Great. Welcome, everyone. Welcome to the team from Keros. Very glad to have you, and welcome to an afternoon session here at the Goldman Sachs Global Healthcare Conference. It's been a long day, apparently. Beautiful. So maybe we'll just start with an overview and an introduction to the company. If you could focus on the pipeline and what you view as the key value drivers for the story over the next couple of years.
Keros is a clinical stage biopharmaceutical company. We have three product candidates that all target the TGF-β superfamily. The most advanced program, KER-050 and elritercept, is in phase 2 trials in MDS and myelofibrosis. We engage with regulators on the design of a phase 3 trial. We'll be sharing more details on that next week.
Monday.
Yes. Elritercept is also in a phase 2 myelofibrosis trial. We'll have additional data readout from that at the end of this week.
Perfect.
And so investors will get to see that data. And then our KER-012 is in PAH trial, which is going really well. And we anticipate that we will have full enrollment in the phase 2 trial in the fourth quarter of this year. We just announced that also last week. And that sort of guides you into 2025 as to when the top-line data would be. And then our third product candidate targets ligands that are negative regulators of skeletal muscle, so increases skeletal muscle, which is a great place for that drug in obesity, where increasing skeletal muscle can reduce fat mass by increasing utilization of fat. So I think over the next two to three years, you're seeing a lot of data readouts. But really, the company is moving from early development to late-stage development, right? So it's a good space for the company.
Great. Well, we'll spend time on all of the programs, but I think I might go backwards of your order.
Sure.
You mentioned KER-065. The asset was previously in development for some muscular dystrophies, but you made the decision earlier this year to pursue proof of concept in obesity. Maybe you could just provide some more background on that decision and the mechanism of action as relevant for obesity?
Yeah. So why shift from neuromuscular to obesity?
Yeah.
Well, look, we were thinking about it for neuromuscular indications because in many of those neuromuscular indications, you have muscle wasting. So you are treating the muscle that is deteriorating with that drug. However, in some of the neuromuscular indications, for example, Duchenne, the treatment standard of care is treatment with glucocorticoids, which also result in muscle loss, but also increase in body adiposity. So the boys with Duchenne, as they transition into being young men, actually have all of the metabolic syndrome that you see in obese individuals. So we thought it was the right place for us to go. However, I think over the last 12 months, we've seen the market for GLP-1 receptor agonists explode. And therefore, the potential to treat the side effects of those GLP therapies, which is muscle loss increase, and the market has been excited.
We thought it was the right time for us to pivot to that.
Great. And maybe spend some more time on the mechanism, but also if you could include in that conversation, there's a number of adjacent sort of approaches, all targeting activin A, doing it in various manners. So maybe you could help us understand kind of the mechanism of targeting myostatin and activin A, why you think both are important, and how you think about the modality that you've chosen relative to kind of the competitive landscape.
Yeah.
I know that's a very big question.
Yeah. And I'll try to address it in a concise manner. I think what we've learned over the years is that there are multiple molecules in this TGF-β pathway that are negative regulators of skeletal muscle. So myostatin is one of those, and we learned about that in the '90s. However, myostatin is only one of those ligands. And activin A is the other ligand that is a negative regulator of skeletal muscle. And they both happen to signal through the same receptors. Therefore, if you inhibit one, but you leave the other one alone, you are not going to get the maximum effect. And it just so happens that the data that we had early on from rodents has misled us a little bit in that in rodents, myostatin levels are very high. However, in primates, including humans, the activin A levels are very high, and myostatin levels are low.
Therefore, we did not see the efficacy that we predicted from myostatin inhibition treatments translate to humans. You see the same biology, but the magnitude of the effect declined as we went up the evolutionary tree. So I think the data, when you inhibit both myostatin and activin A, and that's Regeneron's approach with two different antibodies, the bimagrumab-Lilly approach is to target the receptors that these ligands signal through. And our approach is to bind up the ligands, the multiple ligands, and inhibit them that way. However, there is the selective approach of inhibiting myostatin on its own, Scholar, and Biohaven. Okay, right? I think those are viable, but they are not going to give you the potency that you can get from the Regeneron, the bimagrumab approach, Lilly, and 065.
It does come with some trade-offs. Maybe you could talk to us about the trade-offs that you expect in terms of safety when you hit activin A, but why you think that's worth it?
I think activin A inhibition is always going to result in contraceptive properties. So while you're on the drug, you will see reduction in sperm count, and you will see halting of ovulation. However, it's a contraceptive. So as soon as the drug is no longer there, reproductive activity returns to the normal. So I think that is the side effect that is going to be there, whether it's with 065, whether it's with bimagrumab or other approaches that target activin A. It's always going to be it's going to be a class effect. Not true with the myostatin antibodies, but there, okay, you're going to have minimal activity as well.
