Okay, welcome everyone. I'm Jennifer Kim, one of the biotech analysts at Cantor, and I'm looking forward to hosting this fireside chat with New Amsterdam Pharma. We have Michael Davidson, the CEO, and Ian Somaiya, the CFO. Thanks for being here.
Thanks, Jennifer.
Maybe to start things off, can you introduce yourselves and maybe give a quick snapshot of New Amsterdam?
Sure. So I'm a cardiologist, lipidologist, and been doing research in cholesterol for thirty plus years, and this is my fourth biotech company. New Amsterdam, for me, is a return to my roots. I was the first one to patent CETP inhibition back in the nineties, and always thought it as a very intriguing target because animals that lack CETP cannot get atherosclerosis, and the CETP inhibitor class has been developing along the way, and some unfortunate setbacks, but what we learned more recently is it's all about LDL lowering, and obicetrapib is the most potent CETP inhibitor ever developed. Very low dose, and we now have very profound LDL lowering with this drug.
But more importantly, the tolerability now through many trials, now the large phase three trial is excellent, and the drug has many, many other attributes beyond LDL lowering, such as Lp(a) lowering, particle reduction, small particles, and based on the class history, a lot of benefits on diabetes prevention, so we think these all translate to a drug that patients are seeking to get LDL levels under control, and we believe it could be a single answer for the patients that are taking statins or taking whatever they can take statin-wise, including no statin. obicetrapib becomes the go-to drug to get them to the goals that now have been established. We also have developed a fixed-dose combination with ezetimibe, which gives it even greater efficacy.
Another very well-tolerated drug, ezetimibe, works very well with obicetrapib based on our preliminary phase 2 data, which we're now testing in phase 3. So we have a bigger phase 3 trial called BROADWAY reading out very soon, the next couple months. And then we also have the combination with ezetimibe, a combination pill, comparing it to each component individually or placebo. That'll be reading out pretty soon as well.
Okay, great way to set the stage. I want to get into each of those characteristics of obicetrapib, but maybe to start off more broadly, when you look at the lipid-lowering space and the current therapies that are available, what is the unmet need that obicetrapib really fits into?
Okay, first of all, I think it's important to, you know, put yourself in the patient's mind. You know, they have a high LDL, and they don't want to take medicine in the first place, and so that's how most patients are. They'd rather not take a pill, or not take any medicine if they don't have to. It's asymptomatic, and so they're on their statin, or they don't like statins for whatever reason, and some of them are the muscle aches or the risk of diabetes and things like that. They want to take a drug that is gonna get them to their LDL goal, and they want to have it, ideally with no side effects.
And so that, that's what the patient's thinking about. So unfortunately, we don't have that solution right now available. We either have drugs that are very modestly effective orally, that lower LDL by another 15%-20%, or we have injections, which are effective, and they're generally well-tolerated, but they still require these every two-week injections, and they also have challenging reimbursement kind of requirements from the payers. So, I think, we believe that obicetrapib's profile is ideally suited for what the patients are seeking right now to get their LDL levels under control.
Okay, and Michael, I think you would know more than anyone else that CETP inhibitors were originally developed for their HDL-C raising effects. Can you just walk us through mechanistically how obicetrapib is working to lower LDL-C and sort of the related markers, like non-HDL-C and ApoB? And how has that panned out in the clinical data that you've generated?
Right. So we know from another study that was done with another CETP inhibitor, anacetrapib, that it does upregulate LDL receptors, and that improves clearance of LDL, just like statins or ezetimibe or PCSK9 inhibitors do. The other thing that we know that it does is it makes the LDL particles go from small to large, and larger particles are more readily taken up by the LDL receptor. So it's still the same ultimate pathway of getting, you know, more particles cleared by the LDL receptor. And the third pathway that we also know very well from preclinical models is that obicetrapib enhances the removal of cholesterol through the intestines, called TICE, transintestinal cholesterol efflux.
That's why we believe that the synergy with ezetimibe is so effective, based on our combo studies, that you have a drug that improves efflux of cholesterol through the intestines. You have ezetimibe there to basically block it from being reabsorbed, so the two make a really good combination. So those three things ultimately end up affecting greater LDL clearance by the liver. All three of them affect that overall mechanism of increased clearance of LDL from the plasma.
And then the other sources of residual CV risk that obicetrapib seems to target, I think you talked about small LDL-P, Lp(a), diabetes. What is the mechanistic thinking there, and how important is that for the OB story?
