NewAmsterdam Pharma Company N.V. (NAMS) Earnings Call Transcript & Summary

Sure. Well, the REVEAL trial was the Anacetrapib 30,000 patient trial. And the biggest issue for that trial was it worked. It showed a 9% delta risk reduction with an 11 milligram per deciliter drop in LDL. The baseline LDL was 61. So that was 30,000 patients, and it included a patient with chronic atherosclerotic cardiovascular disease. This was a big study, and if you look at the top tertile, those that had LDLs above 70, there was a 17% relative risk reduction with a 22 milligram per deciliter drop in LDL. And that actually was more than expected, even though it only lowered LDL by 22 milligrams per deciliter. That's the same absolute LDL lowering and clear outcomes, which saw a 13% relative risk reduction. So we wanted to try to maximize. So then who did the best in that trial? Obviously, those that had higher baseline LDLs, those that had high triglycerides, low HDL, high Lp(a), or diabetes. So we designed PREVAIL to try to match that the upper tertile of REVEAL. So we have higher baseline LDL or LDL is over 100, the risk enhancers were -- is as I described, high triglycerides, low HDL, high Lp(a) diabetes, and other risk enhancers where the Anacetrapib showed a greater benefit. So we also, other trials showed us that heart failure -- if you take out heart failure, your risk reduction goes up quite a bit as well, like in the ODYSSEY OUTCOMES and FOURIER, it was 15% overall. If you took out heart failure, it went to 23%. So we think that if you take out the patients that don't benefit, you also enhance your relative risk reduction. And the last kind of thing that we wanted to focus on is duration, because REVEAL also showed us that you don't separate the lines until after 2 years. But you're talking about a very low baseline LDLs. They might separate faster with higher baseline, but nevertheless, we added a 2.5-year minimum follow up, which is the longest minimum follow up ever in a chronic trial for LDL lowering, 2.5-year minimum. So we just finished enrollment. So the 4 -- study will be at least 4.5 years long. We have 2 years to get to this point to enroll now, 2.5 year minimum follow up. So we have a long duration that 2.5 years should translate into a greater relative risk reduction. As an example -- another example in FOURIER, which was the [ Repatha ] a very similar population was a 2.3 year total duration. If they took patients that were on the drug for just a year, the relative risk reduction went from an overall 15% up to 20%. So all those factors, we believe, enrich, PREVAIL with the right patients and the right design to maximize relative risk reduction. And we hope these other attributes, like small LDL particles, Lp(a) lowering, diabetes benefit, could translate into greater outcomes. We'll have to see. I mean, most importantly, we want to try to achieve that greater than 15% relative risk reduction, which is what other LDL trials have shown in the last decade or less. And we want to at least achieve that as our -- as an outcome. But we think we can do better the way our study has been set up and designed. And it's powered, it's powered for that type of relative risk reduction.

Got it. And I guess, on the regulatory path, it sounds like you're waiting for the outcomes trial before going to the FDA and filing this. I guess. Can you talk about the combination of FDA discussions that led to that strategy? And maybe your internal work about how to best approach the market that suggests that you won't be filing on BROOKLYN and BROADWAY?

So -- well, one correction, we will file on BROOKLYN and BROADWAY, but we're not going to file until we know the outcome study is going to complete during the PDUFA period. So we want to wait and kind of track events, and we can -- once we know the events' trajectory in the full enrollment, so roughly a year from now, which is when we have basically the filing ready for BROOKLYN and BROADWAY and TANDEM, our Fixed Dose Combination. We want to file everything at the same time. So we'd go meet with the FDA, Type C meeting, and then assuming everything looks good, we go to a pre-NDA meeting. So we're talking about a modest delay in filing, but we're meeting with the FDA, wants to see the outcome study prior to approval. So we have that in our plans to have that data in the public domain at the time of approval. So the FDA has always approved drugs without outcome data for LDL. LDL alone is one1 of the approvable surrogates without outcome data. But I think it's very important because of the class history, I think we have good explanations for everything, but because of class history, we want to make sure that no one has any hesitancy or concerns about using this drug when it's first approval. And we want to maximize success right off the bat with a drug like this, because having that outcome data in hand is going to make a difference.

So, one question we've been hearing or concern we've been hearing from some cardiologists, and it's great that I have a cardiologist on stage that I can run this by, is that there's been some meta-analysis that maybe CETP inhibitors produce HDL that might not be as functional, and that by administering a CETP inhibitor, though you're lowering the LDL, you're also making the HDL protective effect potentially less functional, I guess. Do you see that as a concern? Do you think that's something to be worried about with this molecular mechanism, or not so much?