Okay. In order to get the efficacy you need, the safety comes with it, but manageable.
Yes.
Yeah. And then in terms of the selectivity profile for some of these other TGF-β family members, I guess, are there any others where, based on the preclinical data, you'd expect to see activity? And what are the relevant implications from a safety perspective? And I think in particular, there's some conversation on GDF-11.
Yeah. I think that's a red herring.
Okay. Expand.
Right. It's a red herring because myostatin antibodies that went into the clinic, including Lilly myostatin antibody, bound GDF-11 very tightly. So you did inhibit GDF-11, and yet they showed no safety signals beyond, okay, the more selective myostatin antibodies. So I think this notion that inhibiting GDF-11 could result in safety signals is driven by the knockout mice. When you delete during embryogenesis GDF-11, you observe skeletal defects. That has been observed with many, many different molecules. But treatment of a newborn or an adult mouse with an inhibitor of GDF-11 has not shown to have any safety signals. So in many ways, people think it's a theoretical, but I think the data is already there because Lilly took their myostatin antibody, which bound myostatin and GDF-11 equally tightly, and they saw nothing in those studies. And they were 12 months of treatment in male individuals.
Okay. That's helpful. You're currently enrolling a proof of concept study for this asset. I guess, can you lay out the key design features of that study and provide a status update in terms of enrollment?
Yeah. So it's a two-part study, single-ascending dose, where individuals get one dose, and then they're monitored for three months to evaluate the safety. We'll always look at some biomarkers and so on, but it's a very small study with Ns of four, and therefore, you're not going to get any substantive efficacy data from that. So you're marching quickly through the dose escalation in the single-ascending dose. Then in the multiple-ascending dose, we do three months of treatment. Now things get exciting because in three months, you can see changes in lean mass. You can see changes in fat mass. So in the multiple-ascending doses is where we now include biomarkers of lean mass by looking at imaging techniques, DEXA, MRI. You can look at the skeletal muscle and the fat at the same time. So that's included.
In addition, we enrich that patient population in the multiple ascending dose to be men 18-55 with a BMI of 27-33, so overweight to obese. And that data should be there in Q1 of 2025.
Okay. So as you think about the endpoints to watch particularly change in BMI, I guess, what would you view as a good outcome that would provide kind of basis to go forward with this program?
Yeah. What I would like to see is an increase in the lean mass of muscle and a decrease in fat mass. Now, based upon previous experience with these kinds of molecules, if this was a study in healthy postmenopausal women, I think we'd be looking at 3%-5% increase in lean mass over three months and a similar decrease in fat mass. This is a male population. It's overweight to obese. So I would expect to see changes, right? I can't actually give you what the magnitude would be.
Okay. As you think about, you said increase. So by that, you mean an absolute increase or a stabilization relative to what you would see with other?
You'd see an absolute increase in lean mass and a decrease in fat mass. Now, it just so happens mechanistically with all of these molecules, it's not going to be any different from bodybuilders, where as you increase that exercise, you build the muscle. So you actually gain weight, and then that muscle burns more energy, and therefore, then you lose. So with time, you'll see a reduction in weight. But this study is so small, I don't think you're going to see that, okay?
Okay. So pending the results look like what you just outlined, what are the next steps for the program? And at what stage do you start to think about partnership?
Thinking about partnerships today, right, simply because I think the mechanism is there. People understand it. Now the question is, does a partner see enough value? Do they see enough value after you've got a phase 1 data or after phase 2? I'm prepared to take it all the way through to phase 2 in order to capitalize on the opportunity.
Okay. And then as you think about, and it sounds like this question will be one for you and a potential partner, but as you think about the registrational path, this has been a source of a lot of questions around this particular mechanism. And so what do you think the right endpoints will be to show both the kind of obvious benefits around weight, but the differentiation between a drug that improves lean mass and drugs that are simply just lowering weight?
Yeah. I think in the end, that's going to be really difficult to show in short-term studies. I think what we're really talking about is the benefit is in terms of ameliorating the sarcopenia, the frailty. And that's going to require somebody to be willing to take the drug into frailty, burst into obesity. And then really, the bigger opportunity is in all frailty. So I think somebody has to have the right vision. In terms of registration strategy, you could get a drug registered as a treatment of obesity by showing a 5% decrease in body weight.
Sure. So it's a straightforward path to approval. It's the question of then showing differentiation to get utilization where.
