Okay, great. Good afternoon, everyone, and welcome to the next session of the Canada Global Health Care Conference. I'm Steve Siedows, and the biotech team. Really, my pleasure to welcome our next participating company for a fireside chat. I'm joined on stage by NewAmsterdam Pharma, specifically CEO Michael Davidson and CFO Ian Somaiya. Thanks so much for being at the conference and for joining for this conversation. As I've been doing typically, I would love to just pass you the mic initially to make some opening comments. Just current state of affairs at NewAmsterdam, really exciting time for the company. You have a great asset in phase 3. Set the stage for us as we head into the back half of the year.
Sure. Thanks, Steve. Great to be here. We just filed in Europe for regulatory approval for obicetrapib, so very excited about that. It's a culmination of starting the company five years ago now and getting our Phase 3 trials, three very important Phase 3 trials, BROADWAY, BROOKLYN, TANDEM, all part of this filing. This excellent kind of safety oral therapy for lowering LDL. We've been publishing our data this year in the New England Journal of Medicine, Lancet, and now another high-profile journal also published. What's exciting about the drug is that it's a very tiny little baby aspirin-sized pill, 10 milligrams, alone or in combination with ezetimibe, Zetia, lowers LDL 35 to 50%. In all my experience of doing clinical research, which is more than 30 years, I've never seen a drug this well tolerated. Very well tolerated profile of safety comparable to placebo.
What I think is the most exciting from a clinical perspective is that we've proven with all these multiple trials that it has an LDL plus benefit. It lowers Lp(a), another exciting high-risk target, very significantly, 40 to 50% in the target population. It lowers the risk of diabetes, which is a critical thing, especially on statins, which statins increase the risk of diabetes. Statins also increase Lp(a). It lowers the small LDL particles, which are the ones that most likely clog up the arteries, by 90%. Now we have this new benefit on reducing pTau-217, a very important biomarker of M1 in the brain, significantly. It's enabled for patients in particular. The LDL story is the basis of our great therapeutic unmet need addresser, which is growing dramatically in the last several years, but also the LDL plus benefits.
I think what makes this drug very exciting for the medical community is another way to address not just heart disease, but more comprehensively than just LDL lowering.
Congratulations, by the way, on the recent MA validation in Europe. Maybe you can expand on that. Just talk about the overall strategy of coinciding the global regulatory approvals for LDL reduction ultimately with PREVAIL MACE data, which will really drive the point home, I think, with prescribers and patients, and maybe lay out the path for the regulatory strategy over the next year.
I'm very proud of the company. We're five years old and we've laid out from the beginning a global regulatory plan that harmonized all the different geographies and their requirements for regulatory approval. That required a lot of thinking about how do we develop a program that addresses not just the U.S. and Europe, but also China and Japan. What we set out to do was we wanted to make sure that we, in our Phase 3 program, were able to include all these geographies in the same Phase 3 program. Also, the outcome study we knew was critical in the U.S. for approval, but also for wide commercial adoption. We started the outcome study at the same time as the Phase 3 trials.
We were very fortunate that we were able to raise the money along the way to get all these studies done, which is a great achievement as a relatively small company now on the NASDAQ. What we knew is that each regulatory body had a little bit of a different view on how to go about LDL approval. Europe from the beginning has a very consistent basic policy that LDL is a proven surrogate. You don't need outcomes for approval. You just have to show safety, cardiovascular safety. That one we knew was going to be our first target submission. China and Japan follow Europe pretty closely. We have enabled those filings as well, and that'll come in time. The U.S., because of the payer requirements and acceptance, because of the history of the class, we knew the outcome data was going to be important. We're going Europe first.
In the U.S., we plan to file when we know that the outcome study PREVAIL will read out during the PDUFA period with enough time for the FDA to review that information prior to approval. That's how we're thinking about the overall global regulatory strategy.
Can you expand on China and Japan a little bit? Just what's the overall sort of scope of those markets?
Yeah, they're big markets. You know, Japan is number three revenue-wise. China is, as you know, a very growing market where you see a drug like obicetrapib would be extremely well received. We've already gotten that feedback from our KOLs community in China because they have a high rate of diabetes, metabolic syndrome. They like low doses, they like pills. They also don't like statins, they don't like the high-dose statins, they like low-dose statins. We feel that obicetrapib could have a tremendous opportunity in China. Japan's similar in that they like low doses, they like to keep the doses down. They don't like high doses of drugs, especially for, they believe their population is more susceptible to different high-dose statins in particular. The diabetes risk that statins have is something that is well known to the Chinese and the Japanese KOLs.
