Great. Thanks, everyone, for being here. My name is Yanan Zhu and I'm one of the biotech analysts here at Wells Fargo. It is our great privilege to have management teams of NewAmsterdam with us for this fireside chat. With me on the stage is Ian Somaiya, CFO for the company. Thank you, Ian, for being here.
Thank you, Yanan, for the invitation and for all of you for joining us this morning. I also wanted to thank you and your team for putting together a comprehensive initiation report. We obviously shared it with the entire team and everyone's very excited.
Wow. Thank you so much. It's great fun working on a story when we launched the coverage recently. Perhaps for people who are less familiar with the story, could you start off by providing an overview of the company and also highlighting the upcoming habits that investors should be focused on?
Sure. I'm happy to do that. The company was founded about five years ago with a singular goal, which was to redefine the treatment of hyperlipidemia. Through the dSPAC and the concurrent financings that ensued, we were able to not only start our LDL studies, and there are three in number, which we'll go into in more detail, where positive data was released last year, but we also took the unique step of starting our outcome study. That's a study that I know, based on your questions, we'll spend a lot more time on. It really puts us in a unique place today as we think about what the company's achieved in those five years. The LDL studies which were read out last year supported our European filing, which we announced a couple of weeks ago was accepted by the EMA.
Very excited that in the next 12 months we expect approval in Europe and shortly thereafter for our partner, Menarini, to launch into that market. The features of the drug, which will help us redefine the treatment of those patients, go really well beyond LDL. At the R&D day, I think what you started to hear from us is LDL+. There are characteristics of the drug that are unique to this mechanism, which include not only reduction of LDL at a level of a true high-efficacy drug, but also reduction of Lp(a) by somewhere between 40% and 50% in the patients which we believe are likely to use the drug most, which are in the 50- 150 nanomolar range. When you think about the class of drugs that are available to patients today, they uniformly decrease large LDL particles.
The risk these patients experience is on the residual risk that remains on the small particles. Based on the data we reported, where we saw virtual elimination of small particles, it does provide for a unique synergy on top of the existing class of drugs and more specifically statins. High doses of statins are associated with, especially the highest dose of statins, an increased risk of diabetes, upwards of 36%. What we've seen from the class, so not just unique to obicetrapib but other drugs in the class, is roughly a 15% reduction in the rate of new onset of diabetes. That's a characteristic which we think will be quite powerful and one that will resonate with clinicians, but more importantly with patients. There are others, and I'm sure we'll discuss those. The most recent finding was related to Alzheimer's, specifically APOE4.
In our data that was most recently presented at the Alzheimer's Conference, we saw a reduction in what is now a well-established biomarker for Alzheimer's disease, PTAS-217. Not just limited to PTAS-217, but a whole host of other biomarkers that are associated with, correlated with, impact on cognition.
Great. Yes. Thank you so much for that overview and the very important differentiations of obicetrapib from other LDL-lowering therapies. Given that your EU commercial partner has submitted a marketing authorization application, perhaps we can start from there.
Can you talk about what was included in the submission package in terms of data, what your expectations are for the label in terms of the magnitude of LDL-C lowering, and whether LDL lowering will be in the label?
Yeah. No. All good questions. The basis for the European regulatory submission for the monotherapy were the Broadway and Brooklyn studies. It's also important to remind everyone that there's a concurrent filing for the fixed-dose combination, which is supported by the Tandem results. The filings in aggregate were accepted by the EMA. As we think about now the label, the translation down to label, we would expect a 33%- 36% reduction in the label for the monotherapy and approximately a 49% reduction for the fixed-dose combination. Unlike the U.S. or the FDA label, EMA has allowed for a mentioning of Lp(a). Specifically with the Inclisiran, Inclisiran is a great example where you'll see a data table which will show LDL, non-HDL, and Lp(a) reductions that we're seeing with the drug. That's something similar to what we would expect in our label.
Got it. Would you be able to comment on the magnitude that you expect to be in the label for Lp(a)?
It depends on the patient population we look at. With that 50- 150, it's somewhere between that 45%- 50%, and the combo was a bit higher.
Great. Do we have a sense of the review timeline, and whether the EU Regulation might want to see the PREVAIL data before they issue approval?
