If you have any questions, please reach out to your Morgan Stanley sales representative. Hello, Jas.
Hello.
Welcome again.
Thank you.
Great to see you and have you here again this year.
Thank you.
Incredible to see all the progress that's been made with your product portfolio. There's always a lot to talk about with well, three products in the clinic with four indications.
Yes. Yeah, I know it is a very exciting time. The team is executing perfectly, and we're seeing a lot of enthusiasm from the academic community, the patients. So what can I say, okay? It's all going well.
Great, that's fantastic. So I think what we'll do is, let's not start with your most advanced clinical trial candidate, but with KER-012 for PAH. And perhaps it'd be great if you could just back up, provide the clinical underpinnings for KER-012 and where we sit today.
Yeah. I think it really comes down to the work that was done at Acceleron, that really showed that the mechanism in PAH of inhibiting certain ligands, the activins, can lead to benefit in patients. And that was done with a drug, sotatercept, that was not designed for this indication. It was repurposed for this indication. And the phase 2, 3 data showed very nice reductions in pulmonary vascular resistance, improvements in six-minute walk test, improvements in functional class. So, you know, it was really nice data and showed the benefit, but it also showed some of the limitations. And really, for me, going back to when I was thinking about Keros, it was about, can you get a molecule like sotatercept without some of the pharmacology that's the rate limiting, which is an increase in red blood cells?
Sotatercept causes very rapid and large increases in hemoglobin, which are the dose-limiting pharmacology. And with sotatercept, Acceleron ended up dosing at 0.3 and 0.7 mg per kg, demonstrating the dose-dependent change in PVR. But at 0.7 mg per kg, you got less than 50% target engagement from the first dose.
So is there more efficacy left on the table? If you don't have that increase in red blood cells, you can dose higher.
That's how KER-012, cibotercept was designed, okay, right? Was basically to have the desirable biology of sotatercept without the undesirable pharmacology of sotatercept.
With that, we did a healthy volunteer study.
We showed that you are indeed getting target engagement. You're getting to maximum target engagement at the highest dose that we tested, which was four and a half mg per kg, so compared to point seven mg sotatercept dose, and there was... The drug was well-tolerated, no increases in hemoglobin. All of the biology that we would have predicted was observed, and we moved on to the phase 2 PAH trial, which is what we announced yesterday, that we-
Congratulations.
Thank you. That the response has been overwhelming.
Mm-hmm.
We have completed screening of patients. It's 28-day screening, so in September, we will complete enrollment in the trial.
... Which now means that we can have last patient out in March of twenty twenty-five.
Right.
With data readout in Q2 2025.
That's great. Fantastic. So if we maybe back up in terms of the differentiation, Winrevair or sotatercept has been launched by Merck, and it is a good launch. But perhaps you can comment on kind of what's being seen in the field or feedback from KOLs, patients, etc., and how it dovetails with the differentiation that you've just discussed.
Yeah. So I think the first thing is that dose-limiting pharmacology of increases in red blood cells. So even at the 0.7 mg per kg dose, you're getting a 1.5-gram-per-deciliter increase in hemoglobin.
So you're having to monitor the patients. And while the label says you've got to do it for the first six doses, first six cycles, and if you've got a stable hemoglobin, you don't need to monitor and, thereafter, what we're hearing from physicians is that they want to continue to monitor-
... because it's unpredictable how that changes in hemoglobin are going to continue thereafter. So that's the first place, okay, right, is that with KER-012, there's no monitoring-
... at all. There's no dose-limiting pharmacology, but there's no monitoring either. And then we're also able to go explore the full dose response.
In TROPOS, we have three dose levels: one and a half, three, and four and a half. At four and a half, we're going to get maximal target engagement.
I think that's really what we're able to explore in this trial. What we're seeing from the hearing and seeing from the data is the safety signals with sotatercept.
... the bleeding events.
They're occurring rapidly... but they're accumulating with time. There's the telangiectasia, the spider veins, that are visible on the surface of the skin, but they are a telltale sign of the same phenomena in all tissue that are vascularized, right? And so if you're seeing telangiectasias on the skin, they're happening in highly vascularized tissue.
such as kidneys, such as, liver, right, in the brain. And actually, the tox studies with sotatercept show that. If you look in the summary basis of approval, you see there were kidney findings, okay, right, and blood in the urine of monkeys, tox in the monkey tox studies. So it's very consistent with the pharmacology, and that's what's being observed in the patients, right?
Okay, great. Any questions on KER-012? Okay, maybe we'll move to KER-050, and obviously you're pursuing two indications there in MDS and myelofibrosis. Maybe we'll start with the MDS phase II trial that's ongoing, and again, just speak to the profile of your product and its differentiation, in this case, from luspatercept.