We see obicetrapib having a tremendous opportunity in those Asian markets.
Yeah, I think you asked the right question from a regulatory perspective. It highlights the benefit of foresight and the knowledge that Michael and John provide in the company, which has guided the trial designs and the data we saw last year. As you think about the future, one of the trials we're very excited about is the RUBIN study because it addresses a lot of the patient needs in the U.S. We're talking about patients with metabolic disease, and these are the patients that did the best in our completed LDL trials. Here's an opportunity to run a dedicated trial in this patient population to really exemplify what the magnitude of the benefit could be in what is a 50+ million patient category in the U.S. alone.
You can imagine, based on Michael's comments, the preference for low dose but high efficacy, safe molecules, and the prevalence of metabolic disease in those territories. This is yet another opportunity that is unique to us.
Can you talk about the timeline on RUBIN and just how that folds into the whole strategy of?
Yeah. We are, I mean, obviously doing our best to get the trial off the ground. The plan is to start the study this year, which would mean patient enrollment starting this year, and data would be available by the end of next year.
Yeah. Okay.
Prior to launch, we want to make sure the data is in the public domain.
Got it. I have to ask every time I speak with you, just simple questions. PREVAIL, I mean, how is the trial execution going? How are events accruing? Any surprises or changes to highlight?
No, everything's going really well. I mean, we could not be happier with our performance metrics. We keep a close eye on drop-in, drop-outs, people off drug, loss to follow-ups. All that stuff is really, really going well. What has helped a lot is the BROADWAY data itself, you know, showing the very excellent safety and tolerability that we saw in that trial can help us now go out and talk to the investigators and say, here's a New England Journal paper with obicetrapib, you know, showing side effects no different from placebo. If you had a patient who had a headache and stopped the drug because of the headache, keep in mind that the headache rates were identical or lower than they were on placebo. Let's go back on the drug, get the patient back on the drug.
That type of data is very helpful in these big long-term studies to get people to realize that this is, you know, whatever the patients are complaining about, you can try to convince them to stay on with that type of information as their ammunition to stay in the trial. That's where we're putting a major effort into going out across all the world. We've hired expert people that understand trials and trial kind of execution at the site level to be very much our advocates out there to get people keeping the study and maintaining the compliance as at all best possible. It's paying off. We're seeing the drop-in, drop-out rate basically flat line, people off drug kind of flat line. We're seeing a real high-quality metric study going forward.
As far as events go, I mean, we were very conservative on the event rate going in because it's always been a challenge as time progresses, predicting these events very well. We had some good trials to use as benchmarks, FOURIER with Repatha and REVEAL with anacetrapib. We kind of picked the lower end of the event rate to be careful. We're tracking, you know, that event rate well. We feel good about that 20% reduction of events hitting that amount of events that we're seeing in our trial. We feel really good. We're going to hit that two and a half year minimum follow-up in October of next year. That's when, assuming the events are, the number of events are where we want them to be, that's when we can start to wind down the trial.
Great. One of the other preparations for launch, I think that you've mentioned and of course would be entailed, is just build out of inventory. Are you comfortable with where models are at and just budgeting for that?
I'm not going to take the bait. I'm not going to take the bait. I'm not going to comment on where models are. We have a very good handle on our inventory, and we're not only going to be supplying ourselves in the U.S., but we're supplying Menarini in support of the European launch. I think we feel good about the manufacturing side.
Great. The VINCENT trial, now this was data that was coming later this year, but there's been some changes adding a cohort to that study. Can you cover that, the reasons for that, and ultimately like how meaningful that data is going to be, what the purpose of it is?
We already have great data on PCSK9. We have over 100 patients on PCSK9 inhibitors in BROADWAY, and the data looks as good, if not better, than people not on PCSK9. It's on LDL lowering and Lp(a) lowering. We felt that with that type of data at hand, the VINCENT, we could expand that track. We learned that the highest end Lp(a) is where the injectables are going to go. That's where the new drugs are. We wanted to focus on a much larger population, which are those that have moderate Lp(a), the 50 to 150. We've added that cohort to our VINCENT trial. The whole objective really was to anticipate that if you have oral PCSK9 inhibitors available by major pharma companies, could obicetrapib be a very good companion drug with that oral.
