A very toasty Las Vegas. I'm very pleased to have join us right now Jeff Finer of Septerna, who will be providing us with a presentation. Jeff?
Okay. Yeah, thanks, Jason. Thanks for the invitation to present with you guys here. It's good to see a few people still in the room late in the day. I'm gonna tell you about Septerna. For those of you who don't know us, we're a company focused entirely on GPCRs or G protein-coupled receptors. We found a new way to do drug discovery for them. The presentation will include some forward-looking statements. Just a kind of quick overview of the company, we've got a platform that we call the Native Complex Platform that's allowed us to do drug discovery for GPCRs in a new way. It's allowed us to tackle previously difficult to drug GPCRs. Part of our portfolio strategy in general has been to go after well-validated targets with early clinical readouts.
Every one of our programs, the ones we'll talk about today, have a meaningful phase I readout that is important. We're well-capitalized. We announced financial results just from the Q1 last yesterday. We've got a cash runway into 2029. Couple lead programs that we'll talk about today. We'll spend nearly the entire time talking about two of the programs. One is SEP-479, which is our parathyroid hormone receptor agonist for hypoparathyroidism. This is one that we recently announced the start of a phase I trial, announced that start just a few weeks back. The second program, SEP-631, is going after a mast cell target called MRGPRX2.
That one we announced very promising phase I data just two months back, just in March, and I'll share that data with you today. I'll briefly introduce you to our thyroid-stimulating hormone receptor program as well. This one is going after Graves' disease. Last but not least, we have an incretin receptor agonist set of programs that we ended up partnering with Novo. We announced the big deal with Novo last year. That collaboration's off to the races. Jumping into our SEP-479 program. For those of you who don't think about hypoparathyroidism all the time, it's important to understand a little bit about parathyroid hormone physiology. PTH is the master regulator of blood calcium levels.
It's secreted by the parathyroid glands, and it has its effects on a receptor called PTH1R in the bone and the kidney. Those effects on the bone and kidney lead to increases in serum calcium, either through mobilization of calcium from bones, resorption of calcium from the kidney, and there's also effects on the GI tract as well. Patients with hypoparathyroidism have generally lost these parathyroid glands and an inability to regulate their blood calcium, they end up with hypocalcemia and a whole bunch of consequences of that, including side effects. SEP-479 is our clinical candidate, we'll spend some time talking about today. It's a very potent selective oral small molecule. In this space, there's been a lot of peptide therapeutics. This is, to our knowledge, the first effective oral small molecule.
This is our second generation compound. We had an earlier one that ran into an unexpected safety finding. SEP-479's our second generation compound. This compound has shown activity that's very comparable to PTH peptides by all measures, cell-based assays, animal models. We've shown efficacy in a rat surgical model of hypoparathyroidism. Don't have time to share that with you today, but I will share with you a very interesting monkey PK/PD study, which we think is a good simulator of what a healthy volunteer study should look like. Compound has excellent pharmaceutical properties that we think project a once-daily dosing. As I mentioned, the phase I trial was just recently kicked off. This is the monkey PK/PD study that I was alluding to.
One thing to know about this physiology is that healthy volunteers are very different than hypoparathyroidism patients. Healthy monkeys have the same situation as a healthy volunteer in that they have intact parathyroid glands. Those parathyroid glands, because the endocrine feedback system is so efficient, they can dial up and dial down PTH release from those glands very efficiently in response to any moves in serum calcium to try to hold serum calcium levels as tight as possible. What you expect to see in a healthy volunteer as well as in a healthy monkey, the first consequence is the endogenous PTH secretion will go down. What we're looking at here is a seven-day study with once-daily dosing followed by a five-day recovery period.