So let's back up all the way to what our hypothesis was, based upon the mechanism. What we observed with elritercept, KER-050, was that it acts on all stages of erythropoiesis and thrombopoiesis. And it inhibits activin A, which is a pro-inflammatory cytokine in the TGF-beta pathway. Luspatercept was designed not to bind to activin A. Okay, so our hypothesis was that you would be able to provide benefit to patients that are RS, non-RS, low transfusion burden, high transfusion burden, and you would see other benefits from inhibiting activin A, right? So what have we observed? We've seen response in RS, non-RS, low transfusion, high transfusion burden patients. And the RS and the... Sorry, the non-RS and the high transfusion burden patients, they're more representative of patients with greater degree of bone marrow failure-
So more advanced in their disease. And what we see is a response rate that's roughly 40% in terms of achieving TI, compared to luspatercept, which was 20%. So there's your first differentiation.
Activity in both RS and non-RS, but also in harder to treat patients. In addition, the durability of response with luspatercept from the MEDALIST trial was thirty point four or thirty point seven weeks. We have not achieved the median duration of treatment, and the last data readout was from the April cutoff, and there we had a third of the patients that had been on treatment for more than a year. So we'll have an additional update towards the end of this year to see, okay, right, if that trend continues, have we reached the median duration of treatment? And that's an important thing for patients as well as payers. Once the patients are on your drug, they can remain on it longer-
And keep, you know, even when their bone marrow might be progressing, you're still seeing benefits. So that's the second place where we're seeing a difference. The third place where we're seeing a difference is really in terms of the quality of life. Patients on luspatercept, while achieving transfusion independence, therefore, they wish they should be feeling great.
However, they're feeling fatigued. Many patients actually want to come off treatment. Their physicians want to keep them on because transfusions are not-
Right
... without risk. So you've got this back and forth between the patient and the physician, wanting to keep them on, but they don't feel great, okay? They're feeling fatigue. We're seeing improvements in the fatigue score. Patients actually feel better on KER-050. So for both patients and physicians, that's an important aspect of the benefit that is there. You want to achieve TI, but you want to feel good as a consequence of achieving that.
So we're seeing this differentiation across the board, and then when we look at some other biomarkers, we're seeing changes there that are very consistent with the original hypothesis that we had.
We think that you're changing the bone marrow microenvironment. That may then translate into better outcomes in longer-term studies.
That's fantastic. Maybe circle back a little bit on quality of life or, because that is really important, and I think there's specifically a composite that you look at, which is the FACIT-Fatigue score. Maybe you can just touch on that so that-
It's one of the... You know, it's a collection of fatigue scores in the overall quality of life, okay, right, that just focuses on fatigue.
And it's one where when you get a change of the minimally important difference of three, okay, right. And we're seeing that it's suggestive, okay, right. The patients are actually doing better on the drug.
Great. Okay, thank you, so I think you have plans to commence a phase III clinical trial, and there has been, as you've indicated, constructive discussions with the FDA.
Maybe you want to touch on the design or when you'd be articulating that design and the alignment that you have with the FDA?
Yeah, so we went to the FDA, and it was really reassuring to see the FDA agreed with our proposal, where the primary endpoint is eight weeks of transfusion independence. But, you know, that's sort of the minimum.
Patients and payers want longer durability of response, and so our secondary endpoint of 24 weeks is there. Otherwise, it's going to be a broad patient population, RS, non-RS, low transfusion, high transfusion-burden patients. We'll talk about the more details of the trial sometime in this half of the year.
Once, okay, the team has got their information as to all the sites where we're doing the trials.
and communication with the investigators.
Okay. And I guess I think you've just articulated this, but in terms of, Reblozyl or luspatercept, you know, they're currently approved, in first line, second line, MDS, I guess, reported last quarter of $425 million-
Yeah
$1 billion for 2023. So in terms of how this clinical trial is going to be set up to differentiate your program, maybe just let's start with that.
Yeah, it's gonna be, it's gonna be in the second line. So it's post-ESAs.
Those patients that have been on ESAs, no longer responding, or patients that are naive to ESAs but have circulating erythropoietin levels of 200 million international units per mL. That is based upon phase 2 trials. When you have circulating erythropoietin levels of greater than 100 million international units per mL, those patients don't respond to ESAs. So even though they're ESA naive, they're not gonna be ESA responders. So it's really post-ESA that we're looking at it at this point in time in this trial. But you make an important point. There is the frontline opportunity, and we will do that as part of our lifecycle management. The patients that don't tolerate Luspatercept, what about those patients?
So we're looking at all of those, but the team's really busy on getting Renu started, which is in that second line, so that we can get to market as quickly as possible and then continue to use those revenues to invest in lifecycle management.
