All right, good day, everyone. Welcome to day three of Cantor's Global Healthcare Conference. My name is Prakhar Agrawal, I'm a biotech analyst here, and for our first session of today, we have Keros Therapeutics, and representing Keros is Jas Seehra, Chief Executive Officer. Jas, thank you for joining us.
Prakhar, thank you for having us and giving us the opportunity to have this chat.
Yeah, a very exciting time for Keros. So maybe we'll just dig into the specifics-
Sure.
If you don't mind. Your lead asset, KER-012, is right now in a phase II trial in PAH. Maybe to level set for folks who may not be that familiar with the asset, sotatercept, which is your key competitor in this space, has shown good efficacy and has seen a very strong uptake. So how does KER-012 improve upon that profile?
I think sotatercept has been a breakthrough for the field. It demonstrates a new mechanism, and that's all very good. Sotatercept was never designed for this indication. You know, as most people are aware, sotatercept started life in the clinic initially as a bone drug, became an anemia drug, and eventually, it was returned to Acceleron for PAH. The big observation with sotatercept was the increase in red blood cells, and therefore, when Acceleron was thinking of repurposing it for PAH, they had to thread that needle between getting enough target engagement and minimizing that increase in hemoglobin to levels that are acceptable to regulators, namely less than one and a half grams per deciliter.
With the dosing scheme of every three weeks, you can get sufficient target engagement to see the efficacy, but it also now comes with this increase in red blood cells and other bleeding events that have been observed, which are part and parcel of the biology of sotatercept. How do you improve on that? First thing is that you have a molecule that doesn't increase red blood cells, so that you can get maximum target engagement and therefore potential for greater efficacy. Without the increase in red blood cells, you'll also have less monitoring, and the bleeding events may also be related to increases in red blood cells.
Okay.
So you could end up with greater efficacy and a better safety profile, so and either is a win. The two together, okay, right, is really, could be very remarkable.
Okay, and so your drug is BMP sparing. Maybe just walk us through the genetic or preclinical evidence out there that BMP sparing could lead to lower bleeding risk.
I think actually the clinical evidence is really very strong. There's a disease called hereditary hemorrhagic telangiectasia. These patients have genetic mutations that result in 50% loss of signaling of one of the BMPs, BMP9, and as a consequence, these patients are born fine. However, as they mature, towards the end of their first decade of life, they begin to show these telangiectasias, and then in the second and third decade of life, those telangiectasias lead to severe bleeding events, gastrointestinal bleeds, cranial bleeds that can lead to death. So it takes a long time with just 50% loss of BMP9 to see this. Then there's the activin receptor IIB, the ligand trap was taken into the clinic by Acceleron and by Atara, and both of them saw bleeding events in a much shorter period of time because you had much greater target engagement.
With both of those molecules and the dosing regimens used, you'd get 90% or more inhibition of BMP9, and now you were seeing bleeding events in the course of 4-6 weeks, okay? So I think the clinical evidence is there, that inhibiting these BMPs leads to increased risk of bleeding events.
Okay. And you had run a phase I trial, so in your phase I, you have shown some PD markers, FSH and BSAP. So just walk us through how the data for KER-012 compare with Sotatercept on those PD markers for the different doses.
Yeah. So with sotatercept, at the highest dose that was tested in the phase I healthy volunteer study via IV dosing of three mg per kg, you got 45% inhibition of FSH. And we know that FSH in post-menopausal women is still controlled through two axes: activin receptor signaling, as well as the GnRH pathway. And there's equal contribution of the two, therefore, if you get 50% inhibition of FSH, that's 100% target engagement and inhibition of the activin receptor signaling. So at three mg per kg IV dosing, which would be equivalent to four and a half to five mg per kg subcutaneous administration, you got maximum target engagement with sotatercept. They are dosing at 0.3 and 0.7 in the phase 2 study. At 0.7, you'll get about 40% target engagement.
That's our calculation based upon the pre-clinical data. With zero, one, two, cibotercept, we also see roughly 50% target engagement at-- Sorry, 50% inhibition of FSH at the highest dose of 4.5 mg per kg. So they're equivalent in terms of inhibition. Sotatercept has a longer half-life, we have a shorter half-life. Other than that, okay, right, you are able to get to the same target engagement. When it comes to BMP signaling, that will show up as bone-specific alk phos, because in the bone, activins promote the bone-resorbing cells, osteoclasts. BMPs promote the bone-forming cells, osteoblasts. Bone-specific alk phos is a marker of bone osteoblasts laying down new mineralizing surface, okay? So when the bone-specific alk phos goes up, it's because you've activated that pathway.
You see with zero, one, two equivalent increases in bone-specific alk phos at low doses of point seven five and one and a half mgs that were observed with sotatercept at maximum doses of three mgs per kg.