What you can see on the left graph is that after just a single dose, the endogenous PTH levels are down about 80% or so. Once you've bottomed out PTH levels, your ability to turn down PTH, you start to get serum calcium increases in healthy volunteers as well. We've learned some lessons from the PTH peptides that have been before us in clinical development, including that the YORVIPATH from Ascendis, which is that if you look back retrospectively at the doses that work in healthy, I'm sorry, in hypoparathyroidism patients, and then see what those same doses would have done in healthy volunteers, you get a target range of calcium that you'd like to see increase in a healthy volunteer to predict a starting dose in hypoparathyroidism patients.
That amount of calcium increase is probably on about the scale of about 0.3 mg per dL-0.5 mg per dL. We're seeing that in this monkey study, which was promising. The rest of the preclinical development for this compound went smoothly. As I mentioned, it's a potent oral small molecule. PK studies we did across multiple species: mice, rats, dogs, and monkeys. It led to a projected human half-life in the range of about 40 hours-80 hours, which again we think should be compatible with once-daily human dosing. We think anything above 20 hours would be good for once-daily dosing. On the safety side, we did three GLP tox studies: rats, dogs, and cynos for this particular compound.
All we saw was on-target effects. On-target effects of hypercalcemia, no other significant side effects. We were excited about this, decided to move it into the phase I trial. Here's a quick overview of this phase I trial design. We're doing a randomized, placebo-controlled, single ascending dose and multiple ascending dose study. We're doing a food effect study as well. The number of cohorts is a variable here. We're gonna dose escalate. We're gonna be looking primarily at a few things. Safety and tolerability obviously always comes with phase I trial, as does PK. We're gonna be looking at those markers that I just mentioned in that monkey study, endogenous PTH going down and calcium going up.
In terms of the translation to human trials, I mentioned this already. Based on the peptide experience, we sort of know what we want to look for. The objectives of this study are to figure out ultimately what that starting dose should be in hypoparathyroidism patient. With that, we anticipate results from this study either late this year or early next year. It, again, depends on the number of cohorts that we end up doing. Quickly moving on to our second program. This is SEP-631 going after a mast cell target called MRGPRX2. I'll call it X2 for short. Mast cells increasingly important targets of a number of diseases, a number of drugs at this point in time.
Mast cells live in proximity to two important systems in tissues. One are sensory neurons, where they control pain and itch, and then also they're near tissue capillaries. Mast cell degranulation can lead to release of immune cells from those blood vessels as well as edema, and these lead to positive feedback loops of activation. A little bit on SEP-631. This is a very potent compound. It has a mechanism that we call a negative allosteric modulator. A negative allosteric modulator is something that binds outside of the endogenous binding site of the endogenous ligands and turns off the receptor. We've got an insurmountable one here.
We've released some recent data on the potency. We've got a very potent compound, high binding affinity, Ki in the 500 pM range, a very slow off rate when the compound's on the target. It's on the target for hours. Importantly, we've been able to show that we're able to lock the receptor in a very inactive state. What we're looking at here is the receptor. From the extracellular view, you can see the very large binding pocket in teal. We've colored one of the X-ray loops in magenta so we can just follow it. If you look at the transmembrane view, you can see that there's an endogenous ligand that fits in there. That's cortistatin-14.
When SEP-631 binds to MRGPRX2, a very remarkable thing happens, which is the extracellular loop, fold over and basically completely block the binding pocket. This is a unique mechanism where if you take this ability to turn off the receptor combined with the very slow off rate, we're pretty much turning the receptor off. That showed good effects in animal studies, led to this phase I study. Phase I was a single ascending dose, multiple ascending dose study, plus a food effect. Importantly, in the multiple ascending dose portion of the trial, we did a skin challenge test that we think is actually quite relevant to this condition. Importantly, on the safety side, this compound was very well-tolerated, pretty much indistinguishable from placebo, which was great. PK properties were also very promising.
