Good morning and welcome to the Keros Therapeutics call. At this time, all participants are on a listen-only mode. Later, we will conduct a question-and-answer session, and instructions on how to ask a question will follow at that time. As a reminder, this call will be recorded, and the link to the recording will be available on Keros' website. I would now like to introduce your host for today's program, Justin Frantz, Keros' Head of Investor Relations. Mr. Frans, please go ahead.
Thank you, operator, and thank you to all that have joined us on this call. As we disclosed this morning, we will be discussing the data from our phase I trial of KER-065 in healthy volunteers. A press release is available on our website at kerostx.com and is also included as an exhibit in the Form 8K that we filed with the Securities and Exchange Commission today. During this call, we will be making a number of forward-looking statements. Please note that these forward-looking statements involve risks and uncertainties, many of which are beyond Keros' control. Actual results can materially differ from those expressed or implied by such forward-looking statements, and any such risks can materially and adversely affect our business, financial condition, results of operations, and trading prices for Keros' common stock.
For a detailed description of applicable risks and uncertainties, we encourage you to review the risk factor section of the company's annual report on Form 10K filed with the SEC on February 26, 2025, as well as the company's other documents subsequently filed with or furnished to the SEC. All forward-looking statements made during this call speak only as of today's date, except to the extent required by law. The company does not undertake any obligation to publicly update its forward-looking statements based upon subsequent events or circumstances. Joining me on today's call are Jasbir Seehra, Chair and CEO of Keros Therapeutics, Yongdong Peng, our Chief Medical Officer, and Chris Rovaldi, our President and Chief Operating Officer. After the prepared remarks, we will open the call for Q&A. I will now pass the call to Jasbir Seehra.
Thanks, Justin, and thank you, everyone, for joining our call this morning. After walking through the rationale for KER-065 and Duchenne muscular dystrophy, I will pass the call to Yong, who will be sharing the exciting results from our phase I trial in healthy volunteers. As a reminder, KER-065 is an investigational modified Activin receptor 2A and Activin receptor 2B ligand trap. Importantly, KER-065 has been designed to bind and inhibit both Activin A and myostatin. We've also designed KER-065 to have reduced binding to BMPs to avoid the vascular and bleeding events observed with the Activin receptor 2B Fc derived from the native sequences. We are developing KER-065 for the treatment of neuromuscular diseases with our initial focus on Duchenne muscular dystrophy, or DMD. DMD is a chronic degenerative muscle disease that manifests as subtle motor defects postnatally, followed by the loss of ambulation and eventually death.
In patients with DMD, the principal symptom is muscle weakness due to the loss of dystrophin, which results in progressive muscle degeneration. The muscle undergoes continuous rounds of degeneration and regeneration, leading to inflammation, fatty infiltration, and fibrosis. The increasing inflammation reduces the ability of the muscle to regenerate and ultimately impacts muscle strength and function. Over time, patients have reduced mobility, eventually leading to loss of ambulation. In older individuals, the progressive nature of the disease results in pulmonary and cardiac dysfunction and loss of muscle function, which impacts mobility. I point you to the graphic on the right side of the slide, which highlights disease progression at each stage. Treatment for Duchenne muscular dystrophy has historically been limited to glucocorticoids, but over the last decade, a few new treatments have been approved, including exon skipping, gene therapy, and HDAC inhibitors.
While glucocorticoids are used regularly and have been shown to help to maintain muscle function in DMD patients, long-term treatment can have significant negative side effects, including premature osteoporosis due to accelerated bone loss, fluid retention, hyperglycemia, and increased adiposity, and severe weight gain, which further exacerbates the loss of muscle function. There are four exon skipping therapies approved by the FDA, all through accelerated approval pathways on the basis of dystrophin production. Notably, these therapies are approved only for individuals with mutations in specific exons, so thus are not available to all patients. The only existing gene therapy was granted full approval for the treatment of ambulatory individuals aged four years and older, and accelerated approval for the treatment of non-ambulatory individuals aged four years and older on the basis of microdystrophin expression.
