Welcome everyone. We will get going on the next session. I am Steve Seedhouse with the Cantor Biotech team, and it really is a privilege for me to welcome our next participating company at our global healthcare conference. This is NewAmsterdam Pharma, and I am joined on stage, of course, by CFO Ian Somaiya. Ian, thanks so much for being here. Exciting time for the company and the field, and looking forward to the conversation, of course.
Always. I am sure you say that about all the companies that you host.
But especially about this one. As a sell-side analyst that learned from you in your time on the sell side, Ian, I can appreciate these moments in my career coming full circle and sitting on the stage with you here. It really is a pleasure. Maybe just given some of the recent developments in the field and the value proposition for obicetrapib as well, you have articulated, including at your recent Analyst Day. Just how are you feeling about the competitive positioning and strategic positioning of the company and of obi as you approach really a key data readout towards the end of the year?
Yeah. No, we continue to feel really good about it. It is rare to have a drug that does so much, right? As we think about the benefits of obicetrapib and what we have been able to generate from a data standpoint, what we have learned, the starting point is obviously LDL. We are able to reduce LDL by 35% to 40% with the monotherapy, and the benefit reaches above 50% with the fixed-dose combination. Importantly, what does that mean? It gets patients to goal, and that is really what matters to patients. To have it in a product form, in a drug that you can take once a day as a pill, with a very manageable safety profile, in a patient population that has many things that they are dealing with, there are many treatments that they are on; convenience matters, safety matters.
Safety matters to the prescriber base when we think about clinicians, vast majority of whom are primary care physicians. To simplify their practice and their experience while knowing that their patient's LDL will get to goal, and then also acknowledging that these patients have other comorbidities. The data that we generated through BROADWAY and through BROOKLYN clearly indicated that we are able to reduce the rate of nuance of diabetes. We are able to improve kidney function. We are obviously able to reduce Lp(a) by a meaningful amount and also virtually eliminate small LDL particles, which represent residual risk in patients with elevated LDL. There is a lot to obicetrapib that we have shared. As a result, from a positioning standpoint, first and foremost, as we think about the branded therapies that are out there today and ones in development, we are the only CETP inhibitor.
As the comparison to other drugs and the comparisons amongst those other drugs is really limited to LDL.
Revisiting the recent Analyst Day and just sort of circling back on some of the key focus areas of that, because they are obviously important for understanding the value proposition, but really handicapping, I guess, probability of success and various scenarios of the interim analysis of the ongoing CVOT PREVAIL that we will get first quarter of next year, the results of, and that will be completed towards the end of this year. One of the details that you have spoken to a lot as a company is the blinded analysis that you conducted through year one. We have seen that data in the investment community through year two at that fixed time point, which we have not seen, but which you have spoken qualitatively to, and I might ask you to do that again.
Yeah.
What is it you are seeing? Do you continue to sort of follow this blinded data, and really, how are you interpreting it, and what is it telling you about?
Yeah.
obicetrapib ?
We've shared quite a bit with you. The importance of the one-year data really couldn't be overstated because we had a very unique vantage point. This was the foresight that Michael and John had when setting up the company and designing the overall clinical program for obicetrapib, which was to design BROADWAY to be a mini PREVAIL, to be our sort of mini outcome study. Having the BROADWAY data and the 21% MACE reduction that we reported, now almost two years ago, was a good proxy, a good lens through a look at the PREVAIL dataset and what we were observing on a blinded basis. That's something we shared. When you look at the blinded PREVAIL data and superimpose it on the re-blinded BROADWAY data, those two lines are right on top of each other.
It's not only that the overall MACE for event rates are tracking on top of each other for those two trials, it's also the individual events were tracking in line with what we saw in BROADWAY. As we take that dataset and then move to year two, the observation that we shared with the investment community is those rates have continued to decline. There is a general expectation for decay in CV outcome studies, so year two rates are lower than year one, and subsequent years follows that trend. What we have seen is an event rate that's lower than what we would have expected and also lower than what we have seen with other contemporary studies. It's an encouraging sign, but we all know the value of analyzing blinded data, that the proof in the pudding is always when you unblind these results.