It's got a 24-hour half-life, which we think will sustain once daily dosing. There was no food effect. We should have an oral pill that could be taken any time of the day, which would be great from a convenience standpoint. The data we're particularly excited about is this icatibant skin challenge data. I'll spend a moment telling you about that. Icatibant is a drug that's dosed subcutaneously. It's got an off-target effect on this receptor that leads to mast cell degranulation and a skin reaction. We did two doses of icatibant: 10 mcg per mL and 100 mcg per mL. As well as a negative control, which is saline, and a positive control, which is histamine.
What we wanted to see, if you inject anything into your skin, you get a skin reaction even if it's just saline. We wanted to see how much we could dampen down the response from icatibant to the saline level. This was the data that we shared at the AAAAI meeting a couple months back, which showed that at the low dose of icatibant, we're able to take this response all the way down to saline, even with our lowest dose tested, which was 10 mg once a day, which is quite exciting.
At the high dose of icatibant, which represents a higher bar, we saw a nice dose-dependent squelching of the icatibant's skin response all the way down to baseline as well at the highest doses. We're excited about what we saw here. We think we've got an effective compound, and this data shows that we're effective in humans in the skin. Where are we going with this compound? There are a ton of mast cell indications. Seemingly every day, there's a new publication with roles of mast cells in different disease states. There's many. Most commonplace that everybody goes with this target and mast cells first is chronic spontaneous urticaria.
We're thinking along the same lines of doing that as well. We're planning to do a phase II study in chronic spontaneous urticaria. We're planning to do a chronic inducible urticaria study along the way with that as well. We're also exploring a whole variety of other indications. Many of which are listed there on the right-hand slide, right-hand part of the slide, including atopic dermatitis, interstitial cystitis, migraine, and asthma as well. We're thinking about cost-effective ways to do signal finding studies and other trials. Just really briefly, with regard to our TSH receptor program, this is one that we're going after Graves' disease. Graves' disease is becoming a hotter area of investigation these days.
One thing that makes Graves' disease quite challenging is that every patient develops their own autoantibodies that activate this TSH receptor in both the thyroid gland as well as in the orbital fibroblasts behind the eyes. That's what leads to both thyroid eye disease and the Graves' phenotype. Again, one challenge is every patient has their own antibodies, and they're polyclonal in many cases. We need an approach to basically turn off all the antibodies if we can. Again, once again, we're using a negative allosteric modulator in this particular case as well. In terms of the status of this program, we believe we've got line of sight to a development candidate and hope to have more to say about that later in the year.
With that, I will just kinda quickly wrap up with a snapshot of the pipeline. Things that we're looking for later this year are the phase I data for SEP-479 in the PTH program either late this year or early next year. For SEP-631 getting into phase II later this year. I'll stop there and probably have time for a question or two.
Questions from the audience? I guess when you take a step back and you think of the platform itself, I mean, obviously, G-coupled protein receptors have been, you know, a focus for many drug developers. I guess, you know, what gives you sort of conviction that kind of the approach here is gonna prove much more, I guess, fruitful, especially just given, you know, worries about off-target effects?
Yeah. It's a great question. Maybe I'll just kinda quickly say just a little bit about our platform and a little bit what's different about it. I've got a slide here that shows this. This Native Complex Platform, we found a way to actually get these receptors outside of cells. That's very important. Nobody had actually ever done that before and kept them functional. They cross the cell membrane seven times. They will quickly denature if you take them out. We found a way to reconstitute them with all of their natural binding partners, including the G proteins, ligands, all in an artificial lipid bilayer. This has allowed us to do structural biology at an unprecedented pace. We've solved more than 150 high-resolution structures for each of our programs to date with this platform.
We've found novel binding pockets that the world didn't know about. Many times they've been cryptic inducible pockets as well. We've also got technologies to allow us to screen billions of compounds and use the combination of technologies to optimize quite quickly. We think we've got a competitive advantage at the early part of drug discovery to find novel binding pockets. We've got, you know, the evidence. Finding small molecule agonists for peptide GPCRs has been a big breakthrough for us. Also finding allosteric modulators is something that the whole world has struggled with.