Duvyzat is an HDAC inhibitor that has been approved for the treatment of DMD by reducing inflammation in the muscle. Duvyzat can cause dose-related thrombocytopenia and other signs of myelosuppression, including anemia and neutropenia. Considering the limitations of these currently available therapies, the need for additional treatments in DMD remains high. We have generated a robust preclinical package demonstrating the potential benefits of KER-065. We believe the inhibition of both Activin A and myostatin are essential in addressing the complex pathophysiology of DMD. Thus, we have shown that our KER-065, a research form of KER-065, can increase muscle mass, decrease fat mass, and improve bone mineral density in normal and D2 mdx mice. Importantly, co-treatment with prednisone and our KER-065 was shown to increase both muscle mass and strength and trabecular bone and strength in mdx mice, demonstrating that KER-065 can counteract some of the negative consequences of glucocorticoids.
Both myostatin and Activin A are key negative regulators of muscle, and inhibiting both ligands has been shown to increase muscle mass more than targeting myostatin alone. We have shown that KER-065 treatment does not only increase the size of existing muscle fibers; it also promotes the muscle regeneration by increasing satellite cell proliferation and differentiation to myoblasts in wild-type mice. Inhibition of Activin A has been shown to reduce inflammation and fibrosis. We've shown in mdx mice that our KER-065 shifts the macrophage population from a pro-inflammatory macrophage to a tissue-repairing macrophage state. Lastly, KER-065 has the potential to address the underlying genetic deficiency. In preclinical models, our KER-065 treatment increased utrophin expression, an embryonic form of dystrophin. Additionally, combined treatment with our KER-065 and exon skipping therapy led to increased lean mass, muscle strength, and enhanced expression of the truncated dystrophin in mdx mice.
This data again demonstrates that combining our KER-065 treatment with other mechanisms has the potential to provide further benefit. We believe the broad pharmacologic benefits observed with our KER-065 in preclinical studies provide a strong scientific rationale to support the development of KER-065 in DMD, regardless of the mutation or current use of DMD treatments. I would now like to pass the call over to our Chief Medical Officer, Yongdong.
Thank you, Jas. I'm excited to walk through the phase one trial data with everyone on the call. Before we begin, I did want to take a moment to express, on behalf of Keros, our gratitude to the volunteers who participated in this trial and the investigators and trial site personnel for their hard work and contributions. We are pleased to report that the phase one trial met the objectives for safety, tolerability, pharmacokinetics, and pharmacodynamics. We believe that the clinical data from this trial, along with our preclinical data, support the rationale for proceeding into a phase two trial of KER-065 in patients with DMD. Here you can see the design for our phase one trial. This was a two-part, randomized, double-blind, placebo-controlled trial in healthy volunteers. We had three cohorts in the single-ascending dose portion and then two cohorts in the multiple-ascending dose portion.
The SAD evaluated a broad range of doses, while the MAD focused on a lower dose range. Note, the MAD lower dose range is at the upper end of where we hypothesize we may need to be in investigating 065 in DMD and other neuromuscular indications. All the data we will present today is as of a cutoff date of February 6, 2025, and through the MAD treatment period, which is day 85. The baseline characteristics were consistent with the population we were looking to enroll, and as a reminder, all participants in the trial were male. To support our evaluation of body composition parameters, we enrolled an overweight and obese population in the MAD portion of the trial. Relative to the population in the SAD, these participants had higher baseline weight, BMI, and waist-to-hip ratio.
There were wide ranges across various characteristics reflecting anthropometric diversity in this small trial population. Let's now proceed to an overview of the safety results. KER-065 was generally well tolerated. Most treatment-emergent adverse events were mild or moderate, and no dose-limiting toxicities or serious adverse events were observed. No bleeding events or telangiectasias were reported. There was one unrelated grade 4 AE of CK elevation in the setting of recent weightlifting. This elevation resolved without sequelae. The participant did not experience a recurrence of their CK elevation upon receiving a subsequent dose of KER-065. The most commonly reported AEs in this trial included injection site reactions, headache, and the laboratory value abnormalities as outlined here on this slide. These events were generally not severe and resolved without sequelae.