Well, first of all, we did a lot of work on HDL functionality, and there's no impairment of functionality, but all the measures you can use actually works even better than without the drug on board. See the HDL functionality always improved, so that is not true in regards to functionality. But we also have a lot more data about this from the other CETP inhibitors. Most importantly, again, it's Anacetrapib, with REVEAL that in the subset of patients who had the highest baseline [ ApoE1 ] or HDL, the drug actually worked better. So those patients would have much higher HDLs on treatment. And if you look at Evacetrapib, there was a total mortality reduction overall in the trial. So if there was HDL dysfunction, you would not expect to see either greater benefits than those who had the highest HDL or even lower mortality when people got the drug. And so that was an old thinking. Back when we first studied CETP inhibitors, HDL is becoming dysfunction. But all the evidence since then has been actually, to the contrary, just the opposite. But the HDL raising is beneficial and leads to other outcome benefits, and particularly it's the diabetes benefit that we believe is HDL-linked. Because HDL does remove toxic sterols from beta cells and improve survival of beta cells. That's -- we believe that's the mechanism, but also HDL, we believe there's a similar thing in the brain and helps remove toxic sterols, cholesterol from the brain. And we showed that hydroxycholesterol 24 and 27, which are linked to causally with dementia and pathology, inflammation of dementia is reduced for the first time with Obicetrapib, and so that this is showing clearly that we can affect these toxic sterols and remove them from tissues where they could have adverse effects like the brain or the beta cells. That's an HDL-mediated effect. So we think it's just the opposite. Just the opposite is, that the HDL is highly functional and having higher HDL, it may not be a MACE benefit, which is clear from the trials done so far, but yet we believe it certainly could have other health benefits that we are evaluating.

And maybe just speaking to it from an adverse event standpoint. So if you look at our Phase II data and you've seen the pool [ of ] safety data there, there was no difference between Obicetrapib and placebo. If you look at the data from the CETP inhibitors, and Michael mentioned Anacetrapib in the REVEAL study, that's 6 years of follow up, 30,000 patients. There was no such imbalance either.

Right.

Yes. No cancer, nothing. No, it's not. I think people just seem to look at the data, it's just not. There's no signal of any harm, so we --certainly no signal of harm. But we still believe there's actually benefits of that HDL raising that we're trying to determine with our studies.

I know, it's early days and a lot of work before we get to the stage, but I'm curious if we can talk a little bit about market positioning and how you see Obicetrapib potentially fitting in, I guess, when the drug launches? I guess, do you see it being used first as preferred add-on to statins? Maybe being used initially in the patients who are intolerant to statins, placing PCSK9s? I guess, maybe all of the above at once. But I guess, how do you see the market evolving? How do you see yourself as a physician first trying the drug, using it before you start using it more and more broadly.

Right, right. I think, I might have a unique perspective being a leading writer of branded lipid drugs and a CEO of a biotech company developing novel lipid drug. And I would say that, that perspective tells -- I see the hurdles that most doctors have when they're trying to write another add on to a statin or replace a statin if they can't take a statin. And we think there are options out there, but they're really limited by, if they're oral, they only have 2 options, Ezetimibe and Nexletol/Nexlizet. And they're both very modestly effective. And for most patients, this is not going to get you there to where you need to be. And you just don't get excited about using a drug that has that minimal LDL lowering effects. So you tend to shout, and I still use them a lot actually, because I still think lower is better. So I'm 1one of the leading writers of Nexletol/Nexlizet in my area, as I am for Repatha and so forth. So I'm a very high decile writer of lipid drugs. But for most doctors, it's just not enough of an effect to get them excited. Now, for the injectables, it's more that they can't have the resources to help them with the training and the prior authorizations. So it's kind of just don't bother. And so I think for the first time, we're going to be able to supply a drug that can be very effective, especially the fixed dose combination. You're talking about LDL lowering, maybe 60%. We'll have to see what -- so we saw that in our ROSE2 trial. So you just have one drug add it to their statin and they're done. Or if they can't take a statin, replace your statin and they're done. Because it uses -- because what we use Nexletol/Nexlizet for is for people who can't tolerate statins. But it's only a 15%, 20% alone, or 36% when you come -- uses Ezetimibe. For most patients, it's not enough efficacy to get them to where they should be. So you want to start with a drug that can just get them there. One single approach and you're done with your therapy. That's the key message. But ultimately, when it comes down to it, when you think of that overall profile of what it can do for other aspects, Lp(a), small particles, diabetes, that's when you get tremendous enthusiasm. Even the HDL raising itself again, we don't want to emphasize any MACE benefit with that, but other benefits that we want to try to highlight in our trials with that is something that we need to continue to develop with this unique drug. We'll get doctors really excited about this option. And for the first time, we do have a very easy oral add-on, well-tolerated, that you can just write a prescript for. Give them a bottle of samples and you're done. And that to me is what's needed for a drug like -- an indication like this, where you want something very simple, well-tolerated, and accessible for patients.

I know we got probably half a second left, but I want to squeeze in one more just around IP life and patent strategy. I guess, can you talk about your confidence in the strength of the patent life for Obicetrapib?

Clearly, we're very confident. As you know, the composition of matter patent does expire in 2027 in the U.S., 2025 in Europe. We do have a second generation patent which is specifically the selection of a low dose of CETP, and very specifically Obicetrapib. So that selection patent takes our IPS state all the way to 2038, 2039. This is a patent that's been issued in over 35 countries. It's a patent strategy that's well -- upheld well in terms of potential challenges. And on top of that, there are additional patents that we've filed, including a new patent that we filed last year which has the potential to issue some point this year, and that's a new composition of matter patent. The fact [indiscernible] all the way to 2043.

Got it. Well, thank you so much for your time. Really appreciate having you here, and I think that concludes our session and conference for today.

Thank you very much. Thank you.