Fortunately, the wait is not that long now, and we're excited about next year.
I think one of the factors that you've, I think, had to answer a lot of questions about that could be confounding that type of analysis is this sort of drop-in back-evolving therapeutic landscape with GLPs in particular. There's a larger conversation to be had about some contemporary studies and whether there's blame to be assigned to GLP drop-ins or whether that's unwarranted. I know you have some thoughts about PREVAIL, in particular, and what's even plausible in terms
Yeah.
Wf the impact of something like that, and you've shared some of that with us, but maybe you could expand on
Sure
Whether there could be any impact from
Yeah.
Something like that.
I think a good study to look at is the Amgen, what is akin to a primary prevention study with their PCSK9 Repatha, and this is the VESALIUS-CV trial. That's a contemporary study, conducted at the same time as some of the ones that you're referencing, and I'm sure you're referencing, at a minimum, the HORIZON trial.
Thinking of ZEUS and HORIZON.
Yeah, exactly. Those two studies. We've definitely seen studies not targeting LDL suggest that the background therapy has evolved to a point of impacting overall event rates and the outcome of those studies. We didn't find that to be true for Amgen's VESALIUS-CV study. Their event rate in the placebo arm was right around 4%, which would've been expected, if not a little bit higher than what would've been expected given the patient population there. And that compares to about 5% that we saw in BROADWAY. When you look at all these studies, our BROADWAY trial, our PREVAIL study, ZEUS, as well as HORIZON, these are studies started and being conducted at the very same time.
Have we really seen an evolution of the treatment paradigm, or are we continuing to see the trend that we've seen historically, which is if you target LDL, it does translate to an outcomes benefit; other drugs, we're still learning. We haven't seen the data from ZEUS; we haven't seen the data from HORIZON. Let's wait for the presentations of those trial data sets before we reach any major conclusions.
On your study, PREVAIL, can we walk through what you are comfortable saying about and just reiterating about the statistical analysis plan for the interim analysis? I think it has been a challenge. I think everyone is sort of on the same page now, but it has been a challenge sort of getting to the same page of what are the p values required, what four-point MACE and three-point MACE definitions are being used.
Yeah.
What is the threshold of efficacy that you need for success? Maybe you can just lay that out and articulate it for us.
Yeah.
What can happen in this interim analysis?
Yeah, no, absolutely. I think that the starting point is we have done everything we could from a design standpoint to enable PREVAIL to succeed. The one additional step we took was changing the definition of four-point MACE, and it was a slight modification from urgent revasc to total revasc. The reality is, in the world that we live in today, the elective revasc is no longer true, right? That is an analysis of data we did in our own study in terms of the BROADWAY data set, and that gave us confidence to make the adjustment in PREVAIL. This definition is pretty much in line with what Amgen used with their VESALIUS-CV study. So really, again, no different there. The benefit of that is it increased the number of events available to us and allowed us to introduce an interim analysis.
As you think about the information we've shared, previously the study was designed to show a 20% benefit with 950 events. Now we have a study that's powered for that 20% benefit, but obviously with many more events. What was said is we're expecting about 20% more events as a result of the change or modification in the definition of four-point MACE. That's why in combination with the blinded observations and the additional powering now, we feel confident moving into the interim analysis next year. On top of that, we've also discussed, obviously, the p-values, and that being 0.01 for the primary endpoint. That's based on the FDA's expectations. They want us to demonstrate overwhelming efficacy because the approval is based on a single study, right? The outcome is a single trial.
There's just a higher bar that's set for single trial approvals, and although the FDA never gives or hasn't provided concrete guidance on what the p-value needs to be, what we've seen the industry adopt and what we have done as well as sort of an internal bar is that 0.01. So you have a sense for the p-value that we want to see to stop the study at the interim for the four-point MACE endpoint. As for sort of the final analysis would be the same, it would be the same, 0.01, but with far greater events. Just remember to differentiate between what the study's powered for versus what would allow us to hit stat sig at the interim analysis.
