will be available on Keros' corporate website. I would now like to introduce our host for today's program, Justin Frantz, Keros' Head of Investor Relations. Mr. Frantz, please go ahead.
Thank you, operator. Thank you all for joining us on today's call. As we announced this morning, we are very excited to provide a corporate update across our pipeline of assets. A press release is available on our website at kerostx.com, and is also included as an exhibit in the Form 8-K that we filed with the Securities and Exchange Commission. During this call, we will be making a number of forward-looking statements. Please take a moment to review our disclaimer slide on the webcast, which notes 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 quarterly report of Form 10-Q, filed with the SEC on May 8th, 2024, as well as the company's other documents subsequently filed 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. Today, we will discuss select updates from our clinical programs. Joining me on this call are Jasbir Seehra, President and CEO of Keros Therapeutics; Chris Rallis, our Chief Operating Officer; and our Senior Vice President of Clinical Development, Dena Grayson. After the update, we will open the call for Q&A. I will now turn the call over to Jasbir Seehra.
Thanks, Justin. Thank you all for joining us this morning. We're excited to provide an update on the tremendous progress we've made. As a reminder, Keros is developing potentially differentiated product candidates designed to alter transforming growth factor-beta, or TGF-beta signaling, and target pathways critical for the growth, repair, and maintenance of a number of tissues and organ systems. On today's call, we will provide updates from our pipeline, including our data that was recently presented from our KER-050, or elritercept, phase 2 clinical trials in myelodysplastic syndromes and myelofibrosis. We will then begin by providing an update from our elritercept program. Myeloproliferative neoplasms, which include MDS and MF, are complex diseases. They are diseases of the bone marrow. Within the bone marrow is an osteohematopoietic niche, where bone and blood cell precursors interact to regulate hematopoiesis.
Disruptions in these interactions can lead to ineffective hematopoiesis and have downstream consequences that lead to the poor systemic outcomes that include anemia, progression to AML, heart failure, bleeding, iron overload, and bone loss. Increasing evidence suggests that imbalanced signaling by TGF-beta superfamily members, particularly activin A, is a key driver of this pathogenesis of MDS and myelofibrosis. Activin A is a pro-inflammatory TGF-beta ligand that is increased in the bone marrow in these patients and has been shown to impair osteogenesis and hematopoiesis. Elritercept is an activin receptor type IIA ligand trap designed to treat ineffective hematopoiesis. It has been engineered to bind select TGF-beta ligands, including activin A, and restore balanced TGF-beta signaling within the osteohematopoietic niche. Elritercept has been designed to promote maturation and differentiation across all stages of both erythropoiesis and thrombopoiesis.
Importantly, this reflects a differentiated mechanism of action relative to ESAs and EMAs, both used to treat MDS, which primarily stimulate only either early or late-stage erythropoiesis precursors, respectively. Elritercept also demonstrated the potential to increase bone formation, improve iron utilization, and reduce myocardial strain, thereby potentially addressing the cascade of poor outcomes we just discussed. I will now hand the call over to Dena to walk through the MDS data presentation at EHA. Dena?
Thank you, Jas. Dysregulated signaling due to somatic mutations, aging, and inflammation lead to ineffective hematopoiesis in MDS. People living with MDS experience multiple cytopenias, including severe anemia, and have reduced quality of life due to factors such as fatigue and the emotional burden of their disease and its treatments. Unmet need remains for treatments that can address the multifaceted pathophysiology leading to ineffective hematopoiesis and the severe consequence of MDS, including progression to acute myeloid leukemia, also called AML, and cardiovascular disease, which actually is the second leading cause of death in MDS patients.... As a reminder, here is the design of our ongoing phase II trial in lower risk MDS. In our phase II trial, we are exploring the potential for elritercept to address ineffective hematopoiesis in lower risk MDS.
As Jas shared earlier, elritercept, with its potent inhibition of activin A, has the potential to ameliorate multiple components of the pathophysiology of MDS, not just anemia. This two-part phase II trial is assessing the safety and efficacy of elritercept in a broad population of lower risk MDS patients, including non-transfused and transfusion-dependent patients, ring sideroblasts positive, also called RS positive, and non-RS patients, as well as patients who are ESA experienced, ESA naive, or unlikely to respond to ESAs. We are currently enrolling Part II and treating ongoing patients from both Part I and Part II at the recommended Part II dose, also called RP2D, of 3.75 milligrams per kilogram every four weeks, with the option to uptitrate to 5 milligrams per kilogram for inefficient response.