As shown in the upper figure, we observed an increase in hemoglobin, most prominently in the highest dose level in the SAD portion of the trial. Now, as noted earlier, the MAD was focused upon characterizing a lower range of doses that we believe are relevant for investigating 065 in DMD and other neuromuscular disorders. As you can see in the lower figure in the MAD portion of the trial, the hemoglobin increase was primarily apparent following the first initial dose and then to a lesser degree after each subsequent dose. The higher dose level of 2 milligrams per kilogram in the MAD was not associated with a greater increase in hemoglobin relative to the 1.25 milligram per kilogram dose level. Overall, the hemoglobin changes in this trial were asymptomatic and reversible.
Now, let's proceed to reviewing the pharmacodynamic data, which are relevant for evaluating Activin inhibition at the tissue level. As shown in the figure on the left, we observed increases in BSAP, a marker of osteoblast activity and bone formation. In parallel, we also observed decreases in CTX, a marker of bone resorption. Taken together, these biomarker data demonstrate the potential of 065 to offer bone anabolic activity by simultaneously increasing bone formation while inhibiting bone resorption. In support of this therapeutic potential for bone anabolic activity, there was evidence of observed tissue level changes, as shown by the increase in bone mineral density at day 85 in the figure on the left and over time in the graph on the right. Beyond the bone effects, we also observed increases in adiponectin, a biomarker of fat mobilization, as shown in the figure on the left.
In addition, we saw decreases in leptin, a biomarker of fat mass, as shown in the figure on the right. These responses are supportive of the potential for 065 to induce fat mobilization. The changes in fat biomarkers and, more broadly speaking, the potential for therapeutic effects upon adipose tissue were further corroborated by imaging data. We observed reductions in whole body fat mass, as shown in the figure on the left, and in visceral fat mass, as shown in the figure on the right. Finally, rounding out the three dimensions of body composition that we evaluated in the MAD, here are the muscle imaging data. We saw increases in skeletal muscle, as reflected by an increase in whole body lean mass and in thigh muscle volume in the left and right-hand figures, respectively. In summary, the phase one trial met the objectives for safety, tolerability, PK, and PD.
KER-065 was generally well tolerated, with no major safety signals observed to date. The biomarker data, together with a profile of body composition effects upon bone, fat, and muscle in totality, provide multiple lines of evidence that we may be achieving sufficient levels of active inhibition across tissues of interest. We believe that the clinical data from this phase one trial, along with our preclinical data, support the rationale for proceeding into a phase two trial of KER-065 in patients with DMD. I will now pass the call back over to Jas before we open up Q&A. Jas?
Thank you, Yongdong. As Yongdong just stated, we believe data from this phase I trial supports the potential of KER-065 to address multiple aspects of DMD, including across important tissues such as bone, fat, and muscle. In DMD, reduced muscle strength, loss of ambulation, and the use of glucocorticoids contribute to the development of secondary osteoporosis. Following treatment of KER-065 in a healthy volunteer trial, we observed biomarker changes that translated to the tissue level, resulting in increased bone mineral density. There is also an increased risk of obesity and associated negative health consequences, including type 2 diabetes and cardiovascular disease in patients with DMD. In this trial, KER-065 elicited biomarker changes demonstrating fat mobilization that correspond with decreases in fat mass.
In addition, the replacement of muscle fibers with fatty and fibrotic tissue in boys with DMD leads to progressive loss of muscle strength and function, resulting in immobility and respiratory and cardiac complications. Following treatment of KER-065, we observed increased lean muscle mass and increased thigh muscle volume. In summary, we are encouraged by the therapeutic potential demonstrated by KER-065 in the phase one trial to treat patients with DMD. Furthermore, we believe the therapeutic potential of KER-065 extends beyond DMD to a broad range of neuromuscular diseases. Neuromuscular disorders arise from either mutations in genes coding for structural proteins that are unable to connect the contractile apparatus to the basal lamina, or failure of transmission of the signal from motor neuron to the muscle. Regardless of the underlying cause, the pathology in the skeletal muscle is similar.
When due to mutations in structural protein genes, it leads to weaker muscle that is easily damaged and results in inflammation. Inhibition of muscle regeneration, replacement of muscle with fat, and fibrosis. When caused by the inability of the motor neuron to stimulate muscle, it leads to muscle damage and replacement of muscle with fat and fibrosis. Based on observed pharmacology in preclinical studies with phase and the phase one clinical trial, we believe KER-065 has a potential for development in multiple rare neuromuscular diseases with high unmet needs. We plan to engage regulators on the design of phase two trial evaluating KER-065 in patients with DMD starting in the third quarter of 2025. Subject to regulatory feedback, we plan to initiate this trial, phase two trial, in the first quarter of 2026.
