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

Good morning, and welcome to the NewAmsterdam Pharma Phase III BROOKLYN Topline Data Conference Call. [Operator Instructions]. I will now hand the call over to Matthew Philippe, Executive Vice President and Head of Investor Relations at NewAmsterdam.

Thank you. Good morning, and thank you to those joining us as we review the positive top line data results from the Phase III BROOKLYN clinical trial. Before we begin, we would like to direct everyone to Slide 2 and remind you that the statements made on today's conference call will include forward-looking statements. Certain statements including in this presentation that are not historical facts are forward-looking statements for the purpose of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. These statements are based on various assumptions, whether or not identified in this presentation and on the current 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 events and circumstances are difficult or impossible to predict and may differ from assumptions. Forward-looking statements reflect NewAmsterdam's expectations, plans and forecasts of future events and view 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 assessment to change. Accordingly, Undue reliance should not be placed upon the forward-looking statements. Neither NewAmsterdam nor any of its affiliates undertakes any obligation to update these forward-looking statements, except as required by law. On today's call, we have Dr. Michael Davidson, Chief Executive Officer of NewAmsterdam; and Dr. John Kastelein, Chief Scientific Officer of NewAmsterdam. Ian Somaiya, our Chief Financial Officer, will also be available for Q&A following the presentation. With that, I'm excited to now turn the call over to Dr. Michael Davidson. Michael?

Thank you, Matt, and thank you to everyone joining us this morning. We are delighted to share the positive statistically significant topline results from the global pivotal Phase III BROOKLYN trial. As a reminder, BROOKLYN evaluated obicetrapib in adult patients with heterozygous familial hypercholesterolemia or HeFH, we call it FH for short, with LDL cholesterol is not adequately controlled despite being on maximally tolerated lipid-lowering therapy. BROOKLYN is the first of 4 ongoing pivotal Phase III studies NewAmsterdam's clinical development program. Today's results mark a meaningful milestone to our company and for cardiovascular disease community more broadly. There remains a significant unmet need for new treatment options that are safe, convenient and able to meaningfully improve LDL-C lowering effects, and we believe obicetrapib has the potential to solve this problem. To present the topline of results is my great friend, a world renowned expert on FH and Chief Scientific Officer at NewAmsterdam Pharma, Professor John Kastelein.