Endpoints include hematologic improvement, or HI-E, for eight weeks per IWG 2006 criteria, and red blood cell transfusion independence for eight weeks in patients who require at least two units of red blood cells at baseline. All the data presented is as of the April third, 2024 data cutoff date. At this data cutoff, 87 enrolled patients had received at least one dose of elritercept, which we refer to as the safety population. The median duration of treatment was approximately 42 weeks, with approximately 53% of enrolled patients ongoing and remaining on treatment. The demographics and baseline characteristics of the patients in the safety population for this trial update are shown here. These data collectively demonstrate that our trial has enrolled a hard-to-treat population with high disease burden.
The vast majority of patients had multilineage dysplasia, and nearly a quarter had thrombocytopenia at baseline, a characteristic that is independently associated with a poor prognosis in MDS. Despite the high disease burden of the enrolled patients, elritercept has been generally well-tolerated. Treatment emergent adverse events, also called TEAEs, that occurred in at least 15% of patients were diarrhea, fatigue, dyspnea, dizziness, COVID-19, nausea, and anemia. Most treatment emergent adverse events were mild to moderate in severity, and importantly, no patients have progressed to AML while on treatment. Here, we see the hematologic response rates observed in the trial. The modified intent-to-treat 24-week population, or mITT-24 population, includes 81 RP2-24 patients with at least 24 weeks of elritercept treatment or who have discontinued as of the data cutoff date.
Response was assessed by 2006 IWG criteria for HI-E or independently transfusion independence, depicted here as TI, depending on the baseline transfusion burden. Overall response reflects either HI-E or TI criteria being met. In the first column, we show response rates for the entire mITT-24 population, while the second column shows response rates for the difficult-to-treat, high transfusion burden subset. HI-E and TI response rates were generally similar in the two groups, supporting the potential for elritercept to treat a broad array of patients with MDS, including those with higher transfusion burden and greater bone marrow dysfunction.
In the third and fourth column, we show the mITT-24 response rates, excluding patients with endogenous EPO levels higher than 500 units per liter, as EPO levels greater than 500 are a negative predictor of erythropoietic response, and historically, this threshold has been used to guide treatment decisions in lower risk MDS. The transfusion independence rate in this subpopulation for RS-positive patients was 52.5%, and in those with non-RS, it was 40%. Response rates in this subpopulation overall were generally higher, particularly in non-RS patients. Here, we review the durability of transfusion independence in the mITT-24 population. In the panel on the left, you can see the rates of transfusion independence over periods ranging from 12 weeks through 24 weeks.
The majority of patients who achieved 12 weeks of TI within the first 6 months of treatment maintained transfusion independence for at least 24 weeks. The observed rates of transfusion independence for at least 24 weeks, shown here, support the potentially differentiated durability of response to treatment with elritercept, and response rates were relatively higher in patients with baseline EPO levels below 500 units per liter, including 32% of these patients achieving a TI of 24 weeks or greater. The durability of transfusion independence can also be seen in the Kaplan-Meier curve shown here. When we reported the data at ASH in December 2023, we had not yet reached the median duration of response. As of this new data cut, which is approximately seven months later than the previous cut for ASH-...
16 of the 26 TI responses were still ongoing, and therefore, the median duration of response has still not yet been reached. Importantly, 11 of 26 patients, or 42.3% of responders, remained transfusion independent for at least one year as of the data cutoff. As we have previously reported, here we show that transfusion-dependent patients receiving elritercept achieved clinically meaningful and durable improvements in FACIT fatigue score. Health-related quality of life is negatively impacted by MDS, where prolonged transfusion dependence and worsening fatigue have been associated with reduced survival. This trial assessed health-related quality of life using various quality of life assessments, including the FACIT Fatigue Scale, a validated 13-question measure of health-related quality of life in patients with MDS. Patients achieving transfusion independence of 24 weeks or longer experienced clinically meaningful improvements in FACIT fatigue scores.
