New Amsterdam. Very pleased to have Michael, welcome.
Okay.
Can I give you the opportunity to maybe just level set us and make some opening-
Sure
framing remarks on the company.
Sure. Thanks, everyone, for being here. We've had a really productive year, firing on all cylinders. All our trials are rolling along on schedule or ahead of schedule. Of course, the most important being PREVAIL, which is our 9,500-patient outcome study. I think we announced just a few months ago that we're going to do an interim analysis. Based on a number of factors, we can go into more detail, but that interim analysis will start the actual point at end of this year, and the readout will be in the first quarter of next year.
Well, that's a great segue into what I think is probably going to take a lot of the discussion, the PREVAIL trial.
Right
Obviously, given how important it is. I want to just maybe double-click a little bit more on the interim analysis. I think just first on timing, you said it's going to be done by the end of the year with the results in the first quarter.
Well, you set a event rate time point, which is going to be the end of this year, approximately, and then it takes time to adjudicate all those events, then go before the DSMB, and then they have a charter which guides them on whether we hit the criteria for stopping the trial at that point.
Walk us through, Michael, the decision to introduce this interim right now, and I know you guys have talked quite a bit about it, but I just would love to just hear.
Sure
the framing again. How did you weigh getting to market potentially a year earlier, versus the risk of potentially also jeopardizing the trial?
Right. Well, we're not jeopardizing the trial in any way. In fact-
the out-
Just to go back, it's really important to go through the history of PREVAIL. When we started the trial, we also started our three LDL trials at the same time. Brooklyn, BROADWAY, TANDEM, and PREVAIL all started at the same time. Basically, we didn't have the funding to finish them off, especially PREVAIL. We were a private company, and our plan was to get our phase III readouts and then raise more money to finish the trials-
accordingly. We went public. We raised the money. Broadway worked out well, but we purposely designed Broadway to be a mini PREVAIL. In fact, for the first time, a lot of companies have copied this since, we made the phase III trials very heavily weighted to Broadway on numbers. 2,500 patients in a single trial, all at high risk, to give us a large number of events in a single trial in phase III LDL that we were hoping would provide a lot of support for PREVAIL working. It was designed as a mini PREVAIL.
It all worked out very well in that regard. We had 2,500 patients. We had a large number of events, again, larger than any other phase III lipid trial done to date.
well over 100 events at one year. We saw this 21% relative risk reduction of our new four-point MACE. We also had decided that Broadway would be informative on the final design of PREVAIL, because we had initial four-point MACE that a lot of companies had used, which was urgent revasc, cardiovascular death, nonfatal MI, and total stroke. That's used. In fact, HORIZON using, I think, the similar. We powered it for 20% relative risk reduction, so roughly 1,000 events. 1,000 events, 20% relative risk reduction. Once we had Broadway, we looked at the event rates, we saw that the four-point MACE that was now being used in more recent trials, like CLEAR Outcomes, FOURIER, and so forth. It's also the CTTC definition of four-point MACE that's being used for all the meta-analysis of all the LDL trials.
That was also where the 0.79 hazard ratio was present. We made the decision, we announced that a year ago, that we were going to change our four-point MACE to that four-point MACE. Broadway's very informative on letting us know that that was the four-point MACE that was recognized as now the new appropriate four-point MACE for the recent trials, it was also our best hazard ratio in the Broadway data. Again, all the events were in the right direction except for stroke, that provided the best benefit for us in the Broadway trial. With the very large number of events and the four-point MACE rate, we raised a lot of money, now we had enough money to go longer to make sure that we powered a study not for 20% relative risk reduction, but now 15% relative risk reduction.
With that in mind, that we would now want to go to 15% relative risk reduction power, because keep in mind that all the recent LDL trials range from 9%-15% on their primary endpoint, four-point MACE. Zetia being 9%, Repatha, alirocumab, and evolocumab, Repatha and Praluent at 15%. We felt that 15% be powered would strengthen the trial significantly. With that requirement to go to 15% power, we knew because we were limited by patient numbers, we were already fully enrolled, we had to go longer. We're going to go longer. We also have more events now because the four-point MACE that included total revasc instead of urgent also gave us about 20% more events. We put in the new event rates, the new four-point MACE. That gave us more events.
