials, that 35%-40% LDL lowering for the monotherapy, it's unbelievably consistent. I just want to make one point, and then I'll turn it over to John to elaborate too, is that when we look at patients on drug, which we've done in these trials, we have PK measurements, the LDL efficacy is 43% median for the mono and 57% for the combination. It's all about the drug works extremely well when they take it, and they don't change their other meds around. It's not a drug issue per se. O bicetrapib has performed beautifully in all our trials.
It's really about the patient population. 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 plots so people get the actual true view of what's happening in each patient. So John, do you want to add to that?
Yeah. Hi, 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.
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, and then in the goal attainment, that the numbers are extremely robust. So going back to Michael's comment, if you read the two 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 one.
So what they've done in the CTT meta-regression is to take a look at the year one mean difference, and sometimes even like with CLEAR Outcomes, bempedoic acid, they've taken the six-month mean difference. And so we have those data right now, basically from our trials, if you look at the mean 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?
Yep. That's great. Thank you very much.
Okay.
Thank you. We will take our next question. Your next question comes from the line of Dennis Ding from Jefferies. Please go ahead. Your line is open.
Good morning. 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 datasets and if you saw any synergies with the combo versus the two mono arms there as well? Then just a quick one on BROOKLYN, Lp(a). Just curious on the 52-week data and why that didn't hit stat sig, and if you could provide some more color there. Thank you.
Yeah. Yeah. Okay. So I'll start with the last question. So stat sig, it was not a study that was enrolled based on high Lp(a). So a lot of variability. So the right analysis is what's called a 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 efficacy for Lp(a). And for TANDEM, it's in line.
I mean, we saw greater numerical numbers, but 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 we talk to folks and we think about it. It could be something that could provide extra clinical benefit that we have to wait and see how that plays out.
Yeah, 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 two 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.
Okay. Got it. Thank you so much.
Thank you. We will take our next question. Your next question comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead. Your line is open.
Hi. Good morning, team, and congrats on the data. A few questions. Maybe first one was, could you maybe comment on what the absolute changes were in placebo across the ezetimibe, OB, 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 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're 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 an imbalance 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. In the placebo and what the placebo was. Yeah.
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.
Perfect. That's perfect.
In the placebo, it was basically negligible. Yeah.
I think it was a 2%-3% increase, if I'm not mistaken.
Yeah. A 2%-3% increase, Yasmeen, which is tiny.
In the placebo arm
Of 97 mg/dL. So that is like 1.8 or something. Very tiny difference in the placebo. So 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 three treatment arms.
Perfect. That's exactly what we wanted to ask. And thank you for clarifying that. That was 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 two 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, again, not for investors to draw any incorrect conclusions?
Yeah. Let me.
Yeah. That would be helpful.
Yeah. Let me take.
To the queue.
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 ROSE II 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, 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.
Yeah. And I just think it all comes down to outcomes. Yeah. And I think what we said we presented at the American Heart Association BROOKLYN data, the outcomes were in the right direction. We'll have to see what happens in BROADWAY, but if we can match that type of outcome benefit from an outcome perspective, I think the LDL lowering is going to be important and 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, and it's going to be available to patients based on BROADWAY yet to come. We checked two boxes now, BROOKLYN, and now TANDEM for the fixed-dose combination. BROADWAY is going to come relatively soon.
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. The LS mean imputation, it's going to be what it is, but the actual drug effect is unbelievably consistent across all the trials.
Also, this is a trial for the fixed-dose combination, not for the OB mono.
Thank you so much for all the great content.
Thank you. We will take our next question. Your next question comes from the line of Debjit Chattopadhyay from Guggenheim. Please go ahead. Your line is open.
Hey. Good morning, and thanks for taking my question. I have a couple here. So as you QC the BROADWAY study, how confident are you potential non-compliance 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? Appreciate it. Thank you so much.
Sure. Well, the ApoB, I think we said, is 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 other trials. So as far as BROADWAY goes, all we can see 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 dropouts, 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.
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.
Thank you. We will take our next question. Your next question comes from the line of Roanna Ruiz from Leerink Partners. Please go ahead. Your line is open.