We believe the potential for elritercept to address the patient's fatigue is an important treatment objective for lower-risk MDS. In summary, we continue to show that in the ongoing phase II clinical trial of elritercept in lower-risk MDS, the majority of patients enrolled had high transfusion burden or multilineage dysplasia, indicating a difficult-to-treat trial population. As of the data cutoff date, elritercept was generally well-tolerated, with a safety profile consistent with our previous updates from this trial. Hematologic responses were observed in 56% of patients, and transfusion independence of eight weeks or longer was achieved in 41% of patients, including those with both RS or non-RS disease. We continue to show a durable transfusion independence response in a broad range of patients, including those with high transfusion burden, and the median duration of the response was not reached as of the data cutoff date.
Looking at a subpopulation of patients with baseline EPO levels less than 500 units per liter, shows improved erythroid responses across the trial population, including in patients with high transfusion burden and/or non-RS disease. In addition to all of those hematologic responses, patients who achieved transfusion independence showed clinically meaningful improvements in FACIT-Fatigue scores, indicating potential for elritercept to improve quality of life in patients with lower-risk MDS. Collectively, we strongly believe that these results support advancing elritercept into a phase III registration trial in patients with lower-risk MDS. I will now hand the call over to Chris Rallis.
Thank you, Dena. As we prepare for a registrational trial, it is important to consider the current treatment landscape and the need for novel treatments for patients living with MDS. Current options for symptomatic anemia include red blood cell transfusions, ESAs, Reblozyl, an erythroid maturation agent, and Imetelstat. MDS patients are often dependent on transfusions, which provide symptomatic relief. However, repeated transfusions lead to iron overload and are associated with increased risk of disease progression and reduced overall survival. ESAs have long been the standard of care in MDS and have been shown to improve anemia, but benefit is limited in patients with high transfusion burden and elevated endogenous erythropoietin levels. Reblozyl is approved in first-line lower-risk MDS and in second-line only in RS-positive MDS.
In the more severe second-line patients with high transfusion burden, only 20% of patients achieve transfusion independence for eight weeks following treatment with Reblozyl. Importantly, in the second-line setting, no improvements in patient-reported outcomes of quality of life were demonstrated with Reblozyl in the phase III trial. On June sixth, 2024, Imetelstat, or uncertain, was approved as a second-line treatment in high transfusion burden MDS patients who have not responded to or have last response to or are ineligible for ESAs. Although the field has progressed in developing assets to improve anemia, the current treatment options do not fully address the needs of patients. New treatments are needed for people living with lower-risk MDS that are safe and that can address the anemia and debilitating impacts on quality of life in both RS-positive and non-RS patients, and regardless of transfusion burden.
As a reminder, here is the reported data from the third-party phase III placebo-controlled trial evaluating luspatercept in an ESA-naive, refractory, or ineligible population of lower-risk MDS patients. I note that this trial enrolled only patients who are RS positive and had no cap on patient baseline EPO levels. Here you can see the data from the phase II trial in comparison to the placebo group, which was included in the BLA submitted to the FDA for review and supported the approval of Reblozyl in second-line low-risk MDS RS-positive patients. In the MEDALIST trial, luspatercept had a 38% rate of transfusion independence in RS-positive patients versus a 13% rate in the placebo group. In high transfusion burden patients, luspatercept showed just a 20% transfusion independence rate versus 4% in the placebo group.
In MEDALIST, luspatercept had a median duration of response in RS-positive patients of 30.6 weeks versus the placebo with 13.6 weeks. We believe this data demonstrates that there continues to be areas of unmet need for patients living with MDS. Here, we highlight data from our phase 2 trial observed as of the data cutoff date. We believe these data highlight the potential of elritercept to overcome limitations of current treatment options and address the unmet need. The mITT 24 analysis includes both RS-positive and non-RS patients, with baseline transfusion burden of two or more units and a baseline EPO level below 500 units per liter.
As you can see, half of these patients treated with elritercept achieved transfusion independence for at least 8 weeks, and 42.9% of the high transfusion burden patients achieved transfusion independence for at least 8 weeks, demonstrating a deep response in difficult-to-treat patients. We also observed a durable response, with 32% of these patients achieving transfusion independence for at least 24 weeks. The durability of response is further supported by the fact that 11 out of 26, or 42.3%, of responders remained transfusion independent for over 1 year, and we have still not yet reached the median duration of transfusion independence as of the data cutoff. We are excited to share that we've received positive feedback from the FDA. The interaction resulted in general alignment on the design and endpoints for the proposed phase 3 placebo-controlled clinical trial in patients with MDS.