Now we decided to go longer to power the study to 15% relative risk reduction. In the meantime, we're tracking our blended event rates, and we're seeing that the blended event rates are much lower than expected, using, again, BROADWAY as our benchmark of what the event rate should be. Because, again, BROADWAY and PREVAIL have the same patient population, the same DSMB, the same adjudication committee, many of the same sites. If any study could tell you what your placebo rate would be in your outcome study, would be BROADWAY. BROADWAY should be a really good, strong predictor of what would happen in PREVAIL.
Knowing the event rates in BROADWAY and knowing they have very similar trials, we can make predictions about what the event rates should be in PREVAIL, and we're seeing lower than expected event rates, which is consistent with that 21% relative risk reduction. If that's the case, then an interim analysis at that point that we designated would give us enough power to stop the trial with the P values that we selected, which are important for regulatory approval for both three-point and four-point MACE. That would get us back on track for that timing of finishing the trial in the first quarter of 2027.
It's a long answer to your question.
No, it's actually a great answer because I want to stay with event rates, believe it or not, for a second.
Yeah.
You've stated that the blinded event rates are dropping in years two and three.
Right
Even more than the expected placebo decay.
Right.
I guess what gives you confidence that this is being driven by obicetrapib's benefit rather than the placebo outperformance or changes in the standard of care? Maybe also just while we're on that thread, talk about some of the analytics you did with other studies that.
Right
helped lead to that decision. You touched on this a bit, but.
Yeah
let's keep going.
Yeah. Like I said, we looked at the first-year event rates with PREVAIL, and they matched almost exactly the BROADWAY one-year event rates across the board. three-point MACE, four-point MACE, death, non-fatal MI, all the composite events matched very closely to PREVAIL. We felt that, again, BROADWAY was an excellent kind of guide to what would happen. Now, historically what happens with placebo event rates across 14 different trials? We know there is a decay, but this was greater than expected decline in event rates, more than you'd expect from a decay over these multiple trials. Again, 14 trials, we can measure the predicted decay and the famous line, for us at least, is, "A good way to lower your risk of heart disease is to be a placebo in a cardiovascular outcomes trial.
Yeah.
Obviously, that's an issue that we know about and we're aware of. Even with that in mind, we're seeing this decline in event rates going forward that would be more than expected and consistent with what we saw in the BROADWAY relative hazard ratio benefit. That gives us, again, confidence that BROADWAY does accurately predict PREVAIL and that this decay that we're seeing is more than expected from all the other trials that have been out there. We've been very carefully monitoring drop-in, drop-outs, add-on GLP-1s or SGLT2s or PCSK9s, and we're seeing very low single-digit drop-ins to any of these that would affect the event rates. In that sense, again, we feel the most likely explanation is that obicetrapib is validating the 21% relative risk reduction we saw in the BROADWAY study itself.
We also looked at 14 different trials for all CVOTs of recent vintage. Again, we know the decay rates. We also know that our event rates, especially when you adjust for our risk, because we designed PREVAIL to be a high-risk population. High LDL is over 100. All patients have ASCVD, 50% have diabetes. You look at SELECT, for example. LDL was diabetes and the event rates, and we know we're lower than. You look at other trials that are done in a contemporary time, that's relatively recent. We're seeing event rates that are lower than those annualized event rates in PREVAIL. Again, we feel that this interim analysis gave us a two shots on goal approach that at the end of the day, we made the study a lot more highly powered for a 15%. That's our primary objective.
We don't want the study to fail the drug. We knew that would take an extra year. Even though we modified the four-point MACE because event rates were slowing down. This lower event rate is giving us, again, encouragement that the interim could stop early the trial and give us a chance to be on the market 1 year ahead of schedule.
Then maybe on the MACE endpoint change, the four-point MACE. You changed the four-point MACE definition from urgent revascularization to total-
Right
revascularization. CTTC definition, which adds roughly-
20%
20%-24% more events.
Right.
I guess, why was that change made? Talk a little bit about that. How does requiring MACE three as well as MACE four at the interim affect the likelihood of an early stop?
Right. Well, again, the four-point MACE was driven by two reasons. One is BROADWAY it was as good as urgent and elective are the same hazard ratio. Again, CLEAR Outcomes and FOURIER are all both using total revasc. They saw no difference in urgent versus total. That to us was kind of a simple reason to go with the total revasc as opposed to urgent. That made a lot of sense. Then again, the CTTC definition also using also REVEAL, which is the center for trial use total revasc. That gave us again a guidance there on that. That to us was a pretty easy decision. Also just keep in mind that the big studies recently done, both one's called COURAGE, one's called ISCHEMIA.