We're planning, that's really a proof of concept study to see what the additivity of the two drugs would be.
That just speaks to the overarching strategy that you should see us execute, which is combinations. We already have one combination with ezetimibe. There's an opportunity to look at the landscape of other modalities, other targets, and an acknowledgment and maybe a realization on our part. We are the only CETP inhibitor. As you look at oral PCSK9s or Lp(a) agents or GLP-1s, they're increasingly a commodity.
It is a differentiator for those sponsors if they had obicetrapib, whereas there is.
is an opportunity for us to pursue development of those types of drugs as well.
Oh, yeah.
Yeah, we think combo drugs is becoming more and more adopted in clinical care because the pill burden is already large. If we can keep that down, that are drugs that are synergistic with each other, that would be a real good place for us to be. What's great about obicetrapib, it's a very easy drug to co-develop with. It's very easy to combine with other drugs. We see that's a kind of value that we want to continue to develop as a company.
Mechanistically, I know it's getting late in the day, but maybe I can ask you to put your scientist hat on and sort of speculate a little bit. Is there a good basis to suspect additive or synergistic Lp(a) lowering with the combo of CETP and PCSK9? Can you walk through the pathways?
Yeah, the issue is we don't know why either of those drugs work on lowering Lp(a) exactly, but we do believe we did do a labeling study. We do think it does decrease production of Lp(a), just like an RNAi or ASO would. The same thing for obicetrapib. I'm sorry, obicetrapib did a study also showing Lp(a) reduction of production. The same thing for PCSK9. We believe it's on the production side as well. There are reasons to believe they would be synergistic with each other.
Interesting.
Yeah.
Just on the overall landscape, can you talk about, first of all, this recent label update for Repatha and the implications that it has from the standpoint of how the FDA is viewing this landscape and, you know, prescribers and simplifying things for the prescriber? Can you walk through the overall take on that?
Yeah, I think it's really nice to see this actually because as a clinician, you want to have a lot of flexibility about how to use a drug for patients. Labeling sometimes can be used by payers in particular to deny access. I think the FDA recognized that. They recognize that when you have a drug that has outcome benefits documented, you should get a broader label. They had limited the labels in two ways. One is they initially, before outcome study, you had only use it on top of statins with atherosclerotic cardiovascular disease or familial hypercholesterolemia, so very, very specific patient populations. Once you have outcome data, you're now allowed to use it broadly like you could for any other LDL drug. You just need LDL lowering, you use this drug. That's what the label basically says.
Also, for the MACE benefit, they've also harmonized things where they used to be a lot more restrictive. You had to show among your MACE benefit, your major adverse cardiac event benefit, your composite, you had to show each of the individual components had to be positive to get in your label. Now they recognize that that's a very difficult challenge because you use a composite to get more events to go together. You should get the full benefit of the composite in your label now. Repatha did not have CHD death because it didn't hit that individually in the very large FOURIER trial. They now have CHD death added to their label, plus the broader label as well. All the lipid drugs that have outcome data are now getting to have that broader label.
That's the reason why we think for us having outcome studies available or even in the label is going to make us a much better launch, much more successful. We want to maximize the, as we maximize the PREVAIL for success, we also want to maximize the launch for success. Having outcome studies in the label and also RUBINs and now our imaging trial showing plaque reduction called REMBRANDT, all that can be in the label at the time of launch now. That's our focus.
What about the Alzheimer’s biomarker?
That's where we're hoping to have at least that type of study done around launch time, confirmatory study. We hope to go from there with a true definitive trial, depending on what the FDA tells us the next step should be.
The other dynamic in the sort of marketplace and the landscape that I think is going to be really important to watch is just these Lp(a) targeted agents in Phase 3, the impact on outcomes. Can you just lay out like the different scenarios, maybe from the HORIZON study in particular, because I think that would be first, that could play out and how you would read that onto CETP and your own MACE data?