We look forward to providing additional updates, including the design of the phase two trial, following our regulatory interaction. I will now pass the call back to the operator to open the question and answer session.
Thank you. The floor is now open for questions. If you would like to ask a question, please press star one on your telephone keypad at this time. A confirmation tone will indicate that your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up the handset before pressing the star keys. Again, that is star one to register a question at this time. Today's first question is coming from Kripa Devarakonda of Truist Securities. Please go ahead.
Hey, good morning, guys, and thank you so much for taking my question. The first question I have is, the changes that you saw in the lean body mass and thigh muscle volume, especially the thigh muscle volume, could you, given that you plan to go forward in DMD, could you put that in context for a DMD patient? Any metrics to better understand what sort of functional benefit that might translate into for patients? On the hemoglobin changes, was this something that was expected as per your preclinical data? Is there a sense of what the hemoglobin levels, baseline hemoglobin levels in DMD patients are? Would this be considered something that you would need to monitor in the phase two trial? Thank you.
Yeah. Good morning, Kripa. Thanks for the question. I'll let Yongdong address the hemoglobin question first, and then we'll come to the functional consequences of the increase in thigh muscle volume that we observe.
Yeah. Hi, Kripa. Good morning. In terms of the hemoglobin increases, based upon the data and our standard to date, we believe that should hemoglobin increases be observed in a phase two DMD trial, it would be manageable and not present any major challenge to the program. To reiterate what we saw in the phase one trial, at least through the data cutoff, we have not seen any dose-limiting toxicities, hemoglobin or otherwise, and the increases that you saw were asymptomatic. The hemoglobin increases were also reversible. In other words, as the drug exposure levels start coming down, the hemoglobin also starts coming down. Also, at least from the MAD data we just presented, it appears in this trial that the hemoglobin increases occurred to a lesser extent upon subsequent dosing.
When you put all of this together, what that puts forward is the potential to manage this in a future phase two trial where you can do just some monitoring with just routine blood draws for hemoglobin labs. If you end up needing to, you could delay or modify a dose in a given patient until the hemoglobin levels come down enough to resume dosing. You want to make sure that hemoglobin levels do not go up too fast or too high in absolute level, and of course, avoid any symptomatic effects. It is just also as a reminder, in DMD, there is no background elevation in hemoglobin at baseline in general. We believe that this proposed approach makes sense overall, and it would be part of our trial design-related interactions with regulators to see if they agree.
On the second part, with respect to the changes in lean mass and muscle thigh volume, I think Kripa would guide you back to the Acceleron ACE-031 with three months of treatment where there were observations of lean mass increases as well as changes in thigh volume in the healthy volunteer study. That resulted in stabilization of disease as measured by a six-minute walk test. Understandably, that was a short study, but nevertheless, there were hints, right, of functional benefit in that study.
Okay. Thank you so much. I'll get back to you.
Thank you. The next question is coming from Tyler Van Buren of TD Cowen. Please go ahead.
Hey, guys. Thanks very much for the data and the question. I realize the standard of care bar is low for DMD and that these patients are ultimately losing ambulation. As we think about the 1%-2% increase in lean mass that we're seeing at 85 days here, is there any reason to believe that the impact is plateauing, or are you seeing something that suggests that it could continue to improve over the longer term? The second question is just, do you expect the phase two study to have relatively traditional design, or would you propose one with unique endpoints given 065's mechanism of action?
Let's break that question into two parts. First being the 1%-3% increase in lean mass. Is this reaching a plateau? I don't believe so, okay, right? I think it has the potential to be greater. However, I think that is not the critical thing in boys with DMD. Boys with DMD start off being slower to walk, but they eventually all walk, and they continue to gain strength through their single-digit years. That's important because that increase in strength is because they have good regenerative capacity in their skeletal muscle. As they get towards the end of their first decade of life, that is when the inflammation now inhibits the regenerative capacity of that muscle, and they eventually lose ambulation.