In my field, as a cardiologist, they both showed that using medical management versus a stent, there was no outcome benefit. The care has changed-
in the last several years where revasc is becoming much more evidence-based decisions. Like instead of seeing a lesion and dilating it, you got to have symptoms, you have to have new onset of symptoms or symptoms that are getting more severe before you get a stent put in. Even payers are demanding more.
Yep
The blurring between elective and urgent is much less than it used to be.
10 years ago.
I guess on the MACE three requirement.
Yes
Why is hitting three-point MACE a requirement to stop at the interim, but not strictly for the final analysis? How much of a second-year event decline is coming from the three-point components, which is non-fatal MI, stroke,
Right
CV death.
That is our own conservative thinking on the three-point has to hit also because even though the primary endpoint is four-point MACE, in Europe in particular, regulators like to see three-point MACE positive. We would hate to have a situation where the four-point hit and the three-point did not. We don't want that. That's our secondary endpoint. There are a lot of academic schools of thought, even the FDA itself, there's never been an example where this has happened, but if you hit on a four-point but did not hit on three-point, then your regulatory certainty is in question. You want to hit on both. We felt that if we're going to do an interim analysis, it would be easier not to have three-point in there to stop the trial.
For us, that would be an unfortunate situation if four-point hit and three-point did not. We want to make sure three-point hits as well. The threshold for three-point hitting is not as much as the four-point because it is a secondary endpoint. It's still a very significant P value to stop the trial. That part, it's more of a, we don't want the study to fail the trial. If we could have gone a year longer and hit the three-point and we stopped for that reason, we would've regretted that decision. We want to make sure that both four-point and three-point hit at the interim to stop the trial.
Very clear. Let's maybe start bridging into the commercial-
Okay
opportunity. We've spent a lot of time on the trial, but I guess regarding the ultimate MACE-level benefit achieved, you've stated that it doesn't really matter what the ultimate benefit is, whether it's 10%, 15%, 20%. Why would you believe that to be true from a commercial perspective?
Well, that's just what all the data tells us. One thing I want to make also a point I forgot. I want to emphasize-
Please
you asked about it was the three-point MACE reduction that we're seeing in. We're seeing all events going down, but in particular, the three-point MACE.
Okay.
That's giving, again, encouragement on the whole thing. Regarding the commercial benefit of 20% versus 15%, we really don't see that driving uptake that much. I mean, it has some impact. Most clinicians, based on our surveys, there's 10% of physicians who care about what the percent MACE benefit is.
Most doctors, all they want to know is the study's positive or not. All guidelines want to know is the study's positive or not. For example, the new guideline just came out. They rank Repatha, Praluent, and bempedoic acid, Nexletol, as the drugs to go to because they have outcome benefits. They don't talk about the relative risk reduction of those drugs. They just have evidence based of benefit. For most doctors, they don't even know. In fact, when you ask them actually what was the relative risk reduction. 90+% get it wrong. They don't know what it is. It doesn't affect utilization as much as you think it would. Another example is Wegovy has SELECT 20% relative risk reduction. Tirzepatide has no benefit on outcomes. People are using tirzepatide a lot more than Wegovy.
It's just an example of these outcome studies, in the academic world, what they are is potentially important, but in the real world, it doesn't matter that much. We feel that the biggest reason why commercial uptake will go gangbusters with obicetrapib is because the LDL plus forced positive benefit on outcome. That checks the box. The Lp(a) lowering, the diabetes reduction, small particles, the Alzheimer's benefit in BROADWAY that we saw, that's going to really drive uptake in our data. It shows that strongly, that we get increased uptake for those other LDL plus benefits compared to other LDL drugs, including the oral PCSK9s in the market.
That's a great segue, Michael, to just talking about the commercial landscape or even the competitive landscape, if you will. You've got the Merck oral PCSK9 launch potentially before the end of this year. Lerodalcibep, you've got AstraZeneca's oral PCSK9 combo strategies across their CVRM portfolio. You framed sort of these entrants as wind in our sails.
Right
Rather than competitive threats. What evidence supports the market doubling beyond the 30 million patients not at goal?
Well, now the number's a lot bigger because of the new guidelines. It went down to 55. It's a much bigger number. That really makes a huge difference on the numbers. It could be as much as double that. Lower is better is the key, especially with Lp(a) lowering, if that is validated. HORIZON doesn't have to be positive in its own right. It could be something that's in between, which could even be better for us. Something that showed a benefit that's more ENHANCE when you have an on-treatment analysis or things like that. HORIZON, it's on the borderline of where it's going to achieve statistical significance based on the powering and so forth. Again, they powered it for 20%.