That's right. Because remember, payers are not necessarily going to pay you for reimburse you for decrease in body weight, okay? They want all of the benefits to be shown, right? The cardiovascular benefit, the renal benefits, right? The metabolic benefits. Well, the metabolic benefits, you'll be able to show in short-term studies, okay? You're going to get improvements in insulin sensitivity. You're going to get a reduction in A1C. You're going to get reduction in lipids and all of them. You could do that in a 6, 12-month study. But cardiovascular events, right? Renal, right? Those are going to take a lot longer study.
Okay. As you think about the market opportunity then for this class of therapies, where do you think they're going to fit relative to what I think GS estimates are now $130 billion in terms of market opportunity for obesity? Where does this fit?
I think it fits in combination with GLP-1 therapies. It fits in weaning patients off GLP-1 therapy. And it could even be in patients that don't tolerate GLP-1 therapy. After all, a significant number of patients just don't tolerate the receptor agonist long enough to benefit from those. So I think those are all opportunities, and they're not insignificant.
Great. You also have an earlier stage asset, KER-034. I guess, how does it compare to 065? And what's your strategic rationale for having this second program in the space?
Yeah. It's very similar in terms of its pharmacologic properties. Half-life, effect on skeletal muscle, fat mass, and so on. But it is a different molecule at the amino acid sequence level. So therefore, it's a different molecular entity. Now you can think about two very different indications where reimbursement is at different levels, and you can take those two molecules in those two different directions.
Okay. That's a great segue into my next question, which is still have interest in the kind of muscular degeneration, muscular dystrophy space.
I've had it for 20+ years. It's not going away.
Perfect. And so now you have the flexibility with the two assets.
That's right.
Okay. Maybe we'll switch gears here to 012. This is another program that's in relatively early stages of development in pulmonary arterial hypertension. It's obviously very similar to the approved drug, Winrevair. So maybe talk to us about the mechanistic similarities, but also differences between those two agents.
So mechanistic similarities is that Sotatercept , WINREVAIR is an activin receptor ligand trap. It inhibits activin. Activin A signaling is increased in PAH patients. And in PAH patients, bone morphogenic protein, the other side of the arm of the signaling pathway, is decreased. And the whole concept of sotatercept was that if you inhibit the activin arm, you will increase the influence of the BMP arm. And they achieved that. However, WINREVAIR, activin receptors sequence, it binds many of the that you get. It's not as great as you could if you had a molecule that didn't bind BMP. That's what KER-012 is. It's been designed so that it has the ability to inhibit the activins while sparing on the BMP. Now, as a consequence, we think that you're going to have a better window in terms of efficacy, but also a better window in terms of safety.
Winrevair could never be dosed at the doses where you can get maximum target engagement. Why? Because it has this other biology of increasing red blood cells. And therefore, you have to limit the increase in red blood cells to 1 gram per deciliter or 1.5 gram per deciliter. Therefore, you could only go at the very low doses of 0.3 and 0.7, where you got roughly up to about 40% target engagement from your first dose. But with the dosing regimen they used, you can get up to 60% target engagement. So is there additional efficacy that you can get when you go to 90%, 100% target? That experiment could never be done with Winrevair. We can do that experiment, right?
Okay. Where are you in terms of that experiment then in patients? How high have you been able to dose, or what would you expect the target engagement to be at doses you've explored?
In the healthy volunteer study, we went up to 4.5 mg per kg, which is maximum target engagement. We were able to show that. We were able to show that we don't see the safety signals that sotatercept, Winrevair, including increases in red blood cells that were observed with that. So I think that data is already there.
Yeah. In terms of clinical sequelae that you see associated with that red blood cell increase, what are some of the key kind of adverse events that we see with Winrevair that you would expect to not have in the context of this program?
Yeah. I think when you look at the label, they're actually spelled out for you. Okay? The first one is that erythrocytosis, red blood cell increase. And lumped in with that is hyperviscosity syndrome. So when you increase red blood cells or you increase the viscosity of the blood by increasing the amount of circulating proteins in the blood, that viscous blood results in breakage of blood vessels. And it happens in tissue where the tissue are very well vascularized. You see it in the liver. You see it in the gut. You see it in the brain. You see it in the lungs and also in the kidneys. So if you look at the label, you see actually evidence of many of those bleeding events, okay? Right? Now, with 012, all of the studies we've done, we don't think we are going to get cytosis, right?
Eventually, the proof is in the clinical setting.
Sure. That brings me to the next clinical update, which I think could be later this year from a heart failure study. What should we be looking for within that data? Will it be enough kind of time on therapy in patients to start to prove this out? And kind of what should we be looking for out of that data?