Hi. Morning, everyone. So with TANDEM data in hand, I was curious if the future outcomes data for OB and PREVAIL shows robust risk reduction on top of standard of care. Would you be able to make an argument that OB 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 as outcome benefits. And you can see, I think, the growth of ezetimibe recently, 20% annually, is a reflection of that kind of turned the corner. It was great when we started using it. It was widely used, and then outcome concerns were raised and stopped being used, and IMPROVE-IT came out. It's taken time, but ezetimibe is very well- established now for outcome benefits. So obicetrapib, having hopefully outcome benefits as well, the two drugs will be seen as a great tandem of drugs. That's why we have the name to use together to maximize LDL lowering in practice. Again, we feel that for most patients who need that 50% LDL lowering, the FDC is there. And for 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 in combination with ezetimibe is the [audio distortion]. At the end of the day, for me, speaking as a clinician, you're on a statin, you have obicetrapib alone or obicetrapib with ezetimibe, and 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 all the small dense LDL reduction, which we believe is a very important factor in 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 that 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 agent 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.
There, a drug that lowers Lp(a) by about 50% could be very beneficial, especially because it also lowers LDL. 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.
Got it. Thanks.
Thank you. We will take our next question. Your next question comes from the line of Matthew Phipps from William Blair. Please go ahead. Your line is open.
Hi guys. Congrats on the positive result today. John, I know you said that the safety was really nothing of substance, but maybe you can just, if there's 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?
Yeah. 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.
Yep. Okay. And then looking at slide 11, you're 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 no levels of OB? And if so, just maybe what was the N for that analysis of the 39.8% mean change in TANDEM?
First of all, this is, as it was defined in ROSE II and also defined in all other programs, this is a PK analysis. We have done pharmacokinetics of obicetrapib in all of our trials. And when you are three standard deviations below the mean, which basically means zero, then 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 had in our other—the same percentage that we had in our other trials.
Good. Thank you. And I know you all recently added the OB 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 analyses. Is that something? Is that what you expect here, or would you look at the overall LS mean number?
Yeah. I mean, we could get that mono on our label. It'll be on our. It'll be on the label for the FDC. But I think we already have a 41% on BROOKLYN that'll be on our label. So that, as you know how marketing works, I mean, you could use all your trials, and you could point out the 41% to clinicians as an efficacy marker. So we'll have that to establish that. But as far as on-treatment, not in this situation. The one we had before was a patient misconduct issue. We could 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 were off the drug. And so that we can't take out and use in analysis.
But nevertheless, we have what we have. So range of the BROOKLYN data, 36%-41%. The TANDEM will have the 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 add the fixed-dose combination together, we're as good as the injectable. So when it comes to efficacy, we have a drug that's all doctors and patients need to get the goal. That's the bottom line. Whether it's 36% or 37% or whatever, that doesn't matter. It's just getting the goal that matters. And these two drugs can do it for the vast majority of patients.
Yep. Great. All right. Thank you, Michael. Thank you, John.
Thank you. We will take our next question. Your next question comes from the line of Leonid Timashev from RBC Capital Markets. Please go ahead. Your line is open.
Hey, thanks, guys. 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? Thanks.
I think Michael can answer a 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. 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 mg/dL goal and you are 68, you'll stop. It doesn't matter whether you're actually at 68 or 64 because that 4 mg/dL difference makes a tiny difference for your risk. 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 the last data we have on the PCSK9 injectable show very similar efficacy to the fixed-dose combination. Michael.
Yeah. Yeah. I think the difference is, if you look at PCSK9 inhibitors, they lower LDL. Repatha, it has a 60% in their label, but the majority of trials are in that 40%-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 us clinically, is they can lower the LDL down to zero 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 to goal in a safe way and everybody getting below 55.
Effectively, with the fixed-dose combination in particular, I see doctors are going to prefer that rather than having an LDL down to below 10, which is what you get with the extra injection sometimes. Overall, I think when people, our 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. It'll be very competitive with any other lipid-drug out there.
Thank you. We will take our next question. Your next question comes from the line of Sebastiaan van der Schoot from VLK. Please go ahead. Your line is open.
Hi, team. Congrats on another great dataset. I was hoping that you could maybe expand on the Lp(a) data from BROOKLYN and TANDEM and whether there's 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, as this also for our phase II, and there is no strong correlation between the baseline LDL level and its reduction, so it seems that obicetrapib 10 mg 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's no difference. Also, I think that the data in BROOKLYN are, of course, day 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, 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 dataset for your regulatory process in both the U.S. and in Europe? Thank you.