When you have a drug that lowers Lp(a) more than the oral PCSK9s, you have a drug that reduces risk of diabetes, not increase the risk, which is in the labels for the PCSK9 inhibitors to some degree, even though I don't think it's a real issue. The diabetes and the Alzheimer's benefit, we think the Alzheimer's benefit is getting a lot of traction with all the KOLs out there because they know that APOE4 is a lipid gene, and the prevention data with p-tau, the strengthening of the benefit of p-tau 217 being highly correlated with amyloid on PET, and that's highly correlated with progression to Alzheimer's. That's a great message. We're going to validate that with an upcoming study called SPINOZA, we're going to validate that. I think all that together gives you highly motivated reasons to use obicetrapib over any other LDL-lowering drug.
Of course, the biggest issue in my mind is the safety and tolerability, ease of use that really drives wide utilization, especially by primary care doctors. Primary care doctors loved the ezetimibe before the whole ENHANCE issue blew up, the benefit. Now it's growing again. It's going again. What's easy about the ezetimibe was it was so well-tolerated and safe, even though the 15% LDL lowering wasn't. They rather get something that's very well-tolerated and safe, as opposed to anything that has any side effects or has challenging use. We feel that's where obicetrapib really excels in that regard.
I guess on the regulatory strategy and the filing timeline, you filed in Europe, which I want to talk about. I guess maybe just staying with that, what are the updated timelines in that region?
Yeah, we filed in Europe. We should have approval this year for Germany and the U.K. Everything's going well on the regulatory side there. We'll be launching across Europe with our partner, Menarini, across many of these different countries.
I guess because you're in the situation where your partner in Europe's going to be launching a drug before you launch in the U.S., explain to us in a world of MFN, how does that affect the pricing architecture as you launch in all of these different markets in Europe?
I don't want to comment specifically. We are working close with Menarini on how best to go about the commercialization pricing strategy.
Okay.
We got Steve Albers, who ran access at Novo Nordisk, as our access public affairs lead, and he's a fantastic expert in this area. We're working with Menarini on, there are ways to structure pricing that gets us closer to the U.S. pricing.
Across the range of countries?
Well, it depends on the country, of course. You remember, there's a very complicated system in Europe, but there are commercialization agreements. There are confidential pricing. Europe is trying to adapt to the MFN world. By the way, we hear recently, and you may know as well as if not better than us, but we feel that anything law-wise, codification is unlikely to happen soon.
On MFN?
On MFN, yes.
The industry is very opposed to it.
Yeah. Right.
Oh, you're saying even if there is something that emerges out of that, this is something that could eventually expire in three years?
Right. We feel that we have a lot of good arguments. We have no control over pricing in Europe.
Sure.
We have arguments that we could make about why that wouldn't affect us. Nevertheless, we are working closely with Menarini on how best to approach the pricing in Europe.
Okay. Then maybe on the U.S. side, Michael, can you file the U.S. application ahead of the interim readout? I think that's the strategy here, is it?
We're talking with the FDA. We're blessed at the FDA with the same team we've had for five years.
How are those discussions going?
They're going well.
Okay.
We both have the same objective, which is that we want to see the drug on the market with outcome data already in hand. We both have the same objective. We want that, they want that. We're working together on how best and how to time that effectively.
Okay. Let's talk a little bit about Lp and HORIZON.
Yeah.
You touched on this briefly. Michael, you and I have had some conversations about this in the past. You've described obicetrapib as serving the 50- 150 Lp range without competing with injectables relegated to the higher-risk established disease patients. I guess, how do the various HORIZON outcomes, success, a near miss, a failure, each play out for Amsterdam?
Right. Listen, I think a total miss is unlikely because it did.
Yeah
pass two interims. Yeah. Let's assume it's the next scenario, which is that it doesn't reach the P value on the primary endpoint that people are hoping for, which if it's not 20% or greater, it may not be statistically significant. It might be a P value that's not below 0.05, let's put it that way. Again, I think that's a scenario. There are other scenarios where then it becomes, okay, let's look about the study itself. There could be relatively high dropouts. It is an ASO. It has a lot of skin reactions. Let's say once you look at on treatment or those that took the drug, it becomes significant. You can look at how much Lp lowering you got and then model that for benefit.