I don't think that study is long enough in duration to show you anything. The reason for that study was very simple. We were getting asked the question by investors. You've already shown in your phase one study that you're having benefit on the biology that sotatercept said, Winrevair showed. How do you know this is going to affect the vasculature? After all, that's what you wanted to show. So we showed that, and we showed in the healthy volunteers that you can reduce NT-proBNP with a single treatment. The next question is, well, yes, that's all very well, but these individuals don't have elevated NT-proBNP. So what about in patients that have elevated NT-proBNP? Well, we showed that with our other program, KER-050 in MDS, where the second leading cause of death is cardiovascular events. Patients have elevated NT-proBNP.
The pharmacology overlaps with 050, and we showed reductions in NT-proBNP. So this study is designed to show changes in NT-proBNP in patients that have elevated NT-proBNP. Today, I think we've generated all of the data that de-risked the program already.
Okay. So not a ton of discovery value for you in this program, but maybe for others.
Maybe.
Confirmation, if you will. Can you?
I think the most important thing for us, okay, right? And I think for investors to focus getting to TROPOS phase 2 data, which I'm sure you're going to ask.
Great segue to my next question. Can you provide a status update on the TROPOS study in terms of enrollment and when we can see data? I think you kind of alluded to this earlier.
Yeah. I think we shared last week that the enrollment is going really well. We believe we will have the 90th patient in treatment in the fourth quarter of this year. Study is 24 weeks of treatment. Therefore, once we know the 90th patient is in treatment, you can estimate that 24 weeks later, they're out. Then a couple of months to 3 months is top-line data.
Sure. Okay. Remind us how that study was designed. What are the parameters and endpoints that you're looking at? What kind of patients did you enroll? Let's just talk about those benchmarks.
Yeah. It's a classic PAH trial with all the same patients that were in all the other trials. There are three dose levels being explored: low dose of 1.5, 3, and 4.5 mg per kg. At the lowest dose of 1.5 mg per kg, we get exposures that are comparable to what was achieved with Winrevair. Then at the highest dose, 4.5 mg per kg, we have the opportunity to explore maximum target engagement. Each cohort treatment arm has got 20 patients per arm. So 60 on treatment, 30 patients in the placebo. So 90 in total. The study is powered to be able to look at the primary endpoint, which is pulmonary vascular resistance in the placebo versus the treatment arms pooled together. Secondary endpoints include six-minute walk tests, etc. But it's a very standard study, PVR being the primary endpoint.
Okay. So as you think about what you'd like to see to make a go-no-go decision post-op program, I guess, what's the best-case scenario sort of result?
I think we want to see PVR changes similar to what were observed with sotatercept, where at the 0.3 mg per kg, it was about 150 dynes reduction and 250 at the 0.7. So in that magnitude, that's what we want to see. I think we see that at a low dose. Then the question is, can we see more at a higher dose? And if we don't, okay, right, let's say that we've captured all the biology that can be captured by this pathway in this patient population. Then that gives us really great opportunity to go into the phase 3 with a single fixed dose on a monthly schedule. That's a pretty exciting place to be.
Will that data be far enough along that you can really start to make conclusive statements around the safety differentiation?
I think we will have enough data to be able to see those signals, but they may not be conclusive enough, okay? Because those safety events, they're small in numbers. This is a small study. I think this is where actually the preclinical data gives you better guidance.
More insights while they're here.
Yeah. Yeah.
Okay. And then maybe last one on this program, but obviously, you'd move into a phase 3 then in PAH. How do you think about the full spectrum of PAH in terms of development programs from early to late?
Yeah. I think if you've got a very safe drug, you can go earlier and earlier in treatment, right? So if you don't have bleeding events and it's a relatively benign drug, okay, you can actually go into newly diagnosed patients. I think if you've got a drug that can give you greater efficacy, you can then also think about later-stage patients. I think some of the biology that you see in PAH is also the biology you see in fibrotic lung disease like IPF. So those are opportunities as well. So I think this study will give us enough data to be able to start thinking about the broader development program.
Maybe with our last few minutes, we can talk about 050. I know you've got an unveil next Monday in terms of the regulatory path there. But first, maybe just give us a rundown in terms of the asset and the data that you've seen to date, including the differentiation in what's kind of an increasingly crowded lower-risk myelodysplastic syndrome market.