Okay. And you mentioned about the shorter half-life for KER-012 versus Sotatercept. So how does that impact the PK profile, and what would be the implications clinically on the efficacy and safety side?
Yeah. So on the clinical side, in terms of efficacy, we believe that the efficacy is driven by the Cmax.
Okay.
Okay? However, we believe that the safety signals are driven by the trough levels. So constant target engagement leads to inappropriate tissue remodeling. However, cycling within Cmax and trough levels allows the resident pool of stem cells to go differentiate down a pathway without depleting. By having those low levels, you are allowing that renewal of those pools for the next cycle. With constant inhibition, you deplete those stem cells.
Okay. And remind us if there was any hemoglobin increase with zero, one, two in phase one, or how, how does that compare with Sotatercept?
Yeah.
-and what they showed in phase one?
So with sotatercept in the phase 1 healthy volunteer study, at the 1 mg per kg dose, first dose resulted in a mean increase in hemoglobin of 2.75 grams per deciliter. Second dose resulted in a mean increase in 3.75 grams per deciliter. We did three months of dosing, and at all doses, including the 4.5 mg per kg, there was no increase in hemoglobin from the first, second, or third dose. So zero increase in hemoglobin. You know, the data is always noisy.
Right.
Okay, right. So there was changes.
Okay. And is there any link between the bleeding events and hemoglobin increase, or are these independent factors?
I believe they are related, and you see that with ESAs. That increase in red blood cells results in increase in viscosity of the blood, and you see bleeding events. And you see that in the sotatercept label, where right at the top, under warnings and precaution, it's erythrocytosis and hyperviscosity syndrome. And then, when you look at the information for patients, there's all the bleeding events that are associated with hyperviscosity syndrome: blood in the vomit, right, blood in urine, et cetera.
Okay, and moving on to the phase 2, you recently announced an enrollment update, completion of screening in the phase 2, so enrollment should be getting completed soon. Maybe just talk about anything that we should be aware of on the patient inclusion, exclusion criteria, the trial population, background therapy, and how would that compare to some of the Sotatercept phase 2, phase 3 trials?
I think over the last five years, it's become pretty standard in terms of inclusion, exclusion criteria, endpoints. So the primary endpoint is a change in PVR, where we're exploring three dose levels: one and a half, three, and four and a half. The pooled treatment versus the placebo, that's what the study is powered for. We hope we can see a dose response as well. But there is really nothing unique in terms of inclusion, exclusion criteria in the study.
Okay. And so what are the benchmarks on important endpoints like PVR and six-minute walk test that investors should be focusing on?
Yeah, well, sotatercept in the change in PVR showed a dose response at the 0.3 and the 0.7, roughly 150 and 240 dynes, so average of around 200 dynes. So that's a guidepost that hoping to achieve, but other studies have shown smaller changes. Gossamer showed about a 100 dynes change. On a six-minute walk test, in STELLAR is 40 meters, in PULSAR it was about 35 meters, so that's possible, okay, again, as the guidepost. However, Merck did quantify how they did it, we don't know, that the increase in red blood cell did contribute to improvement in the six-minute walk test of roughly 10%, 4 meters out of the 40.
Okay. So 10% impact from hemoglobin increase on the six-minute walk test-
Yeah.
- which was 40-meter in their phase 3?
Yes.
Okay, got it. And on PVR, how does that hemoglobin increase impact the results on PVR?
So you can do the calculations, okay, right? As the viscosity increases, so the PVR increases. So if you have an increase in hemoglobin of one, one and a half grams per deciliter, it could be, roughly about 5% change in PVR that's contributed by the red blood cells.
Okay, got it. And on the safety side, the trial is at 24 weeks.
Mm-hmm.
Will that be enough to show differentiation on the bleeding events, or that will ultimately be de-risked when you have longer term data?
You always hope that you can see it in your, you know, in, a top line initial readout at twenty-four weeks, and when you look at the, again, bleeding events in these patients, they're cumulative, and there's a background rate in the placebo, but there's separation at twenty-four weeks, and even bigger separation at one year and longer, so we hope, okay, we can see it at twenty-four weeks, but it's a small study compared to STELLAR, and you never know, okay, right, how the numbers come out, but that separation getting bigger, we believe that in the open label extension, you'll be able to start seeing that separation between the placebo and treatment arms, and if we're not seeing a separation, that's great.
Yeah. And so the trial continues longer term after the 24-week endpoint?
Yes.
Okay. Got it.
Yeah. All patients on placebo roll over to the three mg per kg, the mid dose.
Okay. Pending phase two data, assuming it's positive, how do you plan to enroll the phase three, given sotatercept is approved in the US, the uptake is strong, and EU uptake will also happen?
