Okay. Thanks everyone for being here. My name is Yanan Zhu, and I am one of the biotech analysts here at Wells Fargo. It is my great pleasure to be joined by the management team of NewAmsterdam Pharma. With me here, Michael Davidson, CEO of the company, and Matt Philippe, Head of Investor Relations. Thank you for being here.
Thank you.
Thanks, Yanan.
Thank you.
Great. To kick things off, I hope you could give a brief overview of the company and then we can jump into some questions.
Sure. Thank you for hosting us. NewAmsterdam Pharma is a startup biotech company. We are now six years old. We are developing obicetrapib, a CETP inhibitor for lowering cholesterol, but it has a very differentiated profile from anything else. It is a potent LDL lowering drug. It also raises HDL by 150%. It lowers the risk of diabetes, lowers Lp(a), lowers the risk of p-tau217, a great biomarker for Alzheimer's disease, and it is very differentiated from anything else in LDL lowering. We finished phase III for LDL lowering, and we got approval in Europe, and we are finishing our large phase III cardiovascular outcome trial called PREVAIL. It is our next big study to read out other than we do have one more phase III trial called RUBIN finishing this year for diabetes patient population.
But once we finish PREVAIL, we plan on filing and then launching the drug in the next 12 to 18 months.
Great. Thanks for that overview. I wanted to perhaps start the discussion on Lp(a).
Right.
Given the very big news that came out of Novartis’ HORIZON study, there is some connection with your drug because your drug also lowers Lp(a) to a degree. Could you talk about this outcome? Does it surprise you? What might be your guess of the cause of the failure, and what might be the implication for your program?
Right. I am a lipidologist cardiologist. I see a lot of patients. Lp(a) is a very important cardiovascular risk factor. It attaches to LDL and makes LDL more likely to clog up the arteries or has increased clotting effects. It is a very strong risk factor for heart disease. We know that is clear. We know that genomic studies support its risk and over long-term periods, having lower Lp(a) means lower cardiovascular risk. HORIZON was set up to look at a population that had very well-controlled LDL. In fact, LDL was 60 at baseline. Everyone was put on aggressive LDL lowering therapy prior to entering the randomized period of the trial. What we do know is that does help a lot reduce risk already. When you have a low LDL, Lp(a) risk is significantly reduced.
The question is whether further lowering Lp(a) would in fact, make a difference, and this is what HORIZON was trying to answer that question, looking at two different thresholds. As you mentioned, the readout was not positive. It was a disappointing study. There are many reasons why it may not have worked. One thing is we were aware of is it had a pretty high dropout rate. It started during COVID. There was side effects from the skin site reactions, and it may have been that diluted the benefit, and if they looked at other populations like on treatment or subgroups, there may still be a benefit. What is important for us is, yes, we do lower Lp(a). It is one of our differentiating features.
We have always said, but for us, we already have our own data on benefits on cardiovascular events from our phase III trials, BROADWAY being the largest. It was a large study, 2,500 patients. We showed that in that study, a 21% relative risk reduction on 4-point MACE. We also published that in the analysis looking at Lp(a) lowering, that the lower the Lp(a) got on obicetrapib, the lower the event rates. We already have our own data that obicetrapib in the setting of high Lp(a), the lower the Lp(a) got on treatment, the lower the risk. We already have our own independent data. We also know from the Merck CETP inhibitor, anacetrapib, that when you had a high Lp(a), you had a greater relative risk reduction. We purposely designed PREVAIL to be enriched for having high Lp(a) patients as one of the enrichment criteria.
Either you had to have an LDL over 100, pre-existing heart disease, LDL over 100. If your LDL was 70-100, you had to have either high Lp(a), low HDL, high triglycerides, or diabetes. All risk enhancers that in the Merck anacetrapib trial show a greater relative risk reduction. If we see similar benefits in PREVAIL showing that, like we did in BROADWAY, that when you have higher Lp(a), you have greater relative risk reduction and greater benefits, the lower the Lp(a) becomes on treatment. That provides already substantial evidence that obicetrapib would be a good drug to use for high ApoB patients.