With 065, its ability to inhibit the inflammation, increase muscle regeneration, you have the opportunity to continue ambulation for a longer period of time through those mechanisms. You do not necessarily need to increase the skeletal muscle by 2%, 4%, 5%, whatever the number might be in order to get the benefit. It is just maintenance of that regenerative capacity is sufficient. Seeing these 1%-3% increases, I think, is very exciting. Chris, Yong, anything to add to that?
Yeah. Just in terms of just to add to that in terms of your second question about a phase two trial design, yeah, as Jas described, we're really excited about therapeutic potential of 065 and test our hypothesis through a phase two trial design, through a phase two trial. Now, it's a bit premature to talk about the specifics around the trial design today, but there's a number of key considerations to think about. First off, and this is really important, as Jas described, 065 has the potential to offer meaningful benefit for patients with DMD in so many different ways. These are the ways primarily do not even require muscle mass increases. As Jas described earlier, there are exciting preclinical data around the anti-inflammatory and antifibrotic effects of this molecule in the muscle, muscle regeneration effects, and potentially even upregulation in the levels of dystrophin and utrophin.
In addition to this therapeutic potential, there's the possibility of important cardiometabolic benefits, addressing of bone loss. If any one of those mechanisms translate in patients and turn out to hold true in DMD, then we think that this would be really an exciting and important advance. We have the opportunity to interrogate all those exciting possibilities through our phase two trial to see if 065 can indeed offer benefits on those various fronts. More broadly speaking, in terms of the historical experience with drug development in DMD, as well as rare disease overall outside of Keros, there's been a lot of flexibility shown by regulators. In addition, there's been third-party proof-of-concept trials in DMD and other rare neuromuscular disorders that included open-label approaches in which relatively small numbers of patients may offer meaningful insights and therapeutic potential.
There is a wide range of opportunities available here for us to investigate the potential of 065 in a timeline-efficient and thoughtful manner. Obviously, the actual design of phase two trials is TBD at this stage, but we are looking to think globally in our approach, move expeditiously, and then start engaging with the regulators in the third quarter of this year. As this process proceeds, we look forward to sharing more details around our trial design plans at the appropriate time.
Thank you. The next question is coming from Greg Harrison of Scotiabank. Please go ahead.
Good morning. Thanks for the update, and thanks for taking our question. Curious how you're interpreting the lack of dose dependence when it comes to change in bone mineral density and fat mass. Is this a function of the low end, or are there any implications here you're thinking about for future development in DMD or other indications in the future?
Thanks, Greg, for that question. Yong, do you want to address that?
Yeah. I think just in terms of the, it's not surprising. Remember, this was a phase one healthy volunteer study. There were low ends, as you pointed out. As you may recall from the baseline characteristics, there was a wide range of baseline body composition parameters. It's not surprising to see some variability in what you may observe. Also, remember to layer on that the 1.25 mg/kg and 2 mg/kg doses in the MAD, they have relatively similar dose levels. It wouldn't be surprising to see some overlap in terms of effect. More broadly speaking, when you just take a step back and look at the data, we're really encouraged by what we're seeing here, right? We saw increases in bone biomarkers of BSAP, which is a marker of bone osteoblast activity. We also saw corresponding decreases in a biomarker reflective of bone resorption.
We also saw increases in adiponectin, a marker of fat mobilization, decrease in leptin, a marker of fat mass overall. Importantly, we also saw imaging for the body composition parameters of increases in bone mineral density, muscle mass, and decreases in fat mass. We put it all together in totality, not just one thing in isolation. We are really excited here about the potential to offer a meaningful benefit because we believe these data are supportive, at least in the dose ranges that we are interrogating in the MAD, of the potential to offer meaningful active inhibition at the tissue level. We think this is really exciting, and we look forward to testing our hypothesis in the next phase two trial in DMD.
Just to add to that, I think this is the first study that I'm aware of where it is in a population of males that is relatively young and osteoporotic. Seeing any changes in bone mineral density, to me, is very exciting. We did anticipate that there would be inflections in the biomarkers supportive of that. To actually see increases in bone mineral density in some of the participants, that I think is very, very exciting. It is the first report that I'm aware of in this population, males between the ages of 21- 61 that are not osteoporotic. Altogether, I think, as Yong mentioned, the data is very, very supportive of the mechanism of the molecule that we demonstrated preclinically.