What we've said is, if we show a BROADWAY-like result, so MACE benefit, that's about 20% or even slightly lower, we can hit stat sig. The opportunity is with those higher numbers of events that we can get to a lower MACE value and still hit stat sig at the interim, but even more so at the final analysis. So there's just really a lot of information that you have. Again, putting on my old sell-side hat, I found it rare for companies to be as transparent as we have been, but that's a relationship and a disclosure policy that we've always had and something we want to maintain.
That's the identity of the company, and it really begins with how Michael and John want to interact with the community as a large, and that comes from a clinician mindset, from a care mindset, but obviously, we need to behold ourselves beholden to public company disclosures as well. So we find a balance.
Yeah. Speaking of that transparency, it is fascinating because I want to ask about the mechanism of obicetrapib and how you are thinking about it now. Going back to your Analyst Day, Dr. Kastelein mentioned some of the literature on HDL, and he was talking about some confounding factors, I think, of alcoholism and how that can cause some of the epidemiologic data to be misinterpreted potentially. But also you mentioned a publication coming out showing that, actually, HDL increase in patients with elevated ApoB; maybe in that context, it actually is beneficial.
Whereas isolating HDL in some other populations, you might not see an effect. I think now we might, maybe with IL-6 and maybe with Lp(a), it could be a similar story. When you isolate those variables in the setting where LDL is 50 or 60, you do not see something. But with obicetrapib, as you guys have hypothesized, when you have a patient where basically everything is not adequately controlled and LDL is reduced and Lp(a) is reduced, and HDL is increased, do you still have high conviction that it is that combinatorial LDL plus profile that is driving a 21% MACE benefit in BROADWAY that is driving what we might
Yeah.
Hope to see in PREVAIL and, ultimately, maybe why anacetrapib, despite being less potent, worked as well
Right
Statistically on MACE?
Yeah, look, let's start there. We're not the first CETP inhibitor that's been tried in clinical trials. Obviously, there was a history of failures, and it was based on a failed hypothesis, which tested would raising HDL confer an outcomes benefit? The answer seemed to be no, based on the initial study readouts. But when you look at Merck and their study anacetrapib, which powered for also LDL, what we saw was a clear MACE benefit that hit stat sig, but the reported benefit was far greater than what would've been predicted with LDL alone. The idea of the LDL plus is true for the mechanism.
Where obicetrapib comes in is with a drug that's far more potent against the target, so 97%, 98% inhibition at a 10-milligram dose, and that has led to results in terms of LDL reduction, which is twice as great from an LDL lowering standpoint, as well as the other benefits that we've described in the past. So, there is more to the drug and the mechanism than LDL. It made sense for us to focus on HDL because some of the benefits we're observing, such as the benefit in terms of the diabetes, the reduction onto diabetes, was also observed with a CETP, dalcetrapib, which had an HDL-raising benefit but which had no LDL effect. So clearly it's something else, and we think that something else is HDL. So we already had some inclination of the benefits we could've expected in our studies.
But surprised again to see those at a one-year time point in BROADWAY. Obviously, we expect to confirm those in PREVAIL, which is a four-year study, at a minimum. So, it's that; it's the kidney function improvement that we saw quite clearly in BROADWAY. On top of that, and very excitedly, is the potential benefit and the role that the obicetrapib could have in Alzheimer's. You mentioned a publication. It's the first of many that's going to be focused on HDL, and we want to make sure that captures the benefit that we're observing but also provides a rationale for that expectation.
I'll come back to Alzheimer's, because I do want to ask about that. But first, maybe more near term.
Yeah.
We would be expecting to see some developments of obicetrapib's commercialization in Europe via your partner, Menarini. Can you maybe just update us on what to expect in the coming months or near term and
Yeah.
The implications it would have for ultimately your commercial launch in the U.S.?
Yeah. First and foremost, we received a recommendation by the CHMP for approval in Europe. That should be followed imminently by a formal approval by the EMA, which would then allow Menarini to start launching the drug on a country-by-country basis. What you typically see is Germany and U.K. are the first two, then you move through the other countries, including the EU5. That's the cadence and the schedule that we expect from Menarini. There's not a lot that we can say because contractually, Menarini has really pricing decision authority, and it's up to them to set the price in Europe. I would also say that there's a clear price dynamic that exists in Europe today, and as we've set it as our goal in the U.S., the last thing we want to do is be disruptive in that regard.