Dr. Finer, thank you so much.
Okay. Thanks.
Bank of America Healthcare Conference in extremely toasty Las Vegas. Ending up our final talk of the day, I'm very pleased to have join us the team from NewAmsterdam . This is Ian Somaiya and BJ Jones, Chief Commercial Officer. Gentlemen, thank you so much for joining us. Pleasure.
Yeah, thanks for the invite.
Maybe just to start at a high level for those maybe not as familiar with the NewAmsterdam story, can you give us a brief overview of the company and obicetrapib?
Sure. Look, it's been an exciting couple of years. Obviously, we've shared a lot of data with you from our phase III studies for both of our lead programs, obicetrapib as well as the combination with ezetimibe. Really the goal is to help redefine how patients with elevated LDL are being treated today. The data from the phase III studies has been, you know, quite consistent with the monotherapy showing somewhere between a 35% and 40% reduction in LDL. The combination with benefit, that's in the 50% range. The benefit goes beyond LDL.
That's, you know, when I, when I said, the opportunity is to redefine, the care of patients, is looking at the LDL plus characteristics of the drug. It's the roughly 50% reduction in Lp(a). It's the improvements that are driven by the HDL raising profile of the drug, which include the reduction in the rate of new onset of diabetes, the improvement in kidney function that we recently reported at the ACC, as well as the early Alzheimer's signal, which we're going to be further exploring in short order in a phase II-B study. That gives you a sense for kind of what we've shared over the past two years.
More recently, and specifically last week, we provided an update on our outcome study where based on an evaluation of the blinded data, what we're continuing to see, from, you know, now up through the two-year mark is a continued decrease in the overall event rate, which is obviously quite encouraging. Although the data remains blinded, the comparisons we can make are to our BROADWAY study, which was nearly identical in design, and was conducted at the same time, the first 2.5 years of BROADWAY are the same 2.5 years of PREVAIL. Given the overlapping patient populations, it makes for a very unique basis for comparison.
The fact that the one-year data of PREVAIL on a blinded basis look comparable or in line with what we saw on BROADWAY and now observing the two-year mark where the trends are continuing to be quite encouraging, you know, what we decided to do. We announced this last week, was introduce an interim analysis, which will be triggered by the end of this year. The results shared in the first quarter of next year, where we feel good about the potential for that trial, for the, for the interim to lead to the trial concluding. If we're wrong and the trial needs to continue, we're looking at an extension that goes into the end of next year.
Overall, we think we have two opportunities to deliver on what we expect to be a positive PREVAIL outcome. That ultimately unlocking the what we expect to be a blockbuster opportunity for the drug.
A lot to pick apart there, but maybe let's just start with is there one output that's truly differentiating between ApoB, Lp(a), LDL particles, or is it just the overall breadth of what you can lower there?
Yeah. Do you want to speak to that from a commercialization standpoint?
Sure, I'm happy to. The first thing we need to do, and we've done effectively, is just make sure can we actually address what is the primary, like, metric in some sense, right? That's what's the efficacy associated with LDL. We feel very confident in that regard, as Ian just walked through that data for you. We can say that we are consistent and kind of best in class in terms of efficacy around LDL. We can also say that best in class as it relates to safety and tolerability. We're an oral, obviously. We're in a space in which we're not SNAC technology. We don't have to worry about like, you know, eating and issues of that sort.
It's a very different profile than what's either currently on market or coming to market. That relative benefit that we also see across Lp(a) and diabetes, and small particles, and as Ian also mentioned, you know, the hope in what we see kind of initial in terms of Alzheimer's, in APOE4 folks. I wouldn't say it's any one particular incremental benefit, i t's the host of those benefits. Because what we're doing essentially is like reducing what is the overall risk. Again, with all the primary research we've done with over 1,000 doctors over years now, and basically shown our TPP versus others currently on market or coming. Others will do well. It's a massive market and there's tremendous unmet need, but consistently it shows that obi, obi ce will do better than those competitors.