At the very least, we know if HORIZON shows nothing other than, again, low LDL, ApoB doesn't matter, we know that it's still an important risk factor, so getting LDL levels as low as possible is still a very important treatment consideration for those that have high ApoB, and we have a great drug to do that. We feel this as a, no matter what HORIZON shows, we believe that we now become the first, quote, "ApoB lowering drug" available for patients when it gets approved, hopefully after PREVAIL in the next 18 months or so, that it'll be the go-to option for the high ApoB patient and still one of our important differentiators. But it's not the only one. We have other important factors, like I mentioned, the small particles, the total particles, the diabetes prevention, the Alzheimer's prevention benefit.
All those things make obicetrapib have a very unique LDL-lowering therapy that we think is going to be very well-adopted into the utilization paradigm for those that have high LDL cholesterol.
Got it. That's very helpful. You did mention additional differentiations beyond LDL lowering. You mentioned diabetes. Of course, there's potential small particle effect, that aspect. But I think diabetes is the outcome that you could observe, right?
Yes.
Could have data. Alzheimer's, there could be biomarker data you could observe. Are those being measured in PREVAIL?
Yes, they are. Yes.
Got it.
In PREVAIL, it's one of our adjudicated endpoints is diabetes, development of diabetes or worsening of diabetes is an adjudicated endpoint in PREVAIL.
Okay.
We are going to do biomarkers in PREVAIL as well for p-tau217 and other, like we did in BROADWAY.
Do you also have a capture of kidney function?
Yes, we do also. It is, again, one of our events of special interest that we will be monitoring in the trial.
Right, great. So obviously, PREVAIL is a very important trial for you and also for the field. We needed a cardiovascular study win, given what happened to HORIZON. So the trial undergone some changes because you added an interim study-
Right
interim analysis. Can you talk about how did that come about?
Sure.
Yeah.
I think it's important to provide a historical context. We started PREVAIL at the same time as BROADWAY, knowing that we were not going to launch the drug until we had PREVAIL outcome data in hand. We wanted to start PREVAIL as soon as we possibly could. It started at the same time as our phase III trials. Most outcome studies start after phase III, post-approval type. We wanted to have that available at the time of approval, so that we'd have that evidence available for promoting the therapy in hand. We started at the same time as BROADWAY. The same sites were included, BROADWAY and PREVAIL, almost the same sites. PREVAIL, obviously more, but BROADWAY, the same sites as PREVAIL. We had basically the same inclusion criteria, and so they're very similar studies.
We knew that BROADWAY reading out after one year of treatment, we'd get good insights into what PREVAIL's event rates should be and how to better look at PREVAIL long term. We always were anticipating we would make changes to PREVAIL based on what BROADWAY told us. BROADWAY gave us an opportunity to raise a lot of money to further enhance the chance of success of PREVAIL. One of the things we decided to do was instead of a 20% relative risk reduction powering for P less than 0.01, we decided to make it 15%. Again, 20% was fine. That's what most studies actually have 20% as their benchmark for relative risk reduction. We decided to go to 15% because that look at other LDL trials, and all the LDL trials as you know, have all been successful. I mean, they all been successful.
Ezetimibe, 9%, clear outcomes. Bempedoic acid, 13%. FOURIER, 15%. ODYSSEY OUTCOMES, 15%. VESALIUS-CV, another evolocumab trial, 19%. All the LDL trials have been successful. Getting to a 20% threshold, it would be on the upper end of that. Even though we had designed it that way because we started off with a much higher LDL, we know absolute LDL lowering would be enough to get us to 20%. Just to give us more, being more conservative, we decided to go to 15%. The way to do that was to get more events, and we decided, based again on BROADWAY, that we would go from urgent revasc to total revasc, which adds about 20% more events in general. That provided instead of 1,000 events, more events. Then we decided to go longer to hit the number of events to make it powered for 15%.