Michael, thank you very much for those kind words. And like you, I'm very proud to present the top line efficacy data from BROOKLYN which will show that obicetrapib has a substantial and rapid effect on LDL levels and therefore, it will enable patients even those who fail on maximally tolerated lipid-lowering therapy to achieve their risk-based goals. Now a little perspective for those on the call, I have devoted my career of over 30 years to the study of the treatment and diagnosis of familial hypercholesterolemia, a disease that has been difficult to break, so to speak, and for which many therapies have been developed. So the results of the BROOKLYN trial for me also herald a wonderful day in my history, so to speak. If we can then move to Slide #3, everything is put into perspective in terms of the disease that we're treating in BROOKLYN. Heterozygous familial hypercholesterolemia is by far the most prevalent autosomal dominant genetic disease in the world and 1 in every 250 children has this disease, meaning there are tens of millions of these patients across the globe. When I started studying heterozygous FH premature death at the age of 30 was not uncommon. We have learned since then that if we treat LDL cholesterol levels of FH patients to normal these patients can actually have a normal lifespan. But if you start life with a very elevated LDL, you will need multiple therapies to lower that to normal levels. And it has been a very, very difficult journey to actually achieve that. If we now move to Slide #4, you will realize the study design and baseline characteristics that we have presented before. It's important to realize that the randomization was a 2:1 ratio meaning that there are twice the number of patients on active therapy or obicetrapib in this trial as placebo. The key inclusion criteria were, of course, heterozygous FH and an LDL-cholesterol level over 70-milligram per deciliter while on maximally tolerated lipid-lowering therapy. The baseline lipids are a testimony as to how difficult these patients are to treat. The LDL was 123-milligram per deciliter and you can appreciate the other baseline lipids and lipoproteins. The demographics show that we have achieved gender equality because 53% of our patients were female. They were somewhat younger than normal atherosclerotic cardiovascular disease populations but one noteworthy aspect is the body mass index of 29. When I started, body mass index in FH patients was completely normal and this shows you that even FH patients are getting more obese when time goes on, giving it an additional complexity in the treatment. 90% of patients were on a statin and high-intensity statins were almost 80%. And not only that, half of the patients were on ezetimibe and 14% on PCSK9 inhibitors. There is no FH trial where a drug was tested on top of triple therapy. And in that sense, we are the first Phase III study to do so in heterozygous FH. When we move from Slide #4 to Slide #5, you can see the disposition of all randomized participants. Now Michael will later deal with the safety but I think what's in the yellow box is a very important parameter of how a drug is tolerated and how safe it is. So the discontinuation rate and please take a look at the number between brackets because that's the percentage, the absolute numbers because of the 2:1 randomization are more difficult to interpret, but the percentages are, of course, the important number here. 7.6% of patients on obicetrapib discontinued treatment while 14.4% discontinued treatment while on placebo. That, of course, means that more patients on obicetrapib completed the study, and you can see that on the third line from the bottom, 95.8% of patients in the obicetrapib arm completed the study versus the 93.2% in the placebo arm. Now I'm very proud to actually move to Slide #6, where we show you additional baseline details of all randomized patients. Again, when I go through this, mean age was about 57 years, almost the same number of men and women, a slight preponderance of females. I think the important point that I made on body mass index is shown in the bottom, a body mass index of 29 is, of course, somewhat elevated, which, by definition, will lead to other abnormalities that are -- that make difficult -- that make treatment even more difficult. What's also important is that the patients were diagnosed with FH almost 72% had a genotyping confirmed diagnosis of heterozygous FH or a very definite diagnosis according to the Dutch lipid criteria or to the Simon Broom register. So this is truly a completely definite heterozygous FH population that, in fact, had maximally tolerated lipid-lowering