Thanks. That's helpful. Given the broad range of activity you're seeing here, how do you decide how to prioritize your development going forward beyond DMD? It sounds like other rare diseases could be likely, but there's also activity that could benefit patients with much more prevalent diseases. How do you decide how to focus your efforts?
Thanks. Okay. I'm going to have Chris Ruvaldi talk to that.
Yeah, we agree with you. We think there's a therapeutic rationale for KER-065 and a broad range of neuromuscular diseases, as Jas shared with you. We have a really robust preclinical package. At the appropriate time, we'll come back and we'll share our plans for additional indications. As we think about it, we focus on the patients and opportunities where the scientific rationale provides that differentiated benefit relative to the competitive products in valuable and underserved markets. We'll come back to you with our overall development strategy. For us, we are a lean organization, and we are highly focused on advancing this phase II study in Duchenne muscular dystrophy. Today, based on this data, we believe in the strength of this profile, and we're going to take this product forward rapidly into DMD.
Great. Thanks again.
Thank you. The next question is coming from Thomas Smith of Leerink Partners. Please go ahead.
Hey, guys. Good morning. Thanks for taking the questions, and congrats on the data. Just wondering if we could follow up on the hemoglobin increases and if you could just talk about the effect you're seeing there. Is this an effect you think would be desirable in DMD patients, and how does that impact your thoughts on dosing? Secondly, just operationally, if you could talk a little bit about the gating factors for starting the phase two, what kind of feedback are you looking for from FDA with the meeting in Q3, and how are you thinking about dose selection in the phase two study? Thanks.
Thanks, Tom, for the question. I'm going to let Yong address the question.
Yeah. In terms of the first question, Tom, about hemoglobin being desirable or not, I think the main thing is, putting aside whether it would be desirable or not, I think the main thing was we believe that any increases that we may observe in DMD, we think are manageable, right? This is something where, again, we did not see any dose-limiting toxicities, hemoglobin or otherwise, asymptomatic, and the increases were reversible, right? We think that all presents a great opportunity for the potential to manage through just routine blood draws, just routine monitoring. If needed, you can make some dose pauses or modifications. We think that the overall benefit-risk potential of 065, particularly in a disease with a serious unmet neuromedical need as DMD, this type of approach will make sense. Obviously, we will talk with regulators and go through the approach going forward.
In terms of the gating factors to starting a phase two, obviously, regulatory engagement is going to be very important where the team is hard at work preparing details of the trial design. We'll be engaging with KOLs, obviously, the patient advocacy groups, etc. I think what we'll be doing is this is going to be a global trial, just to emphasize. DMD is a global disease, global unmet need. Obviously, for rare disease, you want to have a global development strategy, and certainly, that will be our intention. We'll be initiating regulatory authority engagement in the third quarter. We're looking to, if all goes well, subject to positive regulatory interactions, look forward to starting a phase two trial in DMD in the first quarter of 2026.
Thank you. The next question is coming from Vamil Divan of Guggenheim. Please go ahead.
Hi, thank you. Yeah, this is Daniel on for Vamil. I have a couple of questions. The first one is maybe can you explain the logic behind the, maybe a little more specifically, explain the logic behind the selections in the MAD, like why the step down going from 2 mg/kg to down to 1.25? The second question is maybe more within DMD. Can you speak to what population of patients for which you believe this drug would be best suited, whether it's ambulatory versus non-ambulatory? Is there a lower limit on the age of patients in which you're comfortable starting treatment with this drug? Thank you.
Yong?
Sure.
Thanks. Yong will address the question.
Yeah. For the first question, in terms of the dosing approach and overall in the MAD, I think just taking a step back, as is common for phase one, first-in-human types of studies, we will look at a broad range of doses, including doses that are on the higher end, right, and evaluate not just safety, but also PK/PD. The PK profile of 065 that we saw was generally consistent with that of a well-behaved biologic. Interestingly, we noticed exposures that seem to be relatively higher than what we may have expected given the history with ligand traps. In terms of the MAD itself, we should note that the dose range is actually at the upper end of where we hypothesize we may need to be in terms of investigating 065 and DMD, as well as other neuromuscular indications.