Yeah, so look, it's approved in the U.S. and in Europe. However, reimbursement, market access, okay, in Europe always takes longer. Germany is the fastest. The rest of the countries are much slower. If you look at all trials conducted in the recent past, 85% of the patients are outside of the U.S. So with TROPOS, that's how it was also designed to capture patients across the world, but with the majority coming outside of the U.S., and we believe that's gonna be the case for the phase three as well. You'll always be able to get some patients in the U.S. because they don't have access to the drug for various reasons.
Okay.
Uh...
Okay, got it. And just longer term, for KER-012, Merck is unlikely to test it outside of pulmonary hypertension because they don't have the rights. But do you think that KER-012, as a mechanism, could have applications elsewhere, and do you plan to test that hypothesis?
Yeah. We think, okay, that with the biology, you have the opportunity all the way from heart failure patients through to fibrotic lung disease, and PH kind of fits in the middle-
Right.
Okay, right? I think the opportunity in fibrotic lung disease is tremendous. Some of the recent emerging data from other companies shows that indeed, you can have a benefit by reducing fibrosis, and they're doing it indirectly in the TGF-beta pathway. So doing directly, I think has a real opportunity there.
Okay.
Heart failure also is an opportunity, but that's not something that I think we can optimally explore.
Okay. We can talk a lot about zero, one, two, but in the interest of time, let's move on to some of the other assets in the pipeline. Maybe zero, five, zero in MDS and MF.
Mm-hmm.
Just talk about the differentiation here versus luspatercept and even Geron's drug that got recently approved in MDS.
Yeah, I think luspatercept works well in patients that are early in their disease, have a bone marrow that's still functioning. But as they advance in that disease, the bone marrow gets more and more compromised, luspatercept does poorly. And you see that, that benefit in patients with low transfusion burden is there, and you saw that, you know, in MEDALIST, it was about a 38% response rate compared to 13% placebo. But then when you look at the low transfusion burden patients, those that are having three units or less, the response was 80% compared to placebo, 40%. But then those that have high transfusion burden, four or more units, the response drops down to 20% with a placebo of less than 5%. Okay?
That shows you that as the bone marrow is getting more and more compromised, luspatercept is not able to provide that much. With elritercept KER-050, what you see in the high transfusion burden patients is a 42%, 45% response rate.
Mm-hmm.
So it's at least twice as the response rate that you're seeing with luspatercept. So I think that shows you the differentiation. We see mechanistically increases in red blood cells as well as in platelets, right? Because of that mechanism, we thought that you would be able to treat the harder to treat patients. You see that in the high transfusion burden, you see it in the non-RS, where they also they're more rapidly progressing in their disease and have a more compromised bone marrow. And then we're also seeing improvements in quality of life, which was not observed with sotatercept, and that. Sorry, with luspatercept, and that's one of the things that is limiting for patients, right? They really achieve transfusion independence, but they feel lousy.
Okay.
Right? With Rytelo, you know, it works in the higher transfusion burden patients, the non-RS, but the safety profile is challenging, right? The drug induces anemia and thrombocytopenia. So we think that in the long run, once zero five zero is approved, it can fit where Luspatercept is, but also where Rytelo-
Mm-hmm.
works, so it actually spans from early to more advanced disease.
Right, and the data that you have shown on fatigue and quality of life looks better than Luspatercept. Mechanistically, why that's what happened?
That's a really interesting question. Okay, right. We think it's really driven by the inflammation. So luspatercept was designed not to bind activin A. Activin A is a very potent pro-inflammatory member of the TGF-beta pathway. It's pro-fibrotic, and we think that by not inhibiting, you're allowing that inflammation to continue, and that's why those patients feel fatigued with luspatercept. With zero five zero, you're inhibiting that inflammation, and we all know that when we have inflammation, we feel lousy. You take a shot of glucocorticoid, and you perk up immediately. Okay, right? And so I think the mechanism is anti-inflammatory properties of zero one two.
Okay, and-
Sorry, zero five zero.
Yeah. And you have some update from this asset later this year in both indications, MDS and MF. Just talk us through what investors should be expecting for that update.
Yeah. For MDS, we've been sharing data for a number of years. I think the data is mature in terms of response rates. We're not enrolling additional patients into that phase II trial, so it's really about the durability of response. We had not reached our median durability, duration of treatment. We had 60% of the patients are high transfusion burden patients, and yet our duration of treatment is likely to exceed that of luspatercept. So we wanna see how we're doing on that, and then really dig more into the quality of life. So that, that'll be for MDS. For MF, we showed improvements in the cytopenias. We'll continue to show that, but what was also exciting, starting with the data at ASH last year, where we saw improvements in spleen, reductions in spleen size, and improvements in symptom score.