And so that was where we were. We are going to go longer, because we always knew we can go longer. We already finished enrollment, so we could not add more patients, but we could go longer. We think going longer actually is a better way to get more events as opposed to adding a lot more patients. We know in the first year, the event rates are not as robust as they are over subsequent years. Going longer is always a good thing to get events. We looked at our events, and we knew that BROADWAY was a really good pre-PREVAIL, mini PREVAIL. We know the event rates, and they looked very similar in PREVAIL to the first year of PREVAIL looked very similar to the first year of BROADWAY. They want the BROADWAY one-year data.
After year 2, the event rates started dropping even more than expected for what we think the placebo rate should be just on the BROADWAY data, as well as many other trials, for that matter. We decided that now we could potentially do an interim and have the study stop our original timeline, which was at over 1,000 events. If we had that 20% range of event reduction for both MACE for the primary and for MACE- 3, the secondary, prime secondary, we would have enough power to stop the trial at that point and be on the market one year earlier without any significant alpha penalty. Of course, being on the market a year earlier, it provides a lot of advantages from a commercialization perspective. That led us to do the interim analysis.
We see this as really a free look at the data, but at the same token, we have made sure we maximize our chance for the overall success of the trial at the end with powering it down enough to get a 15% relative risk reduction.
I just wanted to make one comment on a point you made as well as kind of needing a win for CVOT studies. I think it is interesting because we have had the last two studies, the HORIZON and the ZEUS study, clearly read out negative, and there has been a lot of concern about CVOTs being more difficult or standard of care changing and drop-ins affecting these rates. I think as Michael correctly alluded to, you have to also look at the LDL-C studies. VESALIUS-CV also read out within the last 12 months, and that study was very successful. What is interesting about VESALIUS-CV, started at the same time as both HORIZON and ZEUS, but VESALIUS-CV had a much higher event rate. It shows you that when you are looking at event rates, LDL-C is very important. It still remains the most validated target there is.
You have to remember, that is what PREVAIL is going after. We are going after LDL-C reductions. I think it is easy to get caught up in the last two studies, but you have to remember, ZEUS with IL-6 and HORIZON with Lp(a), these are the first outcome studies looking at these targets. They do not know what the residual risk is. They do not know the ability to offset a lifetime of elevated levels with a short duration of study. All of these things are known with LDL-C. I think although it is disappointing to have recent cardiovascular outcome studies not read out positively, they should not read into the success likelihood of PREVAIL. Remember, BROADWAY was also started during the period of these studies when this perceived standard of care shift and drop-in shift was occurring, and BROADWAY still showed a 5% placebo event rate.
If you look at some of these studies and were to adjust, including the statin studies back 20 years ago, if you were to adjust their event rate, which was about 3.5%, that was MACE-3 , and you look at contemporary studies MACE -3, that is 2.5% today. That could perceive to be that there is a shift in standard of care. What the big difference is, if you look at the studies in the statin era, they run a baseline LDL-C of 140. If you look at the baseline of more contemporary studies, they are in the 90s. That is a 30% reduction in baseline LDL-C for these studies. We know risk is linear. If you reduce your LDL-C baseline by 30%, your risk is reduced by 30%. What is 30% off of 3.5%? That is 2.5%.
I think you start to see that if you design well-validated LDL-C studies, they are extremely predictable and reliable. It is just the recent studies have been sort of in novel targets that has led to some of this confusion. I think we still believe PREVAIL is set up, all the reasons Michael said, but also LDL-C studies tend to have always gone well.
Right. Those are great points. Thank you. Great insights for us to keep in our mind when looking at these studies. I think maybe a quick question here. Michael, you mentioned you looked at the blinded event rate.
Right.
You compared it with a lot of trials' placebo rate.
Right.
Your blinded rate is below that placebo rate. However, if the drug has any effect, it could be expected to be below placebo rate. So that alone doesn't quite suggest a confidence for interim analysis, right?
No. Let me explain how we do this. You look at a placebo rate, and you look at the blended event rate. You know the placebo rate, just simple math, 2.5%. All right, let's keep it simple. We had 5% placebo. I am not using the real numbers, but you have 5% placebo rate in BROADWAY, and you have a blended event rate of 4.5%. That means that if your placebo rate is 5%, you are going to have a hazard ratio of 0.8.