I think most important is the LDL lowering, which we, you know, we have our, you know, our 36%-40% LDL lowering across our trials. Very, very consistent across all the trials, and with ezetimibe in combination, we've seen as high as 58% LS mean difference in the two drugs together in our phase 2 ROSE trial. So we believe we have the solution to lower LDL, but when we look at residual risk, so this is a very important concept. It's been. We've talked about it for many years, actually.
So when someone's on a statin, the risk goes down 30% or so, but 70% of risk is not addressed by statins alone, and some of it is residual LDL risk, which is important, but much of it is due to other factors like high Lp(a), the small particles, which statins don't really lower effectively, neither do other LDL lowering drugs, for that matter. And then we have the diabetes, and hypertension and smoking and things like that, that still induce atherosclerosis. So we think that while statins lower LDL, they don't lower small particles. They raise Lp(a) and they increase the risk of diabetes. The perfect companion to a statin, therefore, would be a drug like obicetrapib, which lowers Lp(a) quite robustly.
In fact, our Lp lowering is actually better than our LDL lowering based on the phase II trials. You know, we're talking about 40-50% Lp lowering. Small particle reduction was 80-90% in our phase II trials, and we've already announced consistency in BROADWAY for that, BROOKLYN for that. And then the diabetes benefit, we'll have to see. We gotta... We know it happens with other CETP inhibitors, but we'll have to wait and see what happens with our ongoing phase III trials because we need large numbers to see that very clearly in the studies. But we saw the right trends in our BROOKLYN data.
Can we dig a little more into the Lp(a) piece of the story? And is there a way to think about the potential additive commercial opportunity that could add? And I know we could see some important data next year in this space-
Right.
That could answer some questions. How do you think about that?
That's... We're all looking forward to the HORIZON data, which is a very potent ASO approach to lowering Lp(a). It's a once-a-month injection, and for people with established atherosclerotic cardiovascular disease. So it's very important for that trial to basically prove the hypothesis that Lp(a) lowering does in fact translate into clinical benefit. So that's a very important study. There's others underway as well to look at that question. But what happens, though, if that reads out positive, which would be great, and it's great for the field, but when it comes to the vast majority of patients, they're not gonna qualify for that therapy because they either have Lp(a) that are not high enough, because they're only talking about the ninetieth percentile and above, and they have to have established atherosclerotic cardiovascular disease.
But for the patients that are in, you know, in the fiftieth to ninetieth percentile, we know the risk is still high based on epidemiological studies, or they don't have heart disease yet. In my lipid clinic, that's what I see. I see the patient coming in who's got a bad family history, and their Lp(a) is elevated, and they want to know what to do about it. And unfortunately, they're hesitant to take a statin because the statins raise the Lp(a) further. We still know that the best way to address high Lp(a) is to lower the LDL as low as you can.
To have a drug that lowers Lp quite robustly and lowers LDL robustly and lowers Lp would be the best oral option, we believe, to address that unmet need for the majority of patients.
Okay, now that we-
Yeah. And just again, you know, following up on that, we are talking about Lp(a)-targeting drugs, injectables being limited to the 10% of patients based on the eligibility criteria that the companies and the trials are utilizing. So as we think about how these patients are being treated today, Michael mentioned the aversion to statins. The preferred agents then do become the PCSK9s, which are injectable and also have a fairly modest effect. So the ability of obicetrapib to more than double the benefit that PCSK9s provide from an Lp(a) standpoint and the potential to evaluate combinations, and that's something we're doing in our own clinical program.
We have a study that's looking at high Lp(a) patients and evaluating the combination of Amgen's PCSK9 Repatha and our own drug, obicetrapib, to see what is the additive effect, and that's data that we'll have by the end of next year.
Okay, great. Maybe we could dive into the clinical program. Can you lay out the phase III trials and sort of the catalyst path over the next 12 months?
Sure. Yeah, so our next large monotherapy trial is called BROADWAY, and it was specifically set up to look at the broadest range of patients. So they have ASCVD primarily, but some of them have FH, and they're on, ideally, maximum-tolerated statins, which we needed to have a commitment to the FDA that roughly 60%-70% would be on high-intensity statins, which they are. But roughly 10% are on no statin. Many of them are on other lipid drugs, 25% are on ezetimibe, and a small percent are on PCSK9 inhibitor. So it represents the, you know, the common high-risk patient on statins, and the LDLs are above the thresholds that have been established.