And that trend continued in at the ER data cut-off, and so at the end of the year, we hope to continue to show that, which will really put us in a position in 2025 to really think about is this beyond treatment of cytopenias? We think it could be, okay, right. This could be a treatment for myelofibrosis, but we won't have that data this year. It'll be there in the first half of 2025.
Right, so first half of 2025, okay.
Yeah.
All right, we should definitely touch on obesity as well, which you have the asset KER-065 in obesity. And maybe just broadly, there's obviously a debate on whether targeting just myostatin or myostatin plus activin likely to produce the optimal drug profile for a lean muscle mass increase. Just provide your perspective on whether myostatin plus activin takes into consideration the efficacy, but also the safety side of things, which has been highlighted by our current competitors.
Yeah. So the data is indisputable, that inhibition of myostatin and activin A simultaneously will give you more potent of increase in skeletal muscle. You can go back and look at the preclinical data dating that was generated by Se-Jin Lee, who discovered myostatin, through some of the Regeneron work, as well as some of the work that we've been involved with over the years in inhibiting myostatin and activin A at the same time is going to be the more potent approach. It is going to come with a liability. The liability is that inhibiting activin A will have contraceptive properties in both males and female. That's always going to be the case. It's reversible, it's contraceptive, it inhibits spermatogenesis as well as ovulation. So that is the only safety signal that is gonna be there. However, in obese individuals, in females, the cycle is already disrupted.
So I think using the more potent drug allows you to get to the right body composition, and then after that, you can come off the drug, so I don't see it as a big issue. I think there's also a debate about myostatin and inhibiting GDF11 could be negative consequences. I think, again, the literature is very, very clear. GDF11 inhibition during embryogenesis results in skeletal defects. However, in the adult or postnatally, there are no changes, and actually, Lilly had their myostatin antibody potently inhibited GDF11, and there were no safety signals that were observed, so I think that's a red herring.
Okay, got it. And you have an upcoming phase I SAD, MAD readout in obesity next year. So maybe just walk us through on what you would expect to see on efficacy, lean muscle mass increase, to continue development of this asset?
Yeah. So we've dose escalated through the SAD, and MAD has started. In the MAD, we have subjects that are overweight to obese, BMIs of 27-33. So we anticipate with three months of dosing to be able to show an increase in lean mass, a decrease in fat mass. And the magnitude is hard to tell because this is a population of males from 18-55. None of the other previous molecules have ever been taken into this, but I'm confident we'll be able to show increases in lean and decreases in fat mass.
Okay. So the bimagrumab trials had women as well in some of their early phase ones?
Mm-hmm.
Okay, got it. And obviously, you know, you're increasing lean muscle mass, but what about the function endpoints, which a lot of physicians are looking forward to? Like, what data are out there that myostatin and activin increase, and the muscle that you're getting is functional as well?
Yeah, that's been a debate, and I think it's, unfortunately, given the myostatin field a bad name, okay, right? That you get more muscle, but it's not functional. It's not true. Actually, if you look closely at the data that's there in the literature, what you'll see is that there were actually improvements in muscle function. Lilly's myostatin antibody in frail, elderly individuals showed improvements in power measures, not in the six-minute walk test, however, in the time to stand up from a sitting position and in the gait, you saw improvements in both of those with a myostatin antibody alone. And then when you look at Bimagrumab, same story, okay, right? You actually see this improvement in the six-minute walk test.
When you look at patients that were extremely frail and had a six-minute walk test of less than 300 meters, you got roughly 50-meter improvement in those patients. So you've got to go to the sickest of patients that have a deficit to be able to show that. If you're doing 450, 500 meters, okay, to show an improvement, then that is... That's impossible because it's a normal rate, so you've got to go to the right patient population. I think this is where it's really exciting, okay, is to find a population that is showing rapid decline and show this change in the slope of that decline. That's the best way to show that functional improvement.
Okay. And you have a lot going on in the company, and developing an obesity asset is a big undertaking. So maybe just walk us through what the plan is to develop this asset further. Would you be looking for a partner, and when is the right time to partner?
We have been very transparent on this. We cannot develop an asset in obesity. It's not as if you can do a single trial, and that's it, right? You're gonna end up doing many, many trials because at the end of the day, payers are going to reimburse you for outcomes measures, right? Therefore, we will be seeking a partner. Our door is open today. We will, we will partner when the right partner comes along that can fully optimize the opportunity and gives us the right economics over time for the molecule. So that can be today, it can be post-phase I data, it could be post-proof of concept in a phase II study. That's as far as we have committed to take the molecule, is a proof of concept phase II study in obese individuals.
Okay. That's all the time we have today, but thank you, everyone, for joining us, and thank you, Jas, for coming to the Cantor Conference.