We're really encouraged to see multiple signals across biomarker and body composition data and multiple different organ systems, as we outlined, that we believe are evidence of the potential for meaningful active inhibition at the tissue level. We're really excited to test our hypotheses, test this dosing range or something in that range in a future phase two trial in DMD. Yes, in terms of the second question, in terms of population DMD, obviously, the specifics about trial design are still too early at this stage to go into detail. We have to have further discussions with regulators, obviously. I think at a high level, we're thinking broadly about the potential for 065 across a wide range of different segments, populations in DMD. As you highlighted, it could include ambulatory, could include non-ambulatory, or a wide range of ages, different background, concomitant medication.
All of that is definitely on the table in our consideration set. What we're really encouraged, again, by is the potential here to really offer meaningful benefit. As Jas outlined earlier, there's a lot of exciting potential in terms of the mechanistic benefits of 065. We have preclinical evidence underlying our hypotheses. If any of those hypotheses hold true, obviously, we want all of them, and we are hopeful that all of them are true. Even if just one turns out to be true, I mean, what an amazing thing it could potentially be for patients with DMD. We're excited to investigate these possibilities. We're looking forward to testing our hypotheses through our development program. Stay tuned.
Great. Thank you.
Thank you. The next question is coming from Kelechi of Jefferies. Please go ahead.
Congrats on the progress, and thank you for taking my questions. I have to firstly, quickly, just curious on the adiponectin biomarker for fat mass. Do we usually see a good inverse correlation between adiponectin and body weight? Secondly, based on your experience previously moving KER-012 from a healthy volunteer to phase two, what would be the key topics to discuss with the agency specifically on safety? Is the current data set in terms of patient number and the follow-up time sufficient for deciding on the phase two dose? Thank you.
Let me answer the first part of the question, Kelly, with respect to adiponectin and leptin. Adiponectin is a hormone that is secreted, and it increases insulin sensitivity. There is data, right, that it is actually secreted by brown and beige fat cells, which are energy-consuming cells. Adiponectin increases could be a marker of increasing brown fat and therefore energy expenditure from fat tissue itself. Leptin is a marker of the amount of fat that you have. The more fat cells you have, the more leptin that is in circulation. Seeing these two changes where adiponectin is increasing and leptin is decreasing is really a very exciting hallmark of fat mobilization and perhaps even changing the phenotype of the fat from energy storage to energy-consuming fat. I think this is a very exciting observation.
With that, I'll hand it over to Yong, okay, on the second part of your question.
Yeah. In terms of, as we look ahead to engagement and regulatory authorities, obviously, as you pointed out, dose selection for the phase two would be an important part of it. There are also other things as well. I think just broadly speaking, there will be a lot of the standard type of engagement questions, such as presenting our safety package, both non-clinical and clinical, along with our phase one data in terms of the PK and PD data that we've outlined today. How that translates into our proposed approach with dose selection is, as we've discussed, we're excited about the potential of 065 at the dose ranges that we believe are relevant in the context of DMD. Armed with the data that you've seen today, we believe there's potential to really interrogate these possibilities.
We will also talk more in depth about the engagement with regulatory authorities about other elements of the trial design, such as population and endpoints, etc., the usual. We look forward to expeditiously getting to starting regulatory engagements with various authorities starting in the third quarter of this year. If all goes well, depending on the outcome of those regulatory interactions, starting our phase two trial in DMD in the first quarter of next year.
Thanks very much.
Thank you. The next question is coming from Jason Zaminski of Bank of America. Please go ahead.
Good morning. Thanks for squeezing us in, and congrats on the update. I wanted to follow up on your previous comments. In terms of development, are you prioritizing any specific stage of DMD? I mean, it sounds like you could expect it could be effective regardless of progression. Is there a level where you think the benefit is more likely to be meaningful or, I guess, more sustainable secondarily? Can you speak to your confidence regarding the bleeding risks that have been a challenge for previous members of the class will not manifest going forward, especially given the elevated hemoglobin levels? Finally, I know you have downplayed pursuing this in the past, but just based on the safety data, do you still believe 065 could be effective, at least in theory, for obesity patients? Thanks.
Thanks for the question. Yong, you want to start?