That's a 2,500-patient trial, 2-to-1 randomization, and that'll be our largest, you know, study to date, both in numbers and, of course, durability, which we saw in BROADWAY. Sorry, BROOKLYN, we saw the durability was sustained across the 12 months. We want to see again. We believe that, you know, we have safety in BROADWAY as good as BROOKLYN, which was across the board, one of the safest trials I've ever seen. We didn't see any side effects different from placebo. If we have the same data on a larger 12-month study, then I think we have obviously a great profile to move forward. That's the monotherapy. The fixed-dose combination is called TANDEM.
That is a four-arm study with roughly a hundred per arm, a little over a hundred per arm, and they're gonna have either placebo or each of the drugs separately, obicetrapib or ezetimibe, and then the combination pill, which is the fixed-dose combination of two drugs together, all double blind, you know, four-arm study, and that's a 12-week study. And that'll be our study for the label for the FDC once approved. We want to try to get both drugs approved at the same time, and so a clinician can have a choice of using obicetrapib alone, if they can get the LDL goals established with monotherapy, or if they need the extra efficacy, which would put obicetrapib very comparable to the injectables on LDL lowering, they'd have that option as well, to go to-
Yes
... as a single pill.
Just from a timing standpoint, BROADWAY is on schedule for the fourth quarter of this year. The one thing we have stated is, we don't want to release the data in the last two weeks of the year. Everyone should enjoy the holidays. We'll release the data either before that or after that, and after that means right before the JP Morgan conference.
Okay.
TANDEM is the first quarter of next year.
Okay. You read my mind. That was gonna be-
Yeah
- the next question. Maybe we can start with, since you read out top-line results recently with the Brooklyn trial, you're planning on presenting detailed data in November. Can you just walk through the key takeaways from that trial and sort of set expectations for the presentation?
Right. Well, the key was the primary point was 36% at day 84, which is 12 weeks, and then 41% at day 365, LS mean difference for placebo. So again, very consistent with our phase II data. So we did release the LDL lowering. We showed the actual timeline of the LDL across the 12 months. It's very, very consistent. We see a drop within 4 weeks, and it stays down for the full 12 weeks, so that it proves there's no, we call tachyphylaxis. There's no loss of efficacy within 12 weeks going on to now a year. And then as I already mentioned, you know, the incredible safety of the drug.
We were pretty transparent about all the safety data, including the MACE events were lower, although the small numbers, the deaths were lower, small numbers. What we did hold back, what we plan to present at American Heart are the all the secondary endpoints, like non-HDL-
Mm-hmm.
Lp(a), ApoB, LDL particles. But we did already give people a view that they're very consistent with our phase II data, which was, you know, the 34% range across the board for non-HDL. Lp(a) lowering was 40%-50%. ApoB was roughly 24%-25%, and the LDL particles were in that 40%-50% range, the small particles being in that 80% range reduction. So we've highlighted that we see consistency again for all the secondary endpoints as well, but we haven't disclosed those numbers yet.
Yeah
... fully. Yeah.
Yeah, and again, we have submitted an abstract for AHA. It hasn't been accepted yet, so, you know, we're hoping to find out soon.
As a late breaker.
As a late breaker, yeah.
Fingers crossed.
Yeah.
I'm looking forward to it. The other thing, I guess you've said is that, by and large, there weren't any differences in efficacy across patients with different background therapies. Is that something we should take a closer look at in November, and why is that important as we think about your other trials?
You know, it's not as important as you would think, because I think what is going on is that as these trials have evolved over the last several years, especially for FH trials, if you're being well controlled on the statin, the statin ezetimibe or statin PCSK9, you don't go into a trial. I mean, you're pretty much treated, and you're treated effectively, and so you're not going into a trial. Now, we're getting patients that are more refractory. The more drugs they're on, the more refractory they are. They have LDL receptor monogenic mutations, but they also have often variants of other LDL receptor genes that make them more challenging to treat.
So the fact that we saw, again, not just consistency from our other phase II trials, but consistency across their coexisting therapies, I think is a very good sign because what we're saying is that it doesn't matter what you're on, we see the drug works.
Yeah.
And so it further brings down the LDL. And so I don't think it matters that much in this type of study whether you're on what other drugs you're taking. The bottom line is your LDL is still too high, and you need something else to lower that LDL.
But, but it's invaluable from a prescriber standpoint, from a patient standpoint. So as you think about whether it's a primary care physician or a cardiologist, they're seeing 20, 30 patients in a given morning. They don't need to really consider the history of that patient from a standpoint of how long they've had elevated LDL, their baseline LDLs, what background treatments they're on. I think they have a sense for what their risk-based goal should be, and we have two product forms, ApoB monotherapy and the fixed-dose combination, which will allow them to get their-- get that patient, and really all, all the patients that they're seeing that morning, to goal, without adding much in the sense of risk. And again, we'll, we'll learn more about safety in our trial from BROADWAY and obviously from the larger PREVAIL outcome study.