Right. We would expect approval in the next 12 months, EMA. The outcome study is not a gating factor. It's really the role of the outcome study data in Europe to support pricing. As you know, in Europe, there is a classic sort of launch cycle. You launch in Germany, which serves as your reference country from a pricing perspective, and you negotiate that price over the ensuing 12 months. Within that 12-month period post-launch, we would expect the outcome study data to become available. That's to support whatever the pricing is that Menarini determines.
Got it. Got it. That pricing decision is your partner's decision. Are you going to have any input or any stake there? I'm asking because I'm thinking about the most favored nation policy and the implication of that.
Yeah. We have a highly collaborative working relationship with Menarini. Having said that, contractually, and this is true of any licensing deal that's done with a European party, the European party is the one that the marketer will be the one determining the price. The collaboration with Menarini entails a lot of market research, just really speaking to a global branding of the product. One thing that we should all keep in mind is we're not launching into a new market segment. Lipid-lowering therapies is well established. There's a price band that's already in place. The question that will get answered is where does Menarini price within that band, with the goal, and it's the same goal as the one in the U.S., we want to provide broad access. We want there to be as broad as possible access in Europe. As I said, the same goal in the U.S.
and recognizing that the prescriber base, primarily in Europe, is a primary care one.
Got it. Interesting you mentioned the pricing band. I think investors are very familiar with the U.S. pricing for PCSK9 stuff. For EU pricing, do you care to comment on that range of that band?
The difference in Europe is the price is the price, right? In the U.S., there's a gross price and net price and discounts provided to support, quote unquote, the other sort of interested parties in the mix. In Europe, the pricing does tend to be lower. The question is really how close is the net price in the U.S. to that price in Europe? That disparity is far less.
Right. OK. Very helpful because I wanted to touch on your economics. What is the peak EU sale relative to the U.S.? I think that pricing discussion is helpful. Can you also address the other points?
Yeah. The pricing is less, I wouldn't say important. I mean, that's really the wrong word. Let's frame it from a standpoint of economics. We collect a royalty on revenues, right? As we think about our focus, it's really going to be what can we do to drive the top line. It's less about the margin structure because that impacts Menarini more so. To Menarini's credit and capabilities, they're present not only in the big five countries in the EU, but they have broad reach. They are a top three player within the cardiovascular space. They have a presence within the primary care community and have had so with established relationships. In many ways, they are an ideal partner, even more so than the names maybe that you would think of, maybe that you have at the top of your list. I think that's one of the points I'd make.
I think beyond that, further from an economics perspective, is we have shared the royalty rate. We did that when we disclosed the acceptance of the European filing. The royalties start at low double digits and go all the way up to mid-20%. If you think about the timing of this deal being right around the Phase 2 trial around the company's dSPAC, it's a deal that was focused on downstream economics. With the realization and recognition that there's a lot of value that we can realize downstream and the opportunity would be quite large. One of your questions is how should we think about the opportunity U.S. and globally. We have spoken to the global opportunity being $8 billion+ . The split is always difficult to what the ultimate revenue split could be geographically. It's always difficult to predict.
If you look at precedents within the cardiovascular space, it could be 50/50 or 60/40 favoring the U.S. That's why we think there is, in essence, a disconnect between how the drug is perceived and the value that the territories outside the U.S. could provide versus how the company is valued today.
Got it. Suppose the PREVAIL data becomes available. In the EU, you discussed Germany's first year and then other markets. In general, if we think about the speed or the pace of the launch compared with the U.S., do you, for this kind of drug, expect a similar curve or a delayed or slower ramp?
It's slower simply because you're launching country- by- country, right? It takes time to get through the approval process in terms of pricing and so on and launch in each one of these countries. When you look at individual countries, Germany looks quite similar to the U.S., so it's a good proxy for what the launch in the U.S. could look like. Ultimately, it's a question on U.S. market dynamics, which are always very unique. A good proxy could be the relaunch of PCSK9s. When I say relaunch, I'm really referring to when the pricing of PCSK9s was reset, when pricing came down to a level where payers broadened access. If you look at that period of time, from the price being reset to the broad access to its sales trajectory, which continues to exist today, it was somewhere between 18- 24 months.
I would say give us the benefit of that time to not only get approval but get on formularies and establish similar access. Then we'll start to see the reflection of prescriptions into what should be sales.
Got it. Thanks for all that color. Let's pivot to U.S. filing strategies. It's a bit unusual that for a drug, the EU filing preceded U.S. filing.