therapy, even 14% of patients were on triple therapy. Now moving to Slide #7. I think this is even more intricately explicated. Again, statin treatment at high dose 78.8% in the obicetrapib arm and 67.8% in placebo and the ezetimibe use is, as far as I know, the highest that I've ever seen in an FH trial 53.8% for obicetrapib and 50% for ezetimibe. Again, denoting that these patients are very difficult to treat. So despite the fact that these numbers, almost 80% of patients on high-dose statins, 50% on ezetimibe and 14% also on PCSK9 inhibitors, Despite that, baseline LDLs were above 120-milligram per deciliter, which kind of denotes the difficulty in treating these patients and getting them to go. Now moving from Slide 7 to Slide 8. You will see the primary efficacy endpoint. So at day 84, the placebo-corrected LDL difference was 36.3% and the secondary endpoint at day 365, the placebo-corrected LDL lowering was 41.5%. But I think what is more important here is to look at the graph on the right-hand side of the slide. The first measured LDL difference between placebo and treatment was at day 30 and you can see that, that actually gets close to a 43.5% lowering of LDL cholesterol. So this is achieved at day 30, a very rapid decrease and then it's, in fact, maintained over the entire course of the year, where at the end of the year, the placebo corrected difference is 41.5%. And those 2 lines, the placebo line and the treatment line are actually parallel over time, the noting that the drug is capable of actually maintaining that treatment difference of around 40% over the space of a full year. And again, what is most important here is that, that placebo corrected difference at 1 year is, of course, the important difference for the patients because that will determine the efficacy in terms of MACE reduction in our cardiovascular outcomes trial PREVAIL. So I hope you are as excited as I am about these numbers and about this efficacy that we've shown now over the course of an entire 52 weeks. And with that, I would like to move to Slide #9 to further dive into the efficacy data. What's very important is in the treatment of heterozygous FH is to achieve guideline directed treatment goals. And as you can see, moving from left to right is that in the obicetrapib arm, 24% of patients achieved less than 50-milligram per deciliter which was in the beginning when I started treatment trials with FH completely unheard of. Then when you move 1 bar to the right, you'll see that obicetrapib 10-milligram was able to get 51% of patients down to less than 70-milligram per deciliter compared to only 11% in the placebo arm. And by the way, all of these differences are highly statistically significant. Now of course, for FH patients that do not yet have atherosclerotic cardiovascular disease, there is a goal of less than 100-milligram per deciliter and in the obicetrapib arm, this was achieved by 77% of patients versus 40% of patients in the placebo arm. This actually tells you that when you add obicetrapib to this wide armamentarium of drugs, then, in fact, you are capable of achieving the guideline directed LDL goal of less than 100 milligrams in almost 80% of patients. Now as I always like to say is that there is nothing more honest than a waterfall plot. And this is an LDL-C responder analysis in the obicetrapib 10-milligram arm. What you can appreciate from this waterfall plot is that the vast majority of patients actually have a significant LDL lowering with adding obicetrapib to their maximally tolerated lipid-lowering therapy. But in fact, 1/3 of patients actually had a more than 50% LDL reduction which is those patients that achieve an LDL bar that gets below the red line. On the right-hand side, there are so-called non-responders which are typical of the FH trials common and seen with other therapies. Now how do these data that we share with you today these exciting data, how do they kind of compare and stack up to our Phase II program. When we look at LS means for our Japan Phase II study, our RO study and our ROCE 2 study. And when we compare that to the primary endpoint in BROOKLYN at day 84, and the secondary endpoint in BROOKLYN at day 365, you can see that this is very consistent with prior clinical trials that we have reported and have actually published in peer-reviewed journals. So that actually tells you that this is now the translation from our Phase II program into our Phase III program in terms of efficacy is a very, very consistent which, of course, makes us bodes very well for our future. And with that, I would like to now ask Michael to, in fact, go deeper into the safety data of this drug. Please, Michael.