Yep.
You can do the simple math. You know that if your placebo rate should be 5% and your blended rate is 4.5%, you know that your hazard ratio is 0.8.
Right
You can see.
You, yeah.
I think to your point as well, you would be correct if you didn't know what the year one rate was. Remember, we're saying we have a good idea because of BROADWAY, where our benefit is after the first year. Now what we're saying is continue that benefit on, and we're seeing further deviation from a continued placebo line. So that tells you we're seeing further benefit above what we saw on BROADWAY.
Okay. Yeah.
We look at the annualized event rates. I am just giving you every year, we see event rates go down and down.
Right
Annualized.
Yeah.
It gives us confidence that something is going on that is bringing the event rates down, and we know it is not add-on therapy. We track that, and we know it is not like drop-ins, GLP-1s or SGLT2s. We can see that those are very low. PCSK9s or drop-ins are very low. We know that we have been really diligent about finding all the events, going to the sites and tracking all the patients, and so we are not missing events. We believe it really is the drug effect.
Got it. Okay. Given that you are conducting this interim analysis and given the alpha that you are given to the interim analysis, I think you said for MACE- 4 is 0.01.
Right.
MACE- 3 is a separate alpha that you have not disclosed, but at least we know MACE- 4 is 0.01.
Right.
Right? I was wondering, based on this setup, what is the power at an interim to detect a 20% relative risk reduction, and what is the power to detect a 15% risk reduction?
We haven't disclosed that.
Yeah, what we've said is we are well powered to detect a 20% or a BROADWAY-like efficacy, so that 20%, 21% efficacy for both MACE- 3 and MACE- 4 at varying levels. I think that's as much guidance as we want to give on that, but I think, obviously, down to 15% just means we have less power.
Right. What about MACE- 3? Was the statement also applied?
Same statement.
Also-
MACE- 3, if we are in that 20% range, we are well powered to see a benefit with our P value that we have designated. Yes.
Okay. Got it. Yeah. In that case, for the interim, how do you feel approaching the interim? Because it does need to have a high confidence that it will succeed. Well, sounds like you need to have a 20% to have a very high confidence because it is very well powered to detect that, right?
Right.
If it is below 20%, then there might be some risk. So how-
Well, like I say, based on our projected, again, we look at this triangulated in three ways. One is we know what the LDL, non-HDL, ApoB lowering, we should be close to 20% or higher, just on those parameters. That is based on 30 plus studies, the relationship between LDL lowering, ApoB lowering, non-HDL lowering. We should be close to 20%, if not greater, based on our magnitude of absolute lowering. That is one way to look at it. The other is REVEAL, which is the Merck study in their upper tertile of 10,000 patients. It was stat sig of 17% with a 23 milligram per deciliter drop in non-HDL. We know our non-HDL lowering is going to be significantly higher than that, in the 35 to 40 milligram per deciliter range.
In the same class of drugs, looking at in the population, the subgroup of patients that match the PREVAIL population, we also would be above 20%. That is two ways of looking at it. Then the third, of course, is the placebo projections, and we looked at it both using BROADWAY placebo, which we think is an excellent benchmark because it was the same patients population and so forth, inclusion. But we also didn't stop there. We said, let's look at every other outcome study that has been done in atherosclerotic cardiovascular disease patients, these people with pre-existing heart disease. What were the three and four-point MACE rates across those multiple trials, and how are we going to do the best apples to apples comparison of our population to these other trials? You can model both things very carefully.
Again, we can look at those three-point and four-point placebo rates, and within those ranges of what they have shown in the past, in all these trials, we again feel optimistic that we are going to be at that threshold where the interim would be stopped for efficacy. Let's say we looked at it in many different ways, and those are the three different main ways we looked at it. At the end of the day, it is a blinded study, and we don't know for sure till we get the results, but we feel optimistic about what those three different ways of looking at it tell us right now about the PREVAIL data.
Got it. If we anticipate that interim analysis, there are obviously two scenarios. One is that you will declare success. The other is the study will continue towards the final analysis, right?
Right.
How should we think about the second scenario if that happens?