Great. And the landscape in MDS has changed a little bit with the approval of Rytelo in the second-line, high transfusion burden MDS patient. How are you thinking about, again, our positioning within the segment?
Yes. I think for patients today, it's a good thing to have another option-
because otherwise, it's transfusions or go to HMAs, hypomethylating agents. So today, I think patients that stop responding to Reblozyl, luspatercept, will go on... Some of them will go on, but it has a very challenging safety profile.
As a consequence of treatment, you get cytopenias.
... anemia, thrombocytopenia and while, okay, physicians are able to manage through that, nevertheless, it is a challenge. So, you know, the conversation a physician has to have with their patient is: "I'm gonna give you this drug that may achieve transfusion independence, but you're gonna really feel bad, okay, right-
when you go on the treatment." So that's the-
The FACIT-Fatigue score is not gonna be positive.
No. Right. So that's the real challenge, okay, right? So I think today there is a place for it, but we think, okay, right, that once the KER-050 is approved, it's gonna start earlier and continue longer, and it has a safety profile that is very benign.
Right. Okay, great. So now maybe we'll address myelofibrosis. So in terms of, you've got, again, another ongoing, phase 2 as a monotherapy and in combination with ruxolitinib.
Yeah.
Yeah. How should we think again about the profile here in the myelofibrosis field and next steps from a data standpoint?
So once again, our hypothesis was you're increasing erythropoiesis and thrombopoiesis. Those are the two cytopenias that are observed in these patients. And ruxolitinib is actually treatment with that results in these cytopenias as well. So 40% of the patients will get anemia, and roughly half of them will have thrombocytopenia.
Right.
So we believe that we could address that. So we've been showing data that indeed, you get increases in red blood cells and in platelets, both in monotherapy as well as in combination with RUX.
But our other hypothesis was, if you're aligned to promote. You're aligning the drug to promote erythropoiesis and thrombopoiesis, and the disease is a result of megakaryocyte precursors, precursors for platelets that are not maturing. They accumulate in the bone marrow, that then leads to inflammation and fibrosis, which degrades the function of the bone marrow, that if you start aligning these precursors to mature, then you will have less inflammation and fibrosis, and maybe you can start restoring hematopoiesis back in the spleen, as in the bone marrow, and therefore, the need for hematopoiesis in the spleen will shrink. And in myelofibrosis, the reason why patients get drugs is because they've got a enlarged spleen, right? So therefore, it could be a treatment for myelofibrosis.
We knew that that would require longer-term treatment. We were pleasantly surprised at ASH of 2023 when we saw that in both the monotherapy and in the combination arms, we're seeing not only improvements in symptom score, but also in spleen size. That data continued through earlier this year at EHA.
We'll have another data cut that we'll report towards the end of the year.
Right. Okay, another big ASH. Okay. Well, now I think we'll move on to KER-065. I was gonna say, you know, another exciting program or, you know, I think we can't... It's obviously very exciting in the obesity and the neuromuscular space. I know you've got, again, a very good history from Acceleron in terms of looking at the whole myostatin field, and again, perhaps a comment with respect to the genesis of this program and what you're trying to achieve there.
Yeah, I think it really builds on the work of Se-Jin Lee in the nineties, where he showed that a member of his family, growth differentiation factor eight, when you delete it in rodents, you result in a hyper-muscular phenotype.
And therefore, he called it myostatin. So getting, removing myostatin leads to this hyper-muscular phenotype. So inhibitors of myostatin were the field focus. But Se-Jin didn't stop at myostatin. He continued to look at other molecules in this pathway, and he came to the conclusion that activin A is the other negative regulator of skeletal muscle. And if you inhibit myostatin and activin A together, you get much more potent increase in skeletal muscle than with myostatin only. And then the work from others, like Regeneron, has shown that in rodents, myostatin levels are relatively high, whereas in primates, including non-human primates, myostatin levels are low, but activin A levels are high. So again, making the argument that you want to inhibit multiple negative regulators of skeletal muscle. So that's how the field has evolved. There's those, of course, who have myostatin-only inhibition.
Then there's others that are inhibiting multiple ligands. Regeneron's doing it through two antibodies, one to myostatin, the other to activin A. Versanis bimagrumab was targeting the receptors, right?
To prevent any ligand that signals through those receptors, the activin receptors two A and two B. We've taken the approach of using a ligand trap that has been engineered to bind to activin and myostatin, increase the skeletal muscle while avoiding some of the binding to other ligands that would lead to the negative consequences in the safety signal. So that's in terms of potency at the highest levels of drug that you get to, whether it's the Regeneron approach, whether it's the bimagrumab Versanis approach, now Lilly or us, you're gonna get to the same magnitude of increase in skeletal muscle.