Yeah. I think where in the low-risk market, MDS marketplace, you see a need is still for a drug that can treat the harder-to-treat patients. Early on in diagnosis, patients respond well to ESAs. They're anemic. Many of them don't even go on any treatments, right? They're anemic, but their hemoglobin is maintained. As the hemoglobin starts declining further, they go on ESAs. They respond for a period of time. And then today, they go on to luspatercept if you're RS positive. Now, with the study that Bristol did that they shared last year, the time on ESAs is getting shorter and shorter. However, the duration of treatment still doesn't change, okay, right? Because these patients eventually, their bone marrow continues to deteriorate and thereby stop responding to ESAs, stop responding to luspatercept. Just recently, okay, last week, imetelstat was approved.
It's able to treat patients with more disease burden. However, you've got significant safety signals with that thrombocytopenia. 050 has shown to have a very benign safety profile to date. It's well tolerated, and yet it treats these harder-to-treat patients. So you can imagine a patient going on treatment early on and being able to stay on the treatment as their bone marrow continues to progress in terms of the disease.
I'm not sure how much you'll tease before Monday, but maybe you can remind us what, when you went in to have this conversation with regulators, your wish list is with respect to the registrational trial design?
You want to go in with looking for the broadest patient population, RS, non-RS, low transfusion burden, high transfusion burden. That is the ideal situation. That's what we went in with. And then you want to get alignment on the registration endpoint. What is your registration endpoint? Historically, it's been 8 weeks of transfusion independence in the first 24 weeks, but there's also been the rolling 8-week window, as was the case with Imetelstat. We need to get alignment on what should be our registration endpoint, primary registration endpoint. Durability of response is important. So what is your secondary endpoint that indicates durability of response? Because at the end of the day, patients don't want to be switching treatment. Physicians don't want to be switching their patients on treatment. So durability of response is important, as is how you feel when you're on the treatment.
We've shared data last year at ASH that patients that go on elritercept actually feel better, and the responders feel less fatigued, which is a good thing for the drug.
So with this phase 3 study in place, I guess, what is your expectation around kind of ability to enroll the trial now that we've got some of these other drugs on the market?
I think in the U.S., patients coming on elritercept phase three are going to be patients that are not reimbursed or where the physician has clearly made a decision that their bone marrow is already sufficiently compromised that they're not going to respond to any of the other treatments, right? So I think we're going to have fewer patients than if those drugs were not available in the U.S. However, I think across the globe, there are still many countries where these treatments are not available. So we think we'll be able to enroll. We don't think it's going to be a huge impact, but it does mean, okay, we're going to have to go into countries where these treatments aren't available in order to supplement the patient.
One of the things you've reported data on beyond just the patient quality of life endpoints is things like NT-proBNP, which you referenced, and some other kind of secondary benefits of the drug. How do you think about using those to differentiate the program?
Yeah. I think once we start our phase three with 050, we have to look at other phase two studies or additional phase three studies that now go in and capture those benefits separately. I think it has to be part of the lifecycle management of the program. You start with a study that's going to get you registered. And then you look at what are the other benefits and design studies to capture those. Because you don't want to throw everything into this same phase three study. It's going to get to be too big, too cumbersome.
Okay. Now that you have alignment, how quickly can you move into the clinic with this phase 3 program?
I think it's typically from the time that you get alignment with the regulator. It takes you another 2-3 months to get alignment and the protocol to work with your key opinion leaders. And so we will share that in the second half of the year. And then it can take operationally another 6 months or so to get the study started.
Okay. We're running a little close on time, but maybe you could briefly tease what we'll see on Friday. What are the key takeaways you'd like us to focus on?
I think on the MDS, it's going to be the continued data readout from the patients that were there at ASH, a few additional patients. But really, on the durability of response, the longer the durability of response, the better it is for patients. I think that's going to be the case. The fatigue scores, that's important. And then I think we've already shared all of the biomarkers, but there will be updates on those. And then in myelofibrosis, we only shared data from the lowest dose cohorts in the dose escalation. The 3 mg and 4.5 mg per kg given monthly, those patients had not had sufficient duration of treatment to be efficacy evaluable. They are now, and therefore, you're going to see data from those patients.
Great. And maybe last question, have to ask because it's biotech. Give us an update on your cash runway and the milestones that are included within the guidance there?
We have $440 million in cash, which gives us runway into Q1 of 2027. So it's a long runway. What's included in that is completion of the TROPOS trial, start of the MDS trial, completion of the phase 1 healthy volunteer study. Does not include the phase 3 TROPOS or a myelofibrosis study that could happen over the next 3 years. So we'll have to raise additional capital. But I think there's enough significant milestones before that.
Perfect. Well, thank you so much for joining us, and thanks to everyone who joined us here and on the webcast. Thank you.
Thank you.