Yes. Yeah. So it's the basis of approval. It's a single trial. And obviously, obicetrapib and the combo will go together in a filing, two separate filings, but at the same time, basically. So we plan on having both drugs available to launch at the same time. So 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 two drugs get launched together.
Just as a reminder, from a timing standpoint, the European filing would be second half of next year, 2025. In the U.S., we're continuing to obviously guide to a filing where the outcome data would become available during the regulatory review period.
Okay. Got it. Thank you, guys.
Thank you. We will take our next question. Your next question comes from the line of George Farmer from Scotiabank. Please go ahead. Your line is open.
Hi. Good morning. Thanks for taking my questions. 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? 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?
They were first-time events. Just to let you know that. That's how we think about. We could total events also. Broadly, we'll have a much larger number of first events and total events. We'll look at both. Yeah. Look at both when we have the data available. The first question was about the.
Yeah. Just thinking about the relevance of this data in total, given that a lot of patients may already be on ezetimibe.
Oh, yeah. In BROADWAY, I think we had talked about this already. About 25% are on ezetimibe, as in PREVAIL also. 25% are on ezetimibe. 50% were on ezetimibe in the BROOKLYN trial, which makes sense because they have FH, and 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.
9%.
What?
4 million-5 million.
4 million-5 million on ezetimibe, and so that's still a very big number. And most of them are not at goal. So yeah, 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 would 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 even target ezetimibe-prescribed patients to go right to the FDC. We see that as a real opportunity for us.
And sorry, [audio distortion]. And then the combination with ezetimibe, say, on top of statins versus a combination with ezetimibe in the FDC, is that kind of equivalent you see? These are very different mechanisms of actions all these drugs have. But does it look kind of similar to how one would expect just by adding ezetimibe on top of a statin as far as the delta is concerned?
No, I think that was the point John tried to make. You get a 15%-20% efficacy of ezetimibe on top of the 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 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. We're going to show this more, but when you add ezetimibe to obicetrapib, you wipe out atherosclerosis in animal models. Completely wipe it out, so that's why we're doing the right trial to try to do a human study to show non-calcified 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. It's called transintestinal cholesterol efflux.
Getting a lot more cholesterol into the 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 the synergy on LDL now three times, three different trials. We've seen the great benefits in animal models for atherosclerosis. And now we're moving forward with our human trial in REMBRANDT. It'll read out at the same time as PREVAIL. So when we have PREVAIL, we 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.
George, a 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. What our data clearly shows is we can get well over 70% to that goal.
Yep. All right. Great. Thanks very much.
Thank you. We will take our next question. Your next question comes from the line of Serge Belanger from Needham. Please go ahead. Your line is open.
Hi. Good morning. 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 statin. Curious if you had any patients that were on PCSK9 inhibitors or if they were excluded from this trial. 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 two. 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 two reductions are, in fact, independent from one another. And so you cannot speak of synergy in the Lp(a) lowering. So PCSK9 numbers are, I think, between 300,000 and 400,000 in the 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've just presented the day before yesterday. In fact, about 20% of our patients were on PCSK9s. And that meant that in that trial in BROOKLYN, we had high-intensity statins, 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 mg does not depend on whether you have one, two, or three other drugs at baseline. Was that an adequate answer? Because I didn't entirely hear your question.
No, thanks. That was 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 last two weeks of December. So that would push the data into early January at the latest.
Thanks for taking my questions.
Thank you. We will take our next question. And your next question comes from the line of Debjit Chattopadhyay from Guggenheim. Please go ahead. Your line is open.
Hey, thanks for letting me back in. 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's a clear delta in events even at month 12?
No, I'm not suggesting anything. I think the word focus, yeah, you can explain it 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 a trial like BROADWAY 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. Yeah. So I mean, what we're hoping for, obviously, is a hazard ratio around one. I mean, that would mean safety, I mean, for MACE in the first year. I mean, look at all the different trials. The lines don't separate.
Maybe 0.91 is what you see overall for the lipid trials. So one would be a great, it would be a great outcome for us for safety trial.
Thank you.
Thank you. 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 question. Like I said, we're excited about the data. TANDEM is a pivotal trial for the fixed-dose combination. We hit all our endpoints, which enables the regulatory filing, which is really important. You realize that if we would have missed one of those p-values, the study would have been not available for filing, and we had to redo the whole study. So excited about the results and 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.