Thank you, John. I'm thrilled to present the safety results of the trial. On Slide 12, treatment immersion adverse events were 70.3% on placebo, 53.7% on obicetrapib. Any study drug-related adverse event was 6.8% on placebo versus 4.3% on obicetrapib. None of these adverse events were considered severe. As far as any adverse events leading to death, it was 1.7% of placebo and 1.3% on obicetrapib. Slide 13 highlights nonserious treatment-emergent AEs seeing greater than 5% in either arm, a total 44.1% of placebo and 40.6% on obicetrapib. The most common events were as expected, things such as influenza, COVID-19, hypertension and nasopharyngitis. The events of interest that I especially look for as a clinician are some of the GI side effects. Diarrhea of 6.8% on placebo versus 3.8% on obicetrapib, back pain 5.1% of placebo versus 3% on obicetrapib, fatigue, 5.9% of placebo on obicetrapib. Slide 14 highlights our prespecified adverse events of special interest. These include elevated liver enzymes more than 3x the upper limit of normal for ALT and AST. We had 0 on placebo, 0 on obicetrapib. Bilirubin greater than 2x upper limit of normal, 2 patients on placebo or 1.7%, 0 on Obicetrapib. Muscle enzymes greater than 5x upper limit of normal, 3.4% of placebo versus 1.3% on obicetrapib. New onset diabetes mellitus or worsening of glycemic control, 22% of placebo, 20.5% of obicetrapib. EGFR less than 30, a measurement of severe renal function or a decrease in 25% in renal function from a baseline, 8.5% of placebo, 4.3% on obicetrapib. Another measurement of kidney function, serum creatinine increasing by greater than 0.3 from baseline 7.6% of placebo, 2.1% of obicetrapib and then age-associated macular degeneration, 0 cases on placebo or 0 cases on obicetrapib. Moving to Slide #15. In conclusion, BROOKLYN met its primary endpoint of LS mean reduction at day 84 of 36.3% p<0.0001. This was consistent with the safety results from our previous Phase II ROSE, ROSE2 in Japan Phase II trials. The LDL reduction at 1 year of 41.5%, again, less than 0.0001 supports the consistency and durability of our LDL-C lowering over a 1-year period of time. 77% of patients receiving obicetrapib achieved an LDL (sic) [ LDL-C ] below 100 milligrams per deciliter and 51% below 70 milligrams per deciliter and 24% below 50 milligrams per deciliter, which our goal is established for this very high-risk patient population. 34% of patients in the treatment arm achieved greater than 50% reduction from baseline in LDL (sic) [ LDL-C] at day 84. These benefits were seen regardless of background therapy or a number of therapies. As I mentioned, as a clinician, I'm especially pleased with the observed safety results comparable to placebo, with no increase in blood pressure or any difference from placebo looking at liver enzymes, hs-CRP, a measurement of inflammation or renal function. We intend to report other secondary endpoints such as non-HDL (sic) [ non-HDL-C ], ApoB and Lp(a) and additional safety data at upcoming scientific conferences. These results were also consistent with data observed in our previous Phase II studies. Moving to Slide 16. The BROOKLYN trial represents our -- the first of our Phase III trials with BROADWAY, our second pivotal Phase III trial for the LDL lowering indication. In this study, we have patients with established cardiovascular disease, predominantly LDL (sic) [ LDL-C ] over 55 milligrams per deciliter with additional risk factors or LDL above 100 milligrams per deciliter without additional risk factors. A maximally tolerated lipid-lowering therapy. As reported previously, the baseline mean LDL-C is 98 milligrams per deciliter. The mean baseline characteristics of Broadway participants are as follows: high-intensity statin therapy is 65%, ezetimibe is 24% (sic) [ 26% ], PCSK9 therapy is 4%, which again represents the standard of care throughout the world where we're conducting this trial. We expect to report top line data from BROADWAY towards the end of this year, and the trials enrolled over 2,500 patients. The BROADWAY trial inclusion criteria are generally consistent with the PREVAIL trial with 9541 patient trial comparing obicetrapib to placebo looking at cardiovascular outcomes. This patient population has ASCVD with LDLs (sic) [ LDL-C ] over 55 milligrams per deciliter with other risk factors. The baseline mean LDL (sic) [ LDL-C ] is 103 milligrams per deciliter, and similar to BROADWAY with majority, 70% are on high-intensity statin and many are also on ezetimibe and have their LDL levels controlled as best possible. Moving to Slide 17. we continue to expect top line results from Broadway in the fourth quarter of 2024 and Prevail in 2026. We're also developing a fixed-dose combination with ezetimibe, and the fixed dose combination trials underway fully enrolled in July this year called TANDEM, we anticipate releasing top line data in the first quarter of 2025. We expect that these results BROOKLYN, BROADWAY and TANDEM is favorable will be the basis of our filing for the monotherapy obicetrapib as well as a fixed-dose combination with ezetimibe for potential regulatory approval throughout the world. BROOKLYN is another exciting milestone for the company and provides us with another market of potential efficacy over 12 months in a challenging patient population. This trial also gives us optimism regarding potential benefits of PREVAIL as our large cardiovascular outcome trial. On Slide 18, we have modeled the BROOKLYN results compared to the baseline data from PREVAIL. 36% LDL-C difference at day 84 provides a 37-milligram per deciliter drop in LDL, which suggests a hypothetical estimated MACE benefit of 22% based on the well-established CTTC regression [indiscernible], especially notable for BROOKLYN is the 365 data. This is the time point generally used to calculate the difference in LDL from outcome studies showing LDL-C lowering of 41%, and this will result in a 43-milligram per dose drop in LDL-C, which adjusts a hypothetical 25% MACE benefit. BROOKLYN continues to provide us with optimism about our ability to achieve the benefits of obicetrapib and our ongoing outcome trial PREVAIL. I want to thank you very much for your attention. We believe today's results support the ability of obicetrapib to significantly reduce LDL-C enabling patients even those who fail our maximum-tolerated lipid lowering therapy to achieve their risk-based goals. These data reinforce our optimism and the opportunity for obicetrapib to overcome limitations of prior CETP inhibitors and to provide patients with better care. We're excited about the results presented today for BROOKLYN our first Phase III trial and are encouraged by the consistent safety data generated for obicetrapib across multiple clinical trials. We look forward to building on today's results with topline data from BROADWAY in the fourth quarter of 2024 and from TANDEM in the first quarter of 2025 and presenting full data for BROOKLYN in the coming months. I thank you for listening. I'd like to turn it over for questions from you, the audience.