We plan to hold an investor call in the second half of the year to provide greater detail on the phase 3 trial design, but let me summarize the core design elements of the phase 3 study. The trial population will include very low, low, or intermediate risk MDS patients who are ESA-naive and/or ESA-experienced with no prior Revlimid experience. We will include a broad patient population, including RS positive and non-RS patients, and we'll have a baseline serum EPO level cap. The planned primary endpoint for this trial is transfusion independence at 8 weeks within the first 24 weeks of treatment, similar to other MDS phase 3 trials. Now, we have presented data from our ongoing phase 2 clinical trial. Given the robust duration of response we've observed in phase 2, key secondary endpoint will be the 24-week transfusion independence rate over 48 weeks of treatment.
I will now pass the call back over to Dena to discuss the updated data from our phase 2 trial of elritercept in patients with myelofibrosis presented at EHA.
Thank you, Chris. Myelofibrosis is a myeloproliferative neoplasm that results in abnormal proliferation of megakaryocytes in the bone marrow, which leads to ineffective hematopoiesis, inflammation, and ultimately, fibrosis in the bone marrow. People living with myelofibrosis experience enlargement of the spleen and multiple cytopenias, including severe anemia, which results in fatigue and reduced quality of life. Treatment objectives for people living with myelofibrosis include ameliorating constitutional symptoms, reducing the enlarged spleen, and addressing cytopenias. Current treatments, including ruxolitinib, provide symptomatic relief and can reduce splenomegaly, but additional treatment options are still needed. Patients experience disease-associated or treatment-emergent cytopenias, including anemia and thrombocytopenia. We believe that elritercept has the potential to address the multifaceted pathophysiology that leads to ineffective hematopoiesis and the severe consequences of myelofibrosis. RESTORE is an open-label, 2-part, phase 2 clinical trial evaluating the safety and efficacy of elritercept in patients with myelofibrosis.
Our aim is to understand the safety and efficacy of elritercept to address ineffective hematopoiesis, either in combination with ruxolitinib or as a monotherapy, both in patients who are ruxolitinib-naive or who have been previously treated with ruxolitinib. Data from the dose escalation part one was used to select the recommended part two dose, RP2D, of 3.75 milligrams per kilogram, with the option to uptitrate to 5 milligrams per kilogram, which are the same dose levels being tested in the MDS phase two trial. The primary endpoints are safety and tolerability, and secondary and exploratory endpoints are evaluating the effects of elritercept, with or without ruxolitinib, in treating anemia, splenomegaly, and constitutional symptoms, along with exploratory biomarkers. The myelofibrosis data we will share with you today are as of the data cutoff date of April third, 2024.
Safety data are presented for all patients who received at least one dose of elritercept, a total of 54 patients. We have completed the dose escalation portion of the trial, and the part two dose expansion is open and enrolling. The patients enrolled in this trial had marked splenomegaly and severe erythropoietic dysfunction. Approximately 30% of patients enrolled were characterized as high risk according to the DIPSS prognostic scoring system. 31% of patients were transfusion-dependent according to IWG 2013 criteria, with a median transfusion burden of 10 red blood cell units for 12 weeks, and the median transfusion burden for non-transfusion dependent patients was 3 red blood cell units for 12 weeks. The patients we have enrolled have been anemic, with a median hemoglobin of 8.1 grams per deciliter.
Additionally, we enrolled a patient population with thrombocytopenia, which was even more severe in the monotherapy arm. Approximately 76% of patients in both the monotherapy and combination arms, excluding those with missing baseline values, had splenomegaly, and marked splenomegaly was observed in some patients, even in the combination arm, indicating that ruxolitinib was not providing sufficient control of disease. Elritercept was generally well-tolerated in these patients who had significant disease burden and complex comorbidities, consistent with a frail myelofibrosis population. Treatment emergent adverse events were observed in most patients, but treatment-related TEAEs were relatively infrequent. The most frequent TEAEs, regardless of causality, were thrombocytopenia and diarrhea. Three patients experienced grade three or higher TEAEs that were considered to be related to elritercept by the investigator. Those were a decrease in platelet count, hypertension, and thrombocytopenia.