Can you talk about the rationale and reason behind that and your U.S. filing strategy?
Yeah. I alluded to that a little bit in terms of the period of time it takes that Europe allows from a pricing standpoint. In the U.S., we want to launch with the broadest possible label. What we've always said is given the timing of the start of our outcome study, we do have an opportunity, a very unique opportunity in this category, to have outcomes data available at the time of launch. We've seen that sort of manifest itself in terms of the uptake of some of our competitors when outcomes data was in the public domain versus when it was included in the label. We've seen more recently action by the FDA to broaden labels for drugs that have outcomes data. More specifically, it's no longer our drugs being limited to patients who have established ASCVD.
Instead, what we've seen, and Repatha is an example of this very recently, the allowance of or the label claim to allow for use in any patient that has elevated LDL. This is a recognition by the FDA that payers were restricting access to drugs that would benefit patients based on label. That was one change that we've seen. The other change we've seen is a broadening of the MACE benefit. Historically, what the FDA has allowed is inclusion in your label specific subcomponents of MACE where statistical significance was reached. What we're now seeing is a label claim for MACE, whether it's a 3-point, 4-point MACE, and all of its subcomponents. As you think about commercializing obicetrapib and the fixed-dose combination in the U.S., there really hasn't been a better time from a regulatory perspective as well as from a payer perspective because now access is broad.
Roughly 95% of covered lives have access to a therapy, to branded therapies. The uptake and success is really defined by patient choice or physician choice and patient need. As you think about obicetrapib, the characteristics that go well beyond LDL reduction put us in a very unique position, one with great advantage.
Got it. Could you, is it possible to comment on the timing of U.S. filing and also the gating factor prior to that?
Yeah. Yeah. As I mentioned, we want to make sure that the outcomes data is available at the time of launch. We can be more precise when we meet with the FDA to determine what their level of comfort is or basically, you know, it's a really simple question. At what point during the PDUFA review period are they willing to look at or accept the outcomes data set? You can imagine it would be quite uncomfortable to engage with an FDA where we're submitting the outcomes data one month before the PDUFA. We have a very healthy relationship with the FDA. They've truly been advocates and have collaborated with us to the extent they're able to. Really, it's a timeline that's also dependent on when we think the PREVAIL outcome study will complete. As we're closer to that time point, we'll have greater certainty.
What I would say from an investor standpoint is we'll be able to provide an update at some point next year.
Got it. It's a good segue into talking about PREVAIL, essentially the gating factor for the U.S. filing. I think it's expected to be completed by year-end 2026. It's dependent on two things: minimum follow-up of 2.5 years for all the patients, participants, and also a target event rate. That's why you're saying you're not sure exactly when that completion will occur.
Right. What we have said is, and you're absolutely right about there's a 2.5 year minimum follow-up. That's one of the unique characteristics of the trial, and it's based on learnings from prior studies. Events take time to mature, and we wanted to make sure that we provided the drug an opportunity or time to provide that benefit. The 2.5 year minimum follow-up is the longest we've seen in any outcome study to date. The other factor that would dictate when we stop the study is getting to requisite events in terms of total events. The other aspect is we want to make sure that we have sufficient events, sufficient specific events, because we want to make sure that we're able to also provide a benefit on some of the subcomponents of MACE, such as MI and stroke.
To date, and this remains true as of now, the trial is on track. This trial is on track to complete because the total event rate is in line with our expectation. At the 2.5 year minimum follow-up, we would be able to complete the study.
The events being on track includes the specific events also on track, right, the components?
At this time point, yes.
OK. Got it. It will take some time for you to put the data together and present to the FDA.
How long is that data preparation time?
Yeah. I sense the enthusiasm and excitement in that question. Every employee in the company would line up to do whatever they could to help with the completion of that analysis. We have a wonderful team, a clinical team that's executed far better than many larger companies have in terms of the conduct of the outcome study and really the clinical program as a whole. It's nearly impossible for me to say how long it'll take them. The one thing I would say is they will forego, just knowing them well, any time off, any sleep to be able to complete the analysis as quickly as possible.
Got it. Great to hear. Can you also talk about the patient number for PREVAIL? It seems to be smaller compared with PCSK9 or e`ven prior CETP inhibitors.
What's the powering assumption that went into this whole calculation and gave you this number?