Right, right, right. There's a way to do a kind of simple model. If you had, let's just take the optimistic view that 100 nanomoles per liter reduction in Lp(a) leads to about a 20% relative risk. Some people think it's 15. Let's say it's 15 to 20% relative risk reduction with leading to that event rate. So 100 nanomoles per liter, we lowered in the right population, we lowered the nanomoles per liter by 40 nanomoles per liter in that 50 to 150 range, 40 nanomoles per liter. So 40 divided by 100 is 40% of that. 0.4 times 20 is about 8%. That's only half the population. You can figure that you have a 4 or 5% benefit of Lp(a) lowering in our trial. That's how you can think of it. If I follow the math, that's how you think about the contribution.
That's what we saw on BROADWAY, which is, we'd expect a 9% relative risk reduction. We got 21%. You add 9% for LDL, 5% or 6% for Lp(a), and another 6% or 7% for the particles, which we think is the right number to think. You get the 21%. We think the Lp(a) did contribute to the benefit. In our published paper in JACC just came out, we did model the on-treatment Lp(a) levels. The lower the Lp(a) levels were on treatment, the greater the relative risk reduction. That really, the greater the event reduction. We feel that Lp(a) was contributing to the benefit in our study. If HORIZON for some reason doesn't confirm that, it could be that platform-specific issues. We'll have to see when OCEAN(a) reads out as well, how that plays out or others to follow.
I think that HORIZON is important, but our data is what it is. We've already seen the benefits. We can model. I think if HORIZON works, that's great. If it doesn't work, it doesn't mean that our Lp(a) lowering is not effective for how we do it in BROADWAY and ultimately then in PREVAIL.
I'm also interested about another scenario there where the efficacy is evident and the outcomes benefit is evident, but there's maybe some idiosyncratic safety concern that emerges for the Lp(a) targeted agents. Maybe they're lowering it too much or maybe given the platform, oligonucleotides, something there is suboptimal. Do you think that's a possibility?
No, it is. I mean, that's the thing. The first generation ASOs were not well. Now they're better with GALNAC and all that. They are better and they're lower doses. I think it was a dose-related thing. They have injection site reactions and things like that that are, at the very least, bothersome. I think I'm hoping not infecting that inflammatory reaction that we know is also linked to heart disease. I want to make sure that there's equipoise that's going to work. I do think it's going to work. We should keep in mind that we should not give up on Lp(a) for sure if Horizon, for some reason, doesn't pan out.
You asked if from a clinical perspective, from a commercial perspective, if there are unique issues that lead to trial failures, the treatment of these patients and the targeting of Lp(a) is unlikely to change, right? Like today, Michael, you prescribe PCSK9s in this patient population. As we think about our data, physicians would naturally utilize obicetrapib given the high degree of benefit we have in targeting Lp(a).
Yeah. Keep in mind, when we launch all the outcome studies, PREVAIL will be completed. We're going to do a lot of work linking the Lp(a) benefit in that trial. Even if Horizon isn't working, our data will speak for itself when we have that.
That can be done through subgroup analysis.
That's exactly right. Like the PCSK9 inhibitor trial showed that the highest Lp(a) quartile had the greatest benefit. Right now in clinic, we do use PCSK9 inhibitors more aggressively if Lp(a) levels are elevated. That's how we think about it.
Is there a role in the future for a study of obicetrapib in that, like, extreme high elevated?
It lowers the actual absolute magnitude benefit is similar, but the % benefit or the absolute benefit is actually more targeted towards that 50 to 150 range.
Got it. Just on Alzheimer's, I want to ask a few questions there because it's fascinating data. It's been over a month or so since you presented that biomarker data at a Congress. What's the reception been from your consultants and the AD community and investors, frankly?
Yeah.
Your response to that?
Right. Investors have been the most disappointing, but the
Why is that?
It's just not, you know, I guess it's hard. You know, something so novel and exciting, sometimes people have a hard time believing it. That's been some of the reaction we've had from some of the KOLs. It's just too good to be true. We've never seen this before. They're so amyloid, you know, kind of removal focused. Thinking about prevention, I think it's got the people that really see the data and understand it extremely excited. We will build upon this because we've already done market research showing that when you have this benefit, just as we have now, just writing it out on a statement, this leads to 30% greater utilization of obicetrapib. We feel that.
Just based on biomarker?
Just biomarker, yeah.
Okay.
Yes, because it's such an unmet need. It's such a motivated patient to have APOE4. I check it on everybody that I see in my clinic. These are very, very motivated people because nothing is more scary than getting Alzheimer's disease.