But to date, when you look at the phase I and II data, and now the first phase III, it's remarkably consistent.
Okay, great.
Yeah.
Maybe we can go into BROADWAY. To start off, in terms of the top-line disclosure, how are you thinking about... What will be included in the top line?
So very similar.
Similar to BROOKLYN?
Yeah.
Yeah.
I mean, we have a commitment to our academic collaborators because they really want to try to publish the data in the top-tier journals, and so we don't want to jeopardize that. So we are committed to just disclosing the very similar to what we disclosed in the BROOKLYN data set. Yes.
Okay. BROADWAY also, as part of its design, has some interesting points. There's a subset of patients you're monitoring blood pressure.
Yeah.
You're also looking at secondary endpoints. Could you sort of set expectations on those endpoints?
Blood pressure, as you know from BROOKLYN, was flat. There was no increase, and no difference from placebo on blood pressure. So there wasn't even a hint of that. There was no effect on blood pressure. So that's 350 patients. So again, we hope that we see, you know, no effect on blood pressure. And what we've done in this study is we embedded a 24-hour ambulatory blood pressure monitoring in roughly 200 patients. So that's a much more accurate way of assessing blood pressure over time. But we've been very careful about the blood pressure measurements. We do basically three measurements. The patient who's been in a dark room, laying flat for at least five to 10 minutes, and so blood pressures are done in a very careful fashion.
And so we hope to see, you know, comparable data again in BROADWAY, which is a critical thing because of the precursor torcetrapib issue, where blood pressure went up by at least five millimeters, if not more. Especially in susceptible patients, it went a lot higher. And we obviously don't see any signal for that whatsoever in any of our trials.
Okay.
Yeah.
But what we can say is we have released, blinded data on BROADWAY, and we see no effect on blood pressure overall in the trial.
And that's as-
That's two-to-one randomization. Yeah. So...
Yeah, but I guess overall trial expectation should be very similar to what we have reported today, so you've seen data from six clinical trials, and whether you look at the phase II or the phase III BROOKLYN data, there's a remarkable level of consistency to the data from a safety standpoint, as well as from an efficacy standpoint, and it's really irrespective of which cardiovascular marker you're looking at, whether it's LDL, as Michael mentioned, ApoB, non-HDL, others, and there's obviously a lot of excitement about Lp(a), so just going back to the AHA, we do want to make sure that we share the Lp(a) data with you.
Okay, and I know that detailed data on BROADWAY might be reserved for after the top line but-
Yeah.
Mm-hmm.
Similar to BROOKLYN, could we expect any color at the time of top line?
We really. Well, we can't say anything right now. Obviously, anything that we have to disclose, you know, we will disclose. I mean, but, we're getting a lot of pressure from our academic collaborators not to jeopardize in any way our major journal publication chances.
That's fair.
Yeah.
The other thing in BROADWAY is I think you're following MACE events in those patients as well.
Yeah. Yeah.
It's just a one-year trial, but any expectations on what you would hope to see, and what data could you leverage from that trial into your outcome trial PREVAIL?
Like we've always said about MACE events, we believe that twelve months is too short to see a major separation of events. So what we want to see is no difference in MACE events between the two would be safe, you know, basically safe, safety of that therapy. So we will see. We'll have. You know, we have a certain number of events that we're tracking, and we're adjudicating the events, and so we'll have that as part of our overall safety assessment.
Okay, and then if we could turn to TANDEM, that data should follow pretty quickly. What are you hoping to show with the fixed-dose combination, and how should we interpret the data from that trial?
We want to show that, as we saw with ROSE2 , that there was at least additivity of the two. This is now the fixed-dose combination as a single pill. So we, instead of giving the two drugs together, we're, you know, you're giving a drug. We know there's no major pharmacokinetic issues with the two drugs together, so we should hopefully see that the two drugs together have greater LDL-lowering efficacy compared to each of the individual components. That's what we want to try to prove with that trial. That, like I said, that'll go into the label.
That'll be an open-label trial, and so, we'll be able to promote that efficacy for whatever it is, you know, where if it's 50% or so in that range, then we have a single pill that is as effective as the injectables, and that would be a great, you know, single pill to give to patients, and they wouldn't have to take an injection.