There are ways that the study, even though it may not be successful as a regulatory approval trial could give us validation that Lp lowering has a benefit. That would be a best-case scenario for us in our situation. I hope not. I hope it's a.
Sure
positive trial because as a clinician, I can tell you in my lipid clinic, I see patients four days a month at University of Chicago. I would say three-quarters of them are high Lp(a) pa tients want something to take for their Lp(a). They have bad family histories. They're worried about it. I think it would be most important to get this drug out there as soon as possible for those patients. With that said, though, it will be relegated to those that have Lp(a) above roughly 150 nanograms per liter and existing heart disease. It would not be available for those below 150, who still have high risk down to 50, and/or they don't yet have heart disease. It's also going to be very expensive, I believe. They'll be pricing it pretty high, in that biologic range probably.
That's how they designed the high-risk group to get the high absolute benefit for the trial. We become the first Lp(a) lowering drug out there, not technically by indication, but by b enefit that people will be aware of that lowers Lp(a) in that 50- 150 range quite effectively by about 50%. Statins, unfortunately, they do help. They lower LDL, which makes a difference, but they actually raise Lp(a). Obicetrapib becomes the really go-to drug for anybody with high Lp(a) in that 50 - 150, which represents the majority of patients that have high Lp(a) out there. We see high Lp(a) official as a real upside for us in the marketplace.
Okay. Maybe in the last couple of minutes, let's talk about Alzheimer's. Michael, you plan to announce a new phase IIb-
Right
at the July AAIC meeting.
It's going to be early August, yeah.
Okay. Presenting four new studies based on biomarker data.
Oh, no, you're right. We are presenting four posters at the m eeting. Our Investor Day is in early August, and we're announcing that the Spinoza start. Okay, I'm sorry.
Okay.
Okay. Yeah, we have four studies coming.
Good preview, though. Okay.
Yeah.
I guess talk to us about the design, the target population, timeline, and how could early intervention expand obicetrapib.
A great question. We use a lot of AI technology in our data. We have a very rich data set. We have 1,500+ patients on obicetrapib for a year. We already announced that in the APOE4 patients, especially the 4-4 homozygotes, we got a benefit across the board on p-tau217 and also on other biomarkers, NfL, GFAP, p-tau181, amyloid-β 40. All the biomarkers improved in the homozygote patients significantly, which was kind of unprecedented, especially NfL, which d oesn't seem to be benefited by even the anti-amyloid therapies. That was quite exciting. Using AI technology, we found that if we enrich the study for those that have a mildly elevated p-tau217 and have either 4/4, 3/4, even 3/3 that are older, they also benefit from obicetrapib. Think about Alzheimer's.
4/4s get it in their 70s, 3/4s get it in their 80s, and 3/3s get it in their 90s. In our study, we found that all 4/4s benefited. We think starting at age 55 is a good starting point. For 3/4s, 60, 65, they start benefiting. Over 75 for 3/3s, they start benefiting.
We think we found, again, it makes a lot of biologic sense that we're trying to treat 20 years before there's cognitive impairment symptoms. We found that obice trapib was benefiting these patients based on those risk markers, and using p-tau as a great biomarker for amyloi d in the brain, that we're seeing this prevention of amyloid accumulation over that 12 months quite significantly across those three types of patient populations. What we're studying, we'll be doing a three cohort, 400-patien t trial with those three cohorts, APOE4/APOE4s, APOE3/APOE4s, and APOE3/APOE3s, having those other enrichment criteria to show what we can do in a prevention model for Alzheimer's. Again, we're really benefited by the fact that the p-tau217 keeps getting validated over and over again as an excellent biomarker for both prediction of progression and benefit in the trials.
Also that the disease is being redefined now . Everyone with Alzheimer used to say that was dementia. Now they realize Alzheimer's is starting 20 years ahead of any cognitive impairment. They want to start treating Alzheimer's 20 years earlier now.
Yeah.
We hope that makes a big difference. If you're in the lipid world like I am, we realized if we used LDL lowering to treat heart failure, we never would have succeeded with LDL lowering. We had to treat LDL lowering before there was heart damage to get the greatest benefit.
Well, we're ce rtainly looking forward to seeing how those trials progress. Best of luck to you, Michael.
Okay, thank you.
Thank you so much for being with us. Very comprehensive discussion. Really appreciate your-
Yeah, thank you very much.
time and translation. Thank you.