There were four TEAEs leading to death, all of which were deemed unrelated to treatment. The causes were pneumonia aspiration, multiple organ dysfunction, transformation to AML, and cerebrovascular accident. We continue to observe changes in markers of erythropoiesis in both the monotherapy and combination arms. Observed increases in markers of erythropoiesis were generally greater at higher doses. Increases in hemoglobin were observed in both the monotherapy and combination arms, and the reductions in transfusion burden observed in both arms further support the potential for elritercept to address both ruxolitinib-associated anemia, as well as anemia due to underlying myelofibrosis. Importantly, in evaluable patients receiving three milligrams per kilogram of elritercept or higher in combination with ruxolitinib, five of 11, or 45.5% of these patients, achieved transfusion independence. We continue to see improvements in platelet counts in patients with baseline thrombocytopenia, particularly in those in the combination arm.
In evaluable patients with splenomegaly, 9 of 17, or 53% of evaluable patients, showed some reduction in spleen size at week 24, with one-third of these patients achieving spleen volume reductions of 35% or more. Importantly, we saw reductions in spleen volume in both the monotherapy and combination therapy arms. Among the seven evaluable patients in the combination arm who showed reductions in spleen volume at week 24,six patients showed reduction in spleen volume without a dose increase in ruxolitinib. Additionally, some reduction in symptom score was observed in 13 of 20 evaluable patients. Three patients had a reduction of 50% or more, including two patients in the monotherapy arm and one in the combination arm. Similar to the phase 2 MDS trial, the myelofibrosis trial has enrolled a broad patient population with high disease burden.
Elritercept was generally well-tolerated in both the monotherapy and combination arms. The observed improvements in hemoglobin, transfusion burden, spleen volume, and total symptom score observed in both the monotherapy and combination arms, including at dose levels below the RP2D, support the potential for elritercept to provide clinically meaningful benefits to patients with myelofibrosis. Enrollment in Part Two of the RESTORE trial is ongoing at the RP2D. I will now pass the call back to Chris to review updates from our other clinical programs.
Thanks, Dena. I'll now cover KER-012, or cibotercept. The TROPOS trial is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of cibotercept in combination with background therapy in adult participants with pulmonary hypertension. As a reminder, cibotercept is a modified activin receptor IIB ligand trap designed to preferentially inhibit select ligands to potentially balance the TGF-beta superfamily signaling without a dose-limiting increase in red blood cells. We completed a randomized, double-blind, placebo-controlled, two-part phase 1 clinical trial to evaluate single and multiple ascending doses of cibotercept in healthy postmenopausal women. In the phase 1 trial, we demonstrated initial safety and tolerability and generated PD data indicating maximal target engagement without observed increases in hemoglobin. We announced IND clearance for the TROPOS trial in August 2023.
Similarly, design trials have taken approximately two years to read out, and we remain in line with those trials. We have been pleased by the momentum of the study and the strong engagement with key investigators in this trial. We recently announced that we expect to complete enrollment in the fourth quarter of this year. The study is progressing nicely, and we now have patients rolling over to the open-label extension. As part of our ongoing portfolio management activities, we have decided to early terminate our open-label phase two biomarker clinical trial of cibotercept in patients with chronic heart failure with preserved or reduced ejection fraction. One of the objectives was to explore the effects of cibotercept on biomarkers, including NT-proBNP, a biomarker of myocardial stress. In a healthy volunteer trial of cibotercept, we demonstrated reductions in NT-proBNP following cibotercept administration.
This, coupled with the observed decreases in NT-proBNP among MDS patients with elevated levels at baseline from our ongoing elritercept MDS phase 2 trial. We believe that cibotercept is likely to reduce NT-proBNP in patients with elevated NT-proBNP, as both assets were designed to inhibit activin A signaling. Additionally, we've encountered difficulties with enrollment of this trial due to the small number of sites we enlisted to execute the trial and the eligibility criteria in the disease population. To date, we have not enrolled any patients into this trial, and as a result, we no longer expect to announce any data from this trial. The planned early termination did not occur on the basis of any safety concerns. Now turning to KER-065, our third clinical asset.
KER-065 is a novel ligand trap designed to bind and inhibit TGF-β superfamily ligands, including the negative regulators of skeletal muscle, myostatin or TGF-β and activin A. We're currently in an ongoing phase I trial in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KER-065 in both SAD and MAD cohorts. We have designed the MAD portion of this trial to enroll healthy volunteers with an elevated BMI of 27-33 in order to better evaluate exploratory biomarkers, including any effect of KER-065 on lean mass, fat mass, and bone mineral density. Based on the Safety Review Committee's recommendation, we have initiated the third cohort in the SAD portion of the trial at a dose of 5 milligrams per kilogram, and we have begun dosing of the first MAD cohort at 2 milligrams per kilogram every four weeks.