Well, you open up a great question. How many patients, you know, don't currently achieve their LDL-C goals? To what extent is this going to be structural versus the pharmacological? You know, when you think about how can an asset like obicetrapib, you know, both capture and grow share?
Well, I'd say-
No, please.
Yeah, is that, you know, when we look at essentially kind of what's happening in the marketplace today, sadly, frankly, you know, tremendous number of patients are actually just not meeting goal. You know, they start on statins, and they do well, but not well enough. What we found is that, you know, even current data basically says there are about 30 million of those folks who are actually not achieving what is their base goal and the target. Now that target is shifting, going to be more difficult to get to, if you will, because of the guidelines, the evolution of guidelines, which is very good for clinicians and for patients to get people actually where they need to be.
Again, we're talking about tens of millions of folks who are kind of in that sweet spot of where we would be used in addition to, you know, the statin. I would say that again, you know, it's there's You asked the question around is it structural, you know, in some sense. It's just a means of people actually, whether they be specialists, but especially in primary care, is that today there's this apathy. Not only on the clinician side, but the patient side as well, in terms of if I just put somebody on a statin is good enough, right? Like I've done my job.
The hope is that in the very near term, we start to see a more aggressive nature in terms of prescribing and really looking to achieve the goals that are necessary to get to the outcomes we're looking for to reduce this overall tremendous burden in CV.
The most important data set that we've seen to drive home that point is Amgen's study, VESALIUS, where in this patient population, the benefit that you can provide by effectively managing LDL in terms of reducing overall risk became quite clear. There was a 19% improvement in their MACE-4 number, 25% when it came to MACE-3, and those are the hard endpoints. For the first time with that drug, we saw a mortality benefit. They addressed one of their biggest criticisms from their secondary prevention trial. There's obviously the guideline changes that BJ spoke to. There's clear clinical evidence. This is the way Europe's been treating patients for forever.
It's the opportunity for the U.S. to catch up, and that 30 million patient number, we don't know what the where that number goes. We could easily be looking at an opportunity that's twice as large as what we had only a couple of months ago. That's why really every company, every drug has the opportunity to benefit. As long as we focus on driving that point home, manage your LDL, get the patients to goal. All options available to them will get utilized.
Maybe we could drill down a little bit deeper into this, Ian. Obviously, you have the expanded use of the parenteral PCSK9s in, you know, first-line setting, but now the orals as well. Is that a risk at all to obi?
Yeah. Well. Look, I learn a lot from BJ, and then obviously these are all commercial-bent questions, so I wanna make sure that he has an opportunity to give his answer.
No, absolutely. We actually don't see this as a risk in some sense at all. Frankly, as we've said, the market is just so large. It's such tremendous unmet need is that it's a good thing for doctors to actually have options and patients to have options as well. What we see in the near term is tremendous increase in terms of overall utilization of branded meds in this space. Even as ezetimibe, right is growing at 20% year-over-year, and in the branded space, driven primarily by Repatha, is growing at, you know, 40% +. We expect that to continue. We look forward to what is, you know, the Merck launch in the near term for PCSK9.
They're going to continue to fuel, right, and promote branded, but also unbranded, right, to get to patients to activate, right, them. That's all positive. Frankly, honestly, it's wind in our sails because when we enter the marketplace, the market will be much bigger. Doctors' and patients' behavior will be changing as well, where they're looking now to address this in a more aggressive way. We come to the marketplace with actually a better, right, opportunity that can not only address LDL, but also the incremental benefits we talked about. We look forward to that.
In order to demonstrate this superiority, can you maybe give us a sense of BROOKLYN, BROADWAY, TANDEM, incremental insights that you provided at ACC, just recently? What stands out in terms of efficacy and differentiation, and how did the data position obi relative to these other approaches?