Whatever the pricing environment is, we'll continue to participate. Menarini has every right to set a price in Europe. But the impact we expect to have in the U.S. based on our observations of what we've seen as an impact through MFN, through the agreements that have been signed by now, well over a dozen, if not close to two dozen, companies, is quite limited.
Can you talk about, and this gets back to something you said earlier. You called obicetrapib safety profile manageable, but I think you're underselling. It's pretty pristine and would make it amenable to combination therapies if you decided to go that route. And there are some maybe obvious candidates that you might think of doing in cardiometabolic disease, whether it's oral PCSK9s, if in fact that side of the equation is amenable to a combo or a GLP. Can you just talk about whether that's something that's of interest to NewAmsterdam Pharma, any work that you've done to sort of set the stage for that, and if at some point strategically it makes sense to c ollaborate and do something like this?
Yeah. Today we're obviously very focused on completing the clinical program for obicetrapib and obicetrapib plus ezetimibe, and there are three studies that are outstanding. One we discussed, PREVAIL. The other two are RUBENS, where both product forms are being evaluated. And then there is what we describe as the outcome study for the fixed dose combination, which is REMBRANDT, and it's an imaging study. And there's really nothing more powerful than an image. And in that case is a CT angiogram of a patient to be able to visualize their plaque burden being reduced. It's really akin to in a cancer patient seeing tumor regression. So it's a powerful message. We hope to be able to deliver it, and there is synergy with those two drugs, and clear preclinical rationale for evaluating that combination. So we're excited about that result as well.
And that result—that's data that we could potentially have in hand by the end of next year as well. So there's a lot of data from that standpoint. Just to address the question you've asked, obicetrapib is an ideal drug to combine with. It's a very simple manufacturing process, obviously a very low dose. Strategically, it does make sense to combine it, and the combination with ezetimibe was the first. You should fully expect us to continue to evaluate additional combinations, both generic and branded, whether we do it on our own through a partnership. I mean, that's obviously something we'll determine and share with you in the future. Much of the enabling work has already been done, so we know it's possible. The question is, what is the approach we want to take to developing those combinations?
There is also a well-established regulatory path for approval of combinations, whether it is through PK studies or a study that resembles what we did with TANDEM, which is a study where we evaluated or compared the combination product to its components.
Speaking of oral PCSK9s, I am curious, as we look to the launch of those products and things like pricing and pace of launch, is there any read that you will take from those launches onto how to navigate obicetrapib's launch into effectively the same or similar overlapping market?
Yeah. There is obviously a lot to learn, and we are very excited about Merck launching because it is yet another voice in the market that is advocating for treatment of patients and controlling their LDL, which represents a significant risk. This is really something that we are excited about. We want to see additional sponsors, marketers in this space because the message is the same. LDL is a controllable risk factor, but the only way to control it is through combination therapy and the combinations with more potent agents. The other thing we can learn from Merck's launch is the unique approach that they have taken to pricing, right? Their list price is obviously lower. We are not aware of what their net price is, but this is a way for them to really test a different type of conversation or negotiation with payers.
We will look to see how payers, or how are payers, receptive to this new sort of calculus? What does payer access look like? Then ultimately, that will help inform, in part, what we do ourselves from a pricing and discounting standpoint.
Speaking of commercial, as you, as CFO, as you think about budgeting the company for 2027 and preparing for a launch
Yep.
It is an interesting notwithstanding, getting yourself and your team nice new briefcases and all of that, Ian. There would be a lot of considerations on how to invest in a sales force and building out this commercial organization.
Yep.
Especially because if the interim hits, that is one timeline on filing and approval.
Yeah.
If the study continues to completion, that is sort of another. So how have you sort of planned for and continued prepping the build-out of the sales organization, and how should we expect that to proceed in 2027?
Yeah. First, just say that we do have a welcome kit for new employees that does not include a briefcase. It is quite nice. It includes a NewAmsterdam Pharma water bottle. There is a nice bag that, I mean, I use for groceries. You can use for anything. It is very economic or environmentally, I would say friendly. That is kind of where we stop, right?