Yeah. In terms of your first question about prioritizing any stage DMD, I mean, just taking a step back, you're right, right, that we believe and are excited about the potential across a wide range of different segments, ambulatory, non-ambulatory age. I think, again, it's a bit too early to go into specifics. If only we need to have some engagement with regulatory authorities. To your point, I think just general principles of how we would approach our phase two proof of concept, we would look to probably enrich a population where we believe there's potential for seeing a greater effect and certainly earlier. We want to take an approach of being very timely and efficient in order to get into data. We obviously want to advance the program in an expeditious path as manner as possible. There's some things in consideration set.
I think, broadly speaking, we're just excited about the potential across a wide range and looking to integrate these possibilities. Again, stay tuned. We'll have more to share as the program progresses.
With respect to your other part of your question regarding bleeding events, based upon all that we know today, we do not expect to observe bleeding events in a phase two DMD trial. We did not observe any of those in the phase one trial or in preclinical studies. We believe that the bleeding events due to an increase in hemoglobin observed in third-party molecules can be attributed to the hypoxic state, which is not associated with DMD. We believe that bleeding AEs observed with the wild-type Activin receptor 2B extracellular domain fused to the FC are due to potent inhibition of BMP9. On the other hand, the bleeding events observed with are potentially linked to erythrocytosis in PH patients whose vasculature has been remodeled due to chronic hypoxia that is a hallmark of PH.
You can see some of that data on our website with respect to the pseudohypoxia model showing bleeding events, but not in the absence of pH.
Great. What is the potential for obesity patients?
Yeah. Look, that's always there. We think, okay, right, the 065 could be a treatment there. I think for us, it's really important to move the product into neuromuscular indications where we have the ability to do small trials as well as move the program all the way to commercialization. Obesity is still an indication that we continue to think about. With 065, our priority is really to move it into neuromuscular indications.
Got it. Thank you for the color.
Thank you. The next question is coming from Andrea Argyrides of Oppenheimer. Please go ahead.
Good morning. Thanks for taking our question and for the progress here on the program. Jas, you previously alluded in earlier comments and just recently on ACE-031. I was curious how these results compare to previous results seen from 031 in healthy volunteers with the understanding that there was a different patient population. Any other color on kind of differences given some similar mechanism, but just differences in the molecules. That'd be helpful. Thanks.
Yeah. ACE-031 was a wild-type Activin receptor 2B, it bound BMP9 very, very potently and inhibited BMP9 signal. Both in the phase I healthy volunteer study, which was in postmenopausal women, and in boys with DMD, there were safety observations of bleeding events, nosebleeds, gum bleeds, telangiectasias. With KER-065, which is derived from 50% of the Activin receptor 2A and 50% of the Activin receptor 2B extracellular domains, it is designed to have reduced BMP9 binding. Again, with three months of treatment in the healthy volunteer study, we do not see any of the AEs that were associated with ACE-031, nor in any of our preclinical studies, even at the highest doses of 50 mg/kg, we see the pathology that was associated with ACE-031.
I think on the safety side, the signals of safety that prevented ACE-031 from being further developed have been dialed out. That is important. When you think about all of the biomarkers of the positive biology that you want to look at, you see increases in lean mass that were observed with ACE-031. You see decreases in fat mass, and you see improvements in bone mineral density even in an adult male population. I think all of that is very, very exciting because directionally, both molecules showed changes in lean, increase in lean, decrease in fat, and improvements in bone mineral density. We are seeing that very nicely with 065. I think biology is replicating from the preclinical studies to the clinical setting. We are excited about moving it into boys with DMD.
Thanks for the color. Congrats again. Thanks.
Thank you. At this time, I'd like to turn the floor back over for any additional or closing comments.
Thank you, Alberto. I want to thank everyone that was able to join the call this morning and for the thoughtful questions we received. I would also like to thank the entire Keros team for their work to date and the continuous efforts as we rapidly advance KER-065 and our entire pipeline. We are focused on creating value through the continued execution of our strategy across our pipeline and believe we can utilize timeline-efficient paths to additional meaningful clinical data. Thank you again for your time, and we look forward to providing additional updates in the future.
Thank you. This concludes today's event. You may disconnect your phone lines or log off the webcast at this time and enjoy the rest of your day.