[Operator Instructions] We will now take the first question from the line of Dennis Ding from Jefferies.

Congrats on the data. Just 1 question from me. Can you just talk about your thoughts on the percent reduction in LDL change from week 12 to week 52. I appreciate that it got better over time. But I'm just wondering should that be people's expectations going into the BROADWAY data in Q4? And then perhaps as a follow-up, what does that mean as to your overall confidence level for the PREVAIL study.

Yes. Thanks, Dennis, and I'll turn it over to John to answer the question.

Thanks, Michael. Yes, Dennis, so in all placebo-controlled, randomized trials of lipid-lowering drugs and especially in trials with heterozygous FH, the reason to include a placebo is because by definition, people will be less adherent to everything they do in life, starting at about 1 month of the beginning of the trial until about 1 year. And so the important thing is -- and that's also, by the way, why the FDA has stipulated that LS means placebo corrected is the right measure to look at. So when you look at the efficacy in the obicetrapib arm at day 30 and then you look further a longer time to day 365, and you do the same for the placebo, you see that these 2 lines are parallel because the trial is placebo-controlled and blinded so patients don't know whether they are on either obicetrapib or placebo, which, by the way, is not true if the drug has a lot of side effects. So this also shows you patients are not aware of their treatment randomization. And so they will, in equal manner, change their behavior over the space of this year, which means they are less adherent to diet. They sometimes forget a tablet of statin. They sometimes forget a little bit of their ezetimibe, et cetera, et cetera. And so you will, by definition, have at 1 year, when you only look at baseline, you'll have less efficacy in both the treatment arm of obicetrapib, but also in the treatment arm of placebo. And so the most important thing here is to look over time at the parallel nature of the lines. And as you can see, these lines are completely parallel. They indicate a 40% to 42% LDL lowering as a difference over time from day 30 onwards. And so that is, if you look at the LS means that we have reported for our Phase II program that is spot on. And so that is the efficacy of the drug in a real-life setting when you take LS means as the primary endpoint. Now, of course, this gives us great hope that the rest of our Phase III program will show similar results, including the PREVAIL trial and we have done our kind of theoretical exercise by using the CTT meta-analysis line and then you can see that whether you take the day 84 or the day 365. And listen, it's my personal conviction that day 365 is much more relevant because that is the long-term kind of outlook of obicetrapib that you end up -- you always end up with a MACE reduction over 20%, and that is ignoring the potential other non-lipid benefits of the drug such as those possibly on diabetes. And so that is our feeling going further with our Phase III program, which, again, is a strong confirmation of the LS means efficacy we saw in Phase II but even more importantly, and I hope that everyone appreciates that the safety of this drug is as far as I'm concerned, really, really impressive. And that, of course, is always very important because it's safety that breaks drugs in Phase III.

We will now take the next question from the line of Roanna Ruiz from Leerink.

So wanted to ask a little bit about the observation that OB had about half of the discontinuation rate compared to the placebo arm. How significant is that in clinical practice? And how do you expect it to impact physician prescribing of obicetrapib down the road, trying to get patients to goal, et cetera?

Yes. Thanks, Roanna. I'll take this on as my clinician has -- Yes. So we rarely see drugs like this in practice where the side effect profile based on the BROOKLYN data is really comparable to placebo. And so I can tell you that every time you have a discussion with the patient about any LDL-lowering drug, it's all about safety. And we know that ezetimibe when it first was launched, it had a 15% LDL lowering, but was very safe and it have sold $4 billion plus a year alone $6 billion with Vytorin as the combo pill. So safety, in many ways, is far more important for primary care doctors and for patients than efficacy. And so we saw here confirmation of this great safety we saw in Phase II. And I think when you talk about what do people worry about -- being worried about in stats particular, the diabetes risk, the muscle aches and pains, liver enzyme elevations, muscle enzyme elevations. All the things that you think about for lipid drugs, we saw none of this with obicetrapib. And so it's going to be again, holds up throughout Phase III, which we have a lot of confidence as well. Based on this trial, 1 year in 350 patients in the study, this will be, I believe, a very well received by the medical community. And we see this as a very important part of the whole commercial strategy of the drug. It's a very efficacious on top of statins or other lipid drugs and it has a very excellent safety profile.