Well, I'd say, part of it, if we're told to continue, we won't know why. Remember, we'll be blinded to the data and what the DSMB saw. There's a couple of scenarios. In our mind, it's mainly a powering consideration. We just didn't have enough power to detect that benefit, because we wouldn't expect the benefit to actually improve significantly over the next, call it, 12 months between the interim and the end of the study. Allowing ourselves an extra year to get more events allows us to have significantly more power at a much lower level. We've said down to 15%, to detect a difference. If you were to look at it narrowly, let's say we narrowly missed and we had 0.011 for our P value.
Just by going a year longer, that would create a P value from enrolling more events that would now be 0.003. So a significant reduction in P value by just going a little bit longer, that allows for a successful outcome. Because ultimately, the outcome is the most important, the MACE benefit. As long as we're at 15% plus, we're going to be in very good shape from a commercial standpoint. I think the other point to be careful of too is we need to realize just because we're told to continue doesn't take a good number off the table. This has happened in many studies in the past, including SELECT, was the most recent one. SELECT allocated very decent alpha to their interim. They were told to continue.
Everyone said, "There's no way you could hit 20% MACE benefit now." When they got to the end of the study, what did they hit? 20%. So I think there's just sometimes you can get unlucky where a few more events could make all the difference, and I think that's what we've ultimately allowed us to do. Everything we've done, all these analysis, the multiple ways we've looked at it, everything that Michael's highlighted points us that we should have every possibility to have a successful interim. But if we're wrong, we have a very big buffer on how wrong we could be and still have a successful study at the end, because that's most important for us, is to have outcomes data available when we launch the product.
Got it. Yep. Then, logistically speaking, how long, I don't know if you can comment on this, how long does it take to perform the interim analysis, and what is the trigger to start that analysis? Again, any more granularity for the timing of the readout, which is
I think we have been pretty granular. As much as any company can be granular on these kind of things, but it is an event-based, so we will hit the number of events for the interim in the fourth quarter of this year, and then that should allow us to read out sometime in the first quarter of 2027. I think we want to make sure everyone understands, the first readout will just be the decision of the DSMB, whether it is to continue or stop the study. That is all we will know. We will still remain blinded at that point. At that point, if the DSMB says stop, that is when we formally close down the study. So it will take a few more weeks or months to actually get the top-line number of what our MACE benefit was.
We have guided that in the first quarter of next year, we will make the announcement of the DSMB recommendation because we are well aware if we do not make an announcement, we are going to get asked every single day, "Have you gotten it yet?
Right.
We will make that update, and then we have to have as much patience as everyone else because we are still blinded even when the DSMB tells us to stop.
Those are hugely helpful. Thank you.
Yeah.
Thank you for going over it here. Wanted to ask about a lot of the investors, given that oral PCSK9 just launched, this has come to the fore as a factor to consider in terms of how obicetrapib can be positioned in today's market. Could you share your thoughts on that?
Sure. I think as a clinician now, I take care of patients, there's other PCSK9 inhibitors. There's Repatha, Praluent, and now Leqvio. Great drugs to lower LDL. Obicetrapib is a small little pill, very well tolerated. No food effect, very easy to dose. Those are critical differences, and a pill that has to be taken fasting without any other pills. Man, these are people that are taking a lot of other pills. Even the older people that doesn't want to take a big pill or worry about swallowing a big pill, you think about just some logistics about what differentiates us. Those are the very superficial things. What it really comes down to is that patients are very selective on what they want to take for side effects, but also for other benefits.
LDL lowering is really important, as we know, but patients really want to take something that could also reduce the risk of diabetes, could also reduce the risk of Alzheimer's, lowers the small particles, and then, of course, the Lp(a). We'll know more about that with the HORIZON full readout. But it's still a very important risk factor no matter what. They're going to want something that can address that issue, even if it just means lowering LDL more. They'll want to choose a drug that, unlike a statin, will lower the Lp(a) instead of raise the Lp(a). We feel that those differentiating features really highlight there's only one CETP inhibitor, and that's obicetrapib. There's multiple other PCSK9s that all compete.