This is another unique aspect of our company. It's the benefit of obviously learnings from prior studies. The foresight and the knowledge that our scientific leaders really provide, specifically referring to Michael Davidson and our CEO and John Kastelein, our scientific founder and CSO, they've had a front-row seat into every single trial that's been conducted in this space. There are two ways that you can drive events, which obviously would allow you to stop a study. One is you run a large trial, which is what the PCSK9s did, to get to an event rate sooner. They had to because there was a foot race between the two drugs, Repatha and Praluent. The other is you run a longer study and allow for the events to mature over time. That also allows the drug to provide maximum benefit.
Based on those learnings, what we designed is a study with a longer minimum follow-up, which gets us to the requisite events in a different manner. The impact of the larger study to get to a quicker enrollment are ones we're all familiar with. It led to a MACE benefit of 15% with the injectable PCSK9 s, which is well below what would have been predicted by simply looking at the LDL reduction. Companies, to their credit, have also done analysis looking at excluding patients that were on treatment for less than nine months. What would the benefit be? That number goes higher, goes from 15% to 20%. It's all the learnings from the prior studies, which have been applied to allow us to report on a successful study. You've seen a semblance of that with the Broadway trial. The Broadway trial was designed to be a mini PREVAIL.
What we would have predicted from that study would have been a 9% MACE benefit based on LDL-C reduction alone. What we reported was a 21% MACE benefit at one year in that study. It's a question that's answered by looking at the other aspects of the drug's profile, specifically the Lp(a) reduction as well as the virtual elimination of small particles and as well as the impact it has on diabetes and HDL and so on. We're confident in reporting a successful outcome in PREVAIL. We've gone as far as to say that we believe that there's an opportunity to report results that are 20%+ , but also recognizing that the bar has already been set by the high-efficacy injectable PCSK9 s and the bar remains 15%.
Got it. You brought up the Broadway, which is only a one-year trial that showed a very impressive 21% MACE reduction, right? How do we think about that in relationship to the much longer trial of PREVAIL if you got to 21% with one year? Obviously, I don't know how we can extrapolate that to PREVAIL and if that expectation you want to set. Can you talk about that?
I think I touched on that with your last question. The Broadway data, in light of the design similarities as it relates to PREVAIL, gives us confidence that we can report on that 20%+ number when PREVAIL concludes.
OK. Got it. In the Broadway, in that 21% MACE benefit, a very large component was driven by revascularization.
Right.
Could you touch on that and talk about is that to be expected or a bit unusual? What's the implication for expectation for PREVAIL?
Yeah, no, that was highly expected. The revascularization is utilized to prevent ischemic events. If these patients weren't revascularized, what we would have seen was an MI or a stroke. That's true of Broadway, and that's true of the modern cardiovascular outcome studies. As we think about PREVAIL, we would expect half of the events to be revascularization and the other half to be components of the other events, whether it's stroke, MI, or cardiovascular death.
OK. Were the revascularization elective or urgent?
Yeah. I love the analogy that Michael brings up at times, which is no longer do we see patients going down a highway experience and are really carted off to a hospital to get an elective revascularization. In fact, we looked at every revascularization in the Broadway study and all these patients had revascularization to prevent an event. The quote unquote elective, because we're dealing with a strict sort of payer dynamic in the U.S. as well, no longer holds true.
Got it. Are you planning to publish the study design for PREVAIL and baseline characteristics at some time before the readout?
Yeah, we do. We do plan to publish a design paper. A lot of the details we've already shared with you in terms of the baseline characteristics, we've also confirmed and discussed at great length the decision as it relates to the MACE, the selection of the MACE endpoints. At this point, I don't know because I haven't seen the manuscript what other elements will be included in the design paper. True to our sort of relationship with the investment community, we've been as transparent as we can in every step of the way.
Great. Let's get into the meaty topic of competitive landscape.
Sure.
There are many therapies for LDL lowering out there. How do we think about the market positioning of obicetrapib and the OBI-EZE fixed-dose combination against PCSK9 antibodies and PCSK9 siRNAs and other existing therapies out there?