Just from a clinical perspective. If you look at data, whether it's the drugs that are on the market today or the drugs that are in development, the benefit is primarily limited to reduction of LDL, which is obviously, you know, very important. The risk that these patients experience goes well beyond that. As we look at the other populations where, you know, risk remains, it's the Lp(a) aspect of it. Obviously, at some point this year, we'll get data from HORIZON, and there are other trials that will follow. We'll have an answer to the question, how much risk is there with Lp(a) ?
When you look at the available options today and the ones in development, we have a pretty dramatic effect on that risk factor. As you think about the LDL particles, CETP is central to the production of small particles. What we've seen in our data set is complete elimination of the small particles. As you know, focus on residual risk with a patient that's on a statin or a combination of a statin or other drugs, this is one aspect, one key aspect of it, which differentiates us from other molecules. The same is true for diabetes.
Diabetes is a risk factor, and that's something that we've Not only us, in terms of obicetrapib in our phase III data, but really the CETP class has consistently shown roughly a 15% reduction in the rate of new onset of diabetes and related endpoints. This is yet another point of differentiation. When you look at statins, the higher the dose of statins, the greater the risk of diabetes. If you're on the highest dose of statins, your risk increases by roughly 35%. There is an opportunity for us to combine with a statin, potentially bring the dose down of that statin and still get the patient to goal.
If we look at the combination data, this is the combination of ezetimibe and the TANDEM study results, we're able to get vast majority of patients to goal, even the new goal, the revised goal of 55 mg per dL. We think this is an ideal product, and the timing couldn't be better. We spoke to the guideline changes. But when you look at the labels, the labels have all been harmonized now. If you have a successful outcome study, what you inherit is a label for treatment of all patients with elevated LDL.
Your MACE benefit is no longer limited to the individual components of MACE where you hit stat sig, you get the full benefit and the label claim for that. It's the harmonization of the labels, it's the treatment guidelines, it's the resetting of the price many years ago, which has opened up payer access and the benefit of having multiple companies saying the same thing, which is get patients' LDL under control.
With that in mind, then why wait for PREVAIL?
Yeah.
Before filing? You know, again, if LDL-C is recognized-
Yeah.
... as validated surrogate for CV risk, you know, how necessary is kind of that standalone outcomes?
Yeah. We still operate within IRA. That's the big consideration for all of us as we contemplate launches in the U.S. Based on the market research BJ and his team have done, what's quite clear is that if we deliver on positive outcomes data, and it's either sort of a yes or no, right? As long as we have the data, we get the broad label and we get broad payer access. That's what's limiting or informing the timing of the filing and approval in the U.S.
Okay. The last one from me. You know, obviously a few days ago with your earnings, you provided an early update on PREVAIL. What are the key implications here as you look towards the first quarter 2027 readout?
Yeah. The update we provided calls for an interim analysis of the results of the interim becoming known to us in the first quarter of next year. Again, if the DSMB recommends that the trial continue, we'll be, we'll get to the requisite target event rate by the end of next year. The implications to the investment community and to us as a company is we just increased the probability of success. We feel very good about the trends that we're seeing. We're encouraged by the observed MACE event rate or the individual events as well as the composite. We believe they're tracking well for us to be able to potentially stop the study at the interim time point, and if we're wrong.
If the DSMB exercises discretion, which they fully have, and recommends that we continue the trial because they're encouraged by some other signal that they're seeing in the trial and they want that data to mature, then we'll continue the trial into the end of the year. If we continue the end of the year, there'll be many more events that will support potentially achieving statistical significance, and as a result, the risk of success increases. I think we've taken at this point every step we potentially can to de-risk the outcome, and as Michael Davidson, our CEO likes to say, ensure that the trial is designed and executed in a manner which allows the drug to succeed.
Ian, BJ, thank you so much for joining us and appreciate you coming by.
Yep.
Thanks for everyone sticking around till the end. Thank you.
Thanks, everyone.