They will all be very effective LDL lowering drugs, some injectable, some formulation that has to be taken without food for 8 hours or not within 30 minutes of any other pill. I think obicetrapib becomes the go-to drug because it has the LDL lowering efficacy you need. It has the 50% lowering in combination with ezetimibe and it has those other attributes that make it, I think, the ideal option to add to the statin or instead of a statin. We believe that all our market research says that we will do very well in that very large growing market, and the market is growing robustly now, and it will get robustly growing even more with the new guidelines and aging of the population. We will see a lot more utilization needed for more LDL-lowering therapies. Remember, this is not a market share gain type scenario.
We are not limited by patient numbers in this market. Actually, the more products that enter the market, the bigger the market becomes, because we are all pushing for the same goal. The goal right now is awareness and getting patients to take a drug, any drug, because if we can get more patients on therapy, that will help everyone, and then you can choose what do you want. It is not going to be a choice of do I want obicetrapib or one of the five other PCSK9s. It is going to be do I want a CETP or a PCSK9? There is going to be a population who prefer a PCSK9, but as Michael said, there is going to be a clear population that prefers a CETP. We are fortunate. We are going to be the only CETP on market.
Physicians will most likely prescribe PCSK9s and CETP, but they are not going to prescribe five different ones. They will pick their favorite injectable, they will pick their favorite oral. The competition is within class. The competition is not outside class because we are so differentiated. We have clear areas that we will be the preferred go-to treatment. This works very well with payers as well. Payers will cover PCSK9s. They will cover CETP. They may cover one injectable, one oral PCSK9, but they will also cover the CETP. We are the only one available. I think the ability for us to offer choice is also a huge value driver for the overall product.
Got it. Very helpful. In the remainder of the time, I wanted to ask about the RUBIN study.
Yes
which has data coming soon.
Very soon. Yeah.
Very soon.
We will be finishing this year, very close to the end of the year. It is an important study because it is the diabetic patient population where obicetrapib has a very unique and special differentiation. It lowers LDL more in those patients. They have a very high burden of small particles, and so having a drug that can lower the small particles, lower LDL more effectively, also, we believe prevent worsening of diabetes over time. We will not have that from the RUBIN study per se. That will come from PREVAIL, the longer-term study. RUBIN will provide the lipid parameters that we can put in the label that we can enhance with our marketing efforts to clinicians.
I see. So that's the role this could fulfill in terms of how the-
Yeah. A labeling study for promotion about a special population like diabetics, which are the key high-risk patient population for heart disease.
Got it. Are there unmet need? I know statin probably could have caused some diabetes, but what about PCSK9 and-
Yeah, they also increase the risk slightly, too. Not as much as statins, but the risk is there in the labels for PCSK9s. Patients bring it up, actually. They bring up the risk of diabetes with PCSK9 inhibitors to me. They read the labels, and so can we have a drug that would prevent it, and we would have that information out there in the public domain in some way or another.
Got it. Yeah. Lastly, wanted to ask about the Alzheimer SPINOZA study.
Right.
Where are you with that?
We're getting started very soon. It's exciting study because it looks at APOE4 homozygotes, heterozygotes, and also E3, E3s that have high Alzheimer's risk as well due to elevated p-tau217. We know that p-tau217 is a very potent predictor of future Alzheimer's disease. It's a great biomarker for measuring benefit. We'll have that as our primary endpoint as well as other Alzheimer's biomarkers, which are now all coming together now as really enhancing how to make a diagnosis effectively, but also very strong predictors of progression of disease. We will have that as part of SPINOZA. We're also going to do cognitive testing, and the plan will be continue to build upon this data, and ultimately, we believe our hope is to have, not just the PREVAIL data, but also, ultimately, evidence that taking obicetrapib will prevent Alzheimer's disease. That is our aspiration.
Got it. That's a great note.
Okay
to end this session. Thank you.
Thank you.
Michael. Thank you, Matt.
Thanks, Yanan.
for a very enlightening session.
Yeah. Thank you. Thank you very much. Thank you.
Thanks. Great.
Bye now. Thank you.