Yeah. If we specifically focus on LDL, because that's where we can make comparisons to other treatments, the question that a clinician is always trying to answer is can I put this patient on a therapy that's going to get them to whatever their risk-based goal is? OK. That's simply a number, right? What % reduction can this treatment provide? When you look at our two product forms, whether it's obicetrapib or the fixed-dose combination with ezetimibe, what we have reported in our Phase 3 clinical trial settings is getting the vast majority of those patients to goal. It's really that easy of a decision or a simplification of that sort of treatment choice when you look at LDL alone. The question is what other risk factors is this patient susceptible to? Cardiometabolic disease, just by definition, is multifactorial.
If a patient is pre-diabetic or at risk of diabetes or has diabetes and as a result is averse to going on to higher doses of statin, OBI would make a lot of sense because we not only offset the increased risk of diabetes that's present with higher doses of statin, we actually reduce it further. When we think about patients that have also higher rates of or high levels of Lp(a), our therapy has shown quite consistently a 40%- 50% reduction in Lp(a). That's more than 2x the level that's been shown with PCSK9 inhibitors in this patient population. The particle is a truly unique characteristic of our drug. Statins predominantly reduce large LDL particles. When you go to a cardiologist and they run a lipid panel, they run it at a baseline and they'll run it approximately a year later to determine what the residual risk is.
Right now, there's not a very good option for these patients in terms of reducing that residual risk. OBI does that quite beautifully. As you think about that aspect, the newest is APOE4. 25% of ACV patients are APOE4 carriers. If you look at the data we presented at the Alzheimer's Conference, now specifically looking at the APOE4, whether it's homozygous or heterozygous, we saw the greatest benefit in that patient population. As we continue to evaluate the Alzheimer's and the role OBI could have, that's another segment, another aspect of the drug's profile that could resonate with patients with cardiovascular disease because there's a high degree of overlap.
Great. Those are all great differentiations and potential advantages. I wanted to ask a quick follow-up to the large particle, small particle thing because that's so unique to obicetrapib. How well accepted is the idea that the small particles are the bad ones, and if you can get rid of them, that will have outsized benefit? Is that a widely known fact by cardiologists, or is that like a fringe or cutting edge kind of idea that needs education?
Oftentimes in sort of disease states, when you're talking about treatments, you need to have a treatment to elucidate an aspect of a drug or aspect of sort of what's missing from a treatment standpoint. That's something we'll obviously need to work on, but it's one that's easy to highlight because we have clinical data supporting it.
Got it. Let's also touch on oral PCSK9.
Yeah.
How do you see data from Merck and AstraZeneca so far, and any caveats we need to think about when we look at the data?
Merck and AstraZeneca's pursuit of an oral PCSK9, I think at a minimum, supports our own strategy and belief that an oral agent, a high-efficacy oral, could do quite well in this marketplace. That's first and foremost. Both companies have alluded to a $5 billion+ opportunity for each of their drugs. We've done market research testing their profile, and we believe that the PCSK9s as a category, which have been growing 30%/ 40%+ , will continue. The oral drugs will also do well. There's not a zero-sum game here. We think the PCSK9 category as a whole will grow. What our market research also supports is it will do better. We've obviously shared with you our expectations for what commercial success looks like.
As you think now more specifically about the individual drug profiles, the orals offer the convenience of a once-a-day delivery and obviously the convenience of an oral administration. Every other aspect of the profile is the same. It's a focus once again on LDL and without any of the additional benefits that obicetrapib will provide to these patients. As you think about it from a payer dynamic, it's maybe a little bit more complicated because payers and formularies will need to make a decision on which PCSK9s they want to incorporate and how they want to tier those. Every formulary will have a CETP. We're the only CETP that's going to be available. Ultimately, if we're successful in garnering broad access, we go back to treatment choice.
The treatment choice is based on not only LDL reduction, but every other aspect of the drug and every other aspect of risk an individual patient experiences.
Great. Thanks for sharing all those perspectives. Lastly, I wanted to touch on IP.
Sure.
Because CETP inhibitor has been around for a while.
Yeah.
What's your confidence in IP position?
Yeah. We had a new composition of matter patent issue the middle of last year. We have a composition of matter in the U.S. till 2043. It's the same patent we'll be prosecuting globally. We also have a selection patent that's been heavily vetted by many law firms. That takes the IP out to 2038, 2039. We're quite confident in the IP estate we have today.
Great. It seems like we have run out of time. I wanted to thank you for all the insights that you have shared with us. Thanks for your time too.
Thank you, Yanan. This was great.
Great.
Thank you all for being here.
Thanks, everyone.