Okay. Maybe we can turn to PREVAIL, the outcomes trial. For those who are less familiar, could you walk through the trial design, the timing of data, and what is the bar here?
Yeah. So we've learned a lot about outcome studies over the years. And we've learned a lot of lessons that help us here in learnings from previous trials. And what we've learned is that to maximize success, you want to have the greatest absolute LDL lowering possible within the realm of what's considered ethical. And so for us, that means you want to have a higher baseline LDL, you know, with our 35%-40% LDL lowering. We want to maximize the absolute LDL lowering, and so that means the greater baseline. Even other studies have shown that when you're roughly around 100 is where the greatest benefit is for LDL. That's where we are on our trial.
I think we're 103 as baseline LDL for PREVAIL, based on our latest data. The other thing is you want to have longer duration. You want to have the minimum follow-up is, I think, more important than the median follow-up. You want to have the last patient enrolled have at least two and a half years of exposure to the drug to make sure you get enough time for the LDL-lowering benefits to occur. You know that at one year, you know, those benefits are pretty flat or very modest, so you want to make sure you have the longer duration. So we built in a two-and-a-half-year minimum follow-up. But what we also learned is there are certain patients that I...
The expression is that, you know, the horse has already left the barn. That, like, for example, heart failure. In the recent trials, if they had heart failure, the benefits of statins were not there, and they diluted the overall benefit. You know, for example, in ODYSSEY OUTCOMES, the overall event rate was, the reduction was 15%. If you took out heart failure, it was 20%. So we took out heart failure patients from the trial. And so what we designed the trial to maximize success, that means greater absolute LDL lowering, you know, higher baseline LDL, and we added risk enhancers that we know from REVEAL, which was another CETP inhibitor, had greater benefit, high Lp(a), high triglyceride, low HDL, diabetes, beyond the higher baseline LDL or higher ApoB.
Those all had greater relative risk reductions compared to the overall study population. So we put all those elements together into PREVAIL to maximize success. We don't, we don't want the study to fail the drug, is what it comes down to. We're monitoring events, and we'll know a lot more in April of next year when the last patient enrolled will be on the drug for at least a year. We'll be able to really get a good assessment of event rates, and that tracks pretty closely to a line you can track. Then we'll know pretty much when we're going to hit our expected event rates.
We want to make sure we don't stop until at least two and a half years of minimum follow-up, which would put us at the end of 2026 for that minimum follow-up of two and a half years.
Yeah.
But, you know, you asked the question as it relates to sort of bar for PREVAIL. We don't need to set a bar for PREVAIL. That's already been set with the injectable PCSK9s. The label benefit that they have shown is 15%. What the BROADWAY trial allows all of us to do is, given the similarities in the patient population and in baseline LDL, is to take the benefit we demonstrate in BROADWAY and plot that LDL number, the percent reduction, on the CTT regression line and gain confidence on what PREVAIL is likely to show.
If the data is consistent in BROADWAY in terms of what we have achieved previously, so somewhere between 36% and 40%, that points to a value that's in excess of 20%. But again, going back to your point on the bar, that's already been set with the injectable PCSK9 to 15%. So we don't need to be north of 20%. Anything above 15% would not only be a successful outcome from a clinical trial standpoint, it would allow us to further differentiate ourselves relative to our competition.
Just touching on the competition, there are a few oral PCSK9s in development.
Sure.
I think we could see phase two data from AstraZeneca fairly soon, and Merck has one in phase three development. Just how do you think about those therapies as competitors alongside your own?
First of all, it's great. I think it does speak to the unmet need of orals. We have injectables, and so these are oral options, and so that's great. And having more share of voice in the market to get people to goals is a great thing for us. But when it comes down to is we're gonna have efficacy similar with our fixed-dose combination, maybe even better, but also these other attributes, the Lp(a) lowering, the diabetes benefit, the small particle reduction, the tolerability, you know, we believe we have a superior profile, and that ultimately is what wins the day when it comes to patient acceptance and utilization.
Okay.
I don't view them as competitors. I would view them more as collaborators. It's been 15-20 years since we've seen major pharma's influence in this space. To get Merck and AstraZeneca, which are household names, at least every clinician and every patient had some level of experience or contact with those companies and their treatments, we need to go back to that. We need heavy pharma influence to get patients to focus on their LDL and really try to get them to goals that are now quite clear and evident in the US.
Then the treatment decision is really left to not simply what treatment can get me to my LDL goal, but what is the best treatment overall to address cardiovascular risk, which is not a single factor. It's multifactorial.
Okay.
Yeah.
Great. I think we're at the end of our time.