However, the differences are going to be in the safety profile and convenience, in terms of route of administration. We think that we have a better safety profile-
... because we're not inhibiting some of the BMP signaling that bimagrumab does, because the activin receptors, while they're used by activin and GDF, in some tissue, those receptors are also the bone morphogenetic protein signaling receptors.
So you don't want to inhibit those.
And will that safety profile manifest itself from the phase 1 healthy volunteer trial?
Some of it could. Okay, right. I mean, with the Acceleron wild-type activin receptor 2B that increased skeletal muscle in the ACE-031, there were bleeding events that were observed in the phase 1 study. Telangiectasias were observed, okay, right. M
... in the healthy volunteer and the multiple ascending dose. So we'll see those. There's been, in the longer-term studies with bimagrumab, there's acne and that's been observed. There's been pancreatitis. We may not see that because this is a very small study.
Right.
Yeah.
Okay, and what happens next after the healthy volunteer readout?
I think we have committed to doing a phase 2 proof of concept in obesity.
So I think you can sort of think about how—what does that—what are the questions you can answer in that? So how much lean mass and fat mass changes can you see from monotherapy, and what does that manifest itself in terms of weight loss?
Okay, so that's monotherapy. And then with GLP-1 receptor agonist, what we have seen is 25%-40% of the weight loss is actually loss of lean mass, right? And therefore, can you ameliorate that? So you can imagine patients that have been on GLP receptor agonist for a period of time, they lost the muscle. Now, you can think about treating them to see if you can build back the muscle, but also get further improvements in reduction in fat mass, does that result in weight loss? And then there's also, once patients come off a GLP receptor agonist, they put back all of the weight.
Right.
And most of it is, again, fat because they lost the lean. So can you now wean them off the GLP receptor agonist and put them on a muscle-building agent that now continues to improve their metabolic characteristics, build the lean mass, and have further loss of fat mass? So I think there's lots of ways of thinking about it.
The team's busy-
Yeah
Trying to think of the permutations that we want to try.
We need to do a small, efficient trial.
As a small biotech company, that's going to be always the goal-
Right
... capital efficiency, so we're looking at that, but after the phase I data, that's what we will be moving on to.
Right. Well, you certainly have been very efficient with your capital.
I think you're currently very well-financed, and as I understand, the cash runway through the 2027 period.
Yes. We have $406 million as of end of Q2, and that takes us into-
2027.
That's great, and there's a lot of milestones in between.
Yes.
Yeah. So with the time we have left, you know, I guess stepping back, you've got these multiple programs ongoing. I mean, how do you see the execution, in terms of the totality of this portfolio? Does partnering make sense? How do we think about it from a global development standpoint?
Yeah. I think when I was thinking about starting this company-
... my vision was always that we're going to be a commercial company.
Right? So we will take a product or two and commercialize them. However, by focusing on the pathway, the disease areas that we can go into are very, very different and therefore, okay, right, to be a company that's commercializing hematology and building a hematology commercial force, a pulmonary-
... commercial force, an obesity neuromuscular, that's not something that we're going to be able to do.
Right.
So partnering has to be part of our strategy, and by moving these products and showing the potential of them through phase II, we have de-risked them. So we de-risk zero five zero at this point in time, in time for MDS. In twenty twenty-five, we'll de-risk it for myelofibrosis, okay, as a treatment for myelofibrosis. In twenty twenty-five, PAH, the same thing. Now, it comes down to, is there a partner who can optimally exploit that opportunity?
And frankly, then it comes down to also the economics that we can then invest in the rest of the pipeline.
So we're open. We've always been open, but it was always that we want to wait until phase II-
... unless somebody is willing to recognize the value early on.
I did forget to ask about the neuromuscular applications on KER-065. Maybe we can just circle back there, since I know you've got a lot going on, but we just focused on-
Yeah. I think, look, muscle wasting occurs in lots of different patient population, and neuromuscular space is an opportunity, and 15 years ago, we took a molecule into Duchenne's-
... and showed that you can build the muscle, you can decrease the fat in those masses, in those patients. Because boys with Duchenne's, because they're on glucocorticoids, actually end up with much of the pathophysiology of obesity.
Interesting.
They're metabolically challenged.
And therefore, you can actually reverse a lot of that. But by building that skeletal muscle, that muscle can preserve the function for a longer period of time.
And that's what the trial start showed. However, there were safety signals-
... that prevented further development. And so we think that we have got a better asset in KER-065, but it's not the only agent that we've got. We've got other molecules that are different in amino acid sequence but have the same property, so we can potentially exploit-
Great
... neuromuscular indications as well.
Fantastic. Well, I really look forward to our conversation next year, because the milestones that you've delineated will put us in an even greater trajectory with respect to all four indications that you're pursuing. So again, congratulations.
Thank you.
Thank you.
It's gonna be an exciting 12 months or so.
It will. It will. Thank you.