Motivated, but they must be educated too as well.
Right, they're not educated.
Right, right.
The pTau-217 is getting more widely. LabCorp does it. Quest does it. Of course, other specialty labs do it. I think we're in the very early phases now of getting into a prevention mindset of Alzheimer's because the LDL lowering analogy I think is very good. I mean, LDL lowering works best when you prevent the first heart attack. That's why we're now talking about not just lower is better, but younger is better for treating LDL. It does prevent the second heart attack if you had a heart attack, but not as well as the first heart attack. Once you have heart failure, LDL lowering has no benefit. We see that the analogy in Alzheimer's is similar. If you have APOE4, if you're a 3/4, you have three-fold higher risk. If you're a 4/4, you have ten-fold higher risk.
If you live long enough to get Alzheimer's, you live long enough because they also have high risk of heart disease, you will ultimately get Alzheimer's disease. The E4/E4 is almost 100% penetration if you live long enough. We believe that population, those are lipid abnormalities. We have an HDL drug that can help remove that excess cholesterol that E4 patients cannot clear properly. HDL does. It makes a lot of biologic sense. I've been working on this for more than a decade. It's exciting to see it starting to come forward with some clinical data. We want to build upon it. Most importantly, we want to reassure investors we're not going to spend a lot of money on this benefit because I know that people think Alzheimer's is kind of the graveyard of failures.
In our situation, we feel it's going to really enhance the differentiation of obicetrapib from any other LDL lowering drug, and that this benefit will be well received by clinicians.
My understanding is that some of these biomarkers, I guess, weren't around, but certainly they weren't measured for the old CETP inhibitors in the studies.
Right.
They may have seen something given the HDL increase.
No, it wasn't around, no. Because we didn't even know when we first heard about pTau-217 was when BROADWAY was fully enrolled. They said, "Why don't you do this new fangled biomarker called pTau-217?" I said, "What are you talking about?" They did a lot of research on it. You know, as you can read, there's been an explosion of data on pTau-217 that's exponential now. What's being published about it as a really good biomarker for diagnosing Alzheimer's or cognition impairment, because it does mark the disease itself. You're looking at the amyloid in the brain and pTau in the blood correlate extremely well.
Yeah, just to emphasize the point, we saw a benefit in pTau-217, but also half a dozen other biomarkers.
Right.
It is the consistency of that benefit across the Alzheimer's patient population that we studied, and the improvement being obviously most pronounced in patients that are at greatest risk. That is what gives us confidence. As you think about the data we've generated, we are excited about it. We are committed to doing a similar analysis in PREVAIL and engaging with the FDA to understand what the path forward looks like. The initial investment would be a phase 2 trial.
Yeah, I mean, can you expand on that point? Because you're being prudent, of course, not investing in some large Alzheimer's study with PET scans, et cetera. You know, meeting with the FDA and understanding a path, maybe even in a preventive setting that some of your KOLs spoke about, which is exciting. I mean, you could do some of that groundwork and that maybe has strategic value.
Yeah, absolutely.
Is that all on the line?
That's what we're thinking. Yeah, definitely a strategic value. We're seeing a lot of the big pharma companies take a major interest in us because of the Alzheimer's data, actually.
Yeah.
As you know, they have the resources to, and this is one for a lot of the big pharma companies, this is one of their major focuses. They want to focus on Alzheimer's.
Yeah.
We see that as a real opportunity for us to build upon that interest.
Yeah, the overarching message is it contributes to the LDL plus that the drug provides. This is just yet another characteristic of the drug in a patient population, patient populations where there's a high degree of overlap.
Just last question. Are you measuring cognition or dementia correctly?
We wish we could, but it's just, you know, we don't have the consent for it in the trials.
Yeah, in PREVAIL, we're not.
We're not, no.
PREVAIL, yeah.
Yes, we don't have consents, and so we can't, it's hard to get that amendment. We don't want to interfere with the actual conduct of the PREVAIL itself. We feel that this could be a little bit of a distraction. That's why we think a separate trial, phase 2 trial, would be the right way to go.
That's going to be interesting, obviously. It's never too early to say the countdown is on to the big PREVAIL data next year. I always appreciate the insight and the conversation. Thanks so much for joining us.
Thank you, Michael.
Thanks for seeing everyone.
Thank you.