It is very responsible.
Yeah, exactly. That is part of the identity of the company. You have to remember how the company was started, right? This is a company or a management team that had an asset that was initially licensed or sold; the drug was sold to Amgen. We reacquired it. Cash was not readily available. Really, it was the benefit of having anacetrapib and the confidence it gave our investors and our initial supporters that allowed this company to form, and we have maximized every EUR that we could spend. That is the sort of the fabric and the identity of the company, which is do more with the resources we have. So we do not look at our balance sheet and say, "Oh my God, we got a ton of money.
Let us just start spending it." The question you are asking is an important one because this is a topic that we are actively discussing as a management team, which is , 'How do we prepare for our launch?" Who do we need on board, and when do we need them? The conversation is really narrowly now focused on, not narrowly, but a large part focused on enabling functions. Because it is just not the commercial team that launches a drug, it is the company that launches a drug. So we need finance teams. So my team. We need legal, we need HR, we need IT, we need all of those to deliver a support system, a process that the commercial team can fully leverage to focus on what they do best.
From a commercial team standpoint, there's been a plan in place from when I joined, so over close to three years ago now, and we continue to refine it. What we have initially done, and I think very thoughtfully, is bring in the right people and the right set of experiences in-house. What that allows us to do is make the right decisions. As we look at the future, it's continuing to build onto that and set ourselves at the right time to build out the larger commercial organization, which really just means sales reps. Sales reps are hired when you're staring at a commercial launch. We think we have the right team in place, and we'll continue to add to it, but it's sort of onesies and twosies, not something massive from an organizational growth standpoint.
As a result, you shouldn't expect a significant increase in spending for the company. It's also coming at a time when R&D will decline. I mentioned RUBENS, I mentioned REMBRANDT, and PREVAIL. All those studies wrap up as you get to 2027. The company as a whole shifts from an R&D organization to a commercial organization.
Great. Just in the last couple of minutes, and before you completely close shop on R&D, obviously the one thing that could be onboarded as the CVOT and the REMBRANDT study and everything come winding down could be Alzheimer's potentially. That's a trial that you've indicated in SPINOZA, the name of the trial you are interested in running. Maybe you can talk a little bit about your current thinking and sort of clinical strategy in Alzheimer's disease, and I guess also when that study would start to—
Sure
Manifest.
Yeah. No, absolutely. We're clearly excited about the BROADWAY Alzheimer's substudy. We saw benefit across a whole host of markers, across half a dozen markers, and it's rare to see that because we saw benefit in markers where we haven't seen any improvement with the other modalities and other targets that have been pursued. Including, and probably most notably, NfL, neurofilament light. It's that data, and now having a biomarker that the field is rapidly adopting, p-tau217, and where that biomarker has been correlated with cognition benefit, and that's data that the A-beta antibody programs have generated. There's just a lot of movement in the direction that we would hope coming at the right time. We're leveraging all that to initiate, as Steve mentioned, a phase II-B study called SPINOZA.
This will be in patients that are preclinical, so preclinical symptoms, but who have genetic markers and p-tau levels that are indicative of Alzheimer's in the future. So at-risk patients. We're going to measure, once again, these various biomarkers, and we're also going to measure cognition. We'll do it over time. I think we're getting very close to be able to announcing the study start. Once we do that, we can obviously share more details, but it's that trial and the data we'll generate, along with the Alzheimer's substudy in PREVAIL. So now think about the BROADWAY population, where we had 25%, 30% of patients that were APOE4 carriers, so at risk for Alzheimer's. With the study that's now four times longer and four times larger in size.
We'll do the same type of analysis, and hopefully, we see results that are similar, if not potentially even better with the longer-term treatment. Those two will inform the investments in future studies.
Appreciate that, and thanks also for the broad spanning conversation of course, across the clinical and the commercial and the future work in Alzheimer's. Ian, I appreciate you and NewAmsterdam being here at our conference and looking forward to continued progress and, of course, the really important update that we're expecting in the first quarter of next year on PREVAIL.
Yep. Thank you, Steve, and thank you everyone for joining today.
Thanks, man.
It's good to see you.
You too, man.
Yeah.
Pleasure.