We continue to expect to report initial results from this trial in the first quarter of 2025. We believe data from this phase I trial will support initiation of a phase II proof of concept clinical trial in patients with obesity. I'll pass the call over to Jas to review upcoming milestones prior to opening the line for Q&A.
I will now quickly review our upcoming key milestones. For elritercept, we plan to announce additional data in the fourth quarter from the ongoing MDS and MF phase II trials. Given our recent alignment with the FDA on the MDS phase III trial design, we will be focused on the operational initiation of that trial. We continue to drive enrollment in the MF phase II trial to continue to generate data in order to support anticipated end of phase II interaction with the FDA. As we just announced, we expect to complete enrollment for cibotercept phase II TROPOS trial in PAH in the fourth quarter of this year. Following completion of enrollment, we will provide the timing of top-line data readout from TROPOS. And lastly, we expect to report initial data from the KER-065 phase I healthy volunteer trial in the first quarter of 2025.
I will now pass the call over to the operator to begin question and answers.
Thank you. We'll now be conducting a question and answer session. If you'd like to be placed in the question queue, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. One moment, please, while we poll for questions. Our first question today is coming from Corinne Johnson from Goldman Sachs. Your line is now live.
Good morning. Thanks, guys. Maybe a couple of questions from us. On the phase III design, I guess what portion of the patients and what absolute number of patients will be ESA naive in the phase III study? And I guess, how are you thinking about that in terms of positioning this drug for potentially, is it frontline usage? And then how big of a frontline population will we need to support that approval?
Good morning, Corinne. Thanks for that question. I'm gonna ask Chris to provide details.
Thanks, Jas. Corinne, great, great question. As we spoke with the regulators about the phase III study design, there's a lot of precedent for being able to enroll patients that are ESA naive but are unlikely to respond. And those patients typically have high transfusion burden and elevated endogenous EPO levels. And so we do plan to enroll those types of patients in this phase III study design. If you look at prior phase III studies with the Imetelstat and sotatercept, what you will see is anywhere from 5%-10% of patients were ESA naive with this ineligibility criteria of a high EPO or high transfusion burden. So we expect that there could be similar rates of enrollment in this study as well.
Okay. It was a bit confusing. I thought it was ESA naive, and then ineligible was a separate group, but that makes more sense. And then in terms of, then the number of patients like that, that present with or are ESA ineligible at diagnosis, I guess, can you remind us what the size of that patient population is?
So sorry, could you repeat the question about the last part there?
Yeah. Just, what portion of patients kind of present with disease that is ESA ineligible, or that would be kind of within that cohort?
Sure. So I think, elevated EPO levels are known, in kind of the experienced patient population, where about 10% are greater than 500, meaning 90% are lower than 500. The exact breakdown of patients that have elevated EPO levels of one or two up to 500 is not known, so I don't think we can address that fully.
Okay. Thank you.
Thank you. Next question today is coming in from Kripa Devarakonda from Truist Securities. Your line is now live.
... Hey, guys. Thank you so much for taking my question, and, congrats on all the progress. I just have a follow-up question to the previous question, continuing on the phase 3 trial design. You know, one, what, uncertain, you talked about, you know, more operational steps remaining. Can we just get a sense of, you know, what timelines we can expect in terms of the initiation? And on the non-RS patients, you know, you continue to have smaller groups, at least where we see the response rates in the target population. Just broadly thinking about the phase 2 trials, do you expect there to be a minimum % of non-RS patients that you would want to enroll so that you could be considered for an all-comers approval? Thank you.
Thanks, Kripa. So I think on, in terms of timing, the team is actively engaged with all, with our steering committee, and now really serving all the potential sites, and countries and sites. So we think the timing for this study is, start of the study is typical, following the end of phase two discussions. And so that, you know, typically is 6-9 months. So I think we haven't got all the numbers as yet in terms of this country site, so it's hard for us to give you exactly, but I think that it has been typically the case. So, you know, end of 2024 into 2025 is going to be the timeframe. With that, I'll let Chris answer your second part of your question.