Got it. Helpful. And a quick follow-up. Are you able to tell at this point, did any of the background lipid-lowering therapies drive higher discontinuation rates in the placebo arm? And could you elaborate like if it was balanced between the active and the placebo arm?

It was -- obviously, there was more distinguishing rates on placebo. We haven't looked at that question exactly yet, Roanna. But I think that our expectation from all the other trials that John and I have conducted that you do see people dropping off over time for various reasons in these trials. And this is kind of the expectation that we were really gratifying that at the end of the day, this is a very high-quality trial, 95% completed this trial. That means they came for the visits at the end and got their labs measured. And so this was a very high-quality trial. We know that based on PK measurements, the people that were randomized to the drug took the drug, so we feel really good about the quality of the data and how this will translate into future trials for the company.

We will now take the next question. The next question is from the line of Debjit Chattopadhyay from Guggenheim.

This is Robert on for Debjit. Congrats on the data. One from us today, and I'll ask on the potential trend in new onset diabetes during the trial. It appears to be slightly favorable towards OB. I'm wondering if that's a trend or too early to tell.

It looks encouraging, and we have more data to follow on this. We'll present at upcoming meetings. But just to say we're encouraged by that data. BROADWAY will, of course, be a better study to look at this. And so we'll stay tuned on that because we feel this is going to be a very important part of our program for establishing the benefit of obicetrapib for treating elevated LDL, but more to come in the months ahead and especially when we have our BROADWAY data.

And then, I'll squeeze 1 more in. Given that BROADWAY is a mix of both HeFH patients and ASCVD, do you expect similar or better absolute reduction in LDL-C compared to the sole HeFH population?

Yes, I'll have John take that question.

Thanks for the question. Well, I would like to turn that question around a bit. Heterozygous FH, especially if they're all maxed out on therapy, which these patients are, you do realize that many of these sites that participated in BROOKLYN were academic sites and to get there, you have to be already quite a complicated FH patient, then they treat you with statins, then they add ezetimibe and 15% -- 14% to 15% of patients, they add a PCSK9. And still, these people were not at goal. And so then they end up in our trial. And by definition, these are difficult to treat patients, no doubt about it. And even then, we saw, as I just described, these 2 lines parallel over 365 days. So I don't think, at this time, it is correct to have all sorts of predictions into the future. But the patients in BROADWAY are definitely not as hard to treat as the patients in BROOKLYN. So I think I would like to leave it at that and just really focus on the fact how amazing it is that in a trial where 15% of patients have triple therapy that we still have achieved such LDL lowering.

We will now take the next question from the line of Tyler Van Buren from TD Cowen.

I have a couple for you. The first one is, can you help us understand how the percent of patients on high-dose statins and ezetimibe baseline compares to the PCSK9 trials in HeFH as we think about comparing the magnitude of LDL lowering across the trials and if this could have had an impact. And the second question is just, given these data, do you believe that the Phase III BROADWAY data next quarter will likely look similar, higher or lower on LDL lowering.

Yes, John, I'll have you take that also.

Tyler, this is John. So I think that we, in Brooklyn have pretty similar patient numbers on high-intensity statins than most recent trials. And then I'm talking about bempedoic acid and inclisiran, for example. I don't think that there are fundamental differences. What is a fundamental difference is that 14% of patients in Brooklyn actually were also on a PCSK9 inhibitor, which, of course, by definition, means triple therapy. So I think that -- and also, what is interesting, if you look, and I'm going to have to name 2 [ out of trial ], when you look at inclisiran and bempedoic acid, for example, they also -- I mean, they showed efficacy numbers in their heterozygous FH trials that were the lowest of all their trials, ORION-9 had definitely lower LDL lowering numbers than ORION-10 and ORION-11. So you can, I think, very well compare these trials and the same actually is true for bempedoic acid. But again, I think it's always dangerous to try to predict the future. The only remark I can make is that in Broadway, we'll have a percentage, but it's not a large percentage of patients that have heterozygous FH. The vast majority of patients are straightforward ASCVD patients, and those patients are usually easier to treat and have less stringent background therapy on average than the average heterozygous FH patient.

We will now take the next question from the line of Yasmeen Rahimi from Piper Sandler.