Great. So again, you're absolutely right. I think in the clinical trial experience, what we're seeing, across different molecules is that the non-RS population is about 30% of the total enrollment. And then your question around will that support a broad label? That is the conversation that we had with, the regulators, FDA, around a phase 3 study design. We will be enrolling both RS and non-RS. We're looking to have that broad label. And I think the recent approval of Imetelstat, shows that they can get a broad label with about 30% of the patients enrolled that are non-RS. So hopefully that addresses your question, Kripa.
Yeah. Thank you. Thank you so much.
Thank you. Next question is coming from Thomas Smith from Leerink Partners. Your line is now live.
Hey, guys. Good morning. Thanks for taking the questions, and congrats on the data updates. Just two on elritercept, please. With respect to the phase three pivotal trial design, can you comment on how you're thinking about the underlying patient population and their baseline transfusion burden? Are you gonna try to enrich for those high transfusion burden patients, where you're clearly having an outsized effect? And then, secondly, we know the agency's been focused on quality of life improvements here beyond just the transfusion independence rates. It looks like you're seeing nice improvements in the FACIT-Fatigue scores. Can you just talk about how you're thinking about incorporating this into a phase three study? Is there anything you can do to help enrich the patient population to show benefit there?
Morning, Tom. Thanks for the question. Chris, you want to start and-
Yes. Yeah, definitely, Tom, great question. You know, the transfusion burden is where we're seeing, one, not just the unmet clinical need, but we're seeing a great deal of response with elritercept. Again, we believe that greater than 50% of the patients that will be enrolled in a phase 3 trial will be high transfusion burden. So this will allow us to establish the safety and efficacy of elritercept in that high transfusion burden population. And maybe on the quality-of-life front, maybe I'll turn it back to Dina to talk through how we plan to leverage our current understanding of the improvements in quality of life in the phase 3 study.
Dena, you're muted.
Thank you. Thank you, Chris, and thank you, Tom, for the question. We currently plan to assess quality of life by several different measures, and again, details on that will be revealed later this year. But, of course, we do plan to include FACIT-Fatigue, given the very encouraging data that we've seen. And you know, of note, in these patients with MDS and anemia, their chief complaint is fatigue. So showing improvements in fatigue is truly meaningful for these patients. So we're, again, we're encouraged by the data, and we think that enrolling transfusion-dependent patients with anemia, there's no need to enrich any more than that for patients with fatigue, because the vast majority of these patients will have fatigue at entry, at baseline.
Got it. That makes sense. And, if I could just squeeze in, one follow-up question on cibotercept. Just wondering if you could comment on the feedback you're receiving from your clinical trial sites and investigators in the US post-sotatercept approval? Are there certain patients that these sites see as better candidates for the 012 study rather than trying them on commercially available sotatercept?
Yeah, we continue to see very, very enthusiastic response to the KER-012 across the globe, including the US, and we haven't seen holding back of patients for sotatercept. You know, I think this has been a consistent pattern now from the time that we started the study. Investigators tell us as to how many patients they think they have, that they will be screening once the site is activated, and we continue to see exactly this number that they projected enroll within a matter of, you know, days of the site being activated. So we've not seen any evidence of slowdown whatsoever, and I think the enthusiastic support that we've seen continues.
I think it highlights, okay, right, the differentiation between sotatercept and zero one two that the investigator community has come to appreciate over the last year or so.
... Got it. That's helpful color. Thanks for taking the questions, guys. Appreciate it.
Thank you, Tom.
Thank you. Next question is coming from Tyler Van Buren from TD Cowen. Your line is now live.
Hey, guys. Good morning. Thanks for the presentation. Couple, first one, so for elritercept, the goal is clearly to replicate these results in phase 3, and your phase 3 design seems pretty straightforward so far. So I guess just to be clear, can you highlight the key difference, any key differences to the luspatercept phase 3 COMMANDS trial that will allow you to differentiate, if there are any? And then the second one is just regarding your update on plan for enrollment completion for the phase 2 TROPOS study for luspatercept by Q4. Can you tell us what % of patients have been enrolled in the trial to date so we can get a sense of how far along you guys are?
Yeah. Chris, thanks, Taylor, for those two questions. Chris, why don't you start with the first one?
Sure. So again, Tyler, great, great question. The phase 3 study design is very consistent with our phase 2. And I think that's really an important point to make, is that we've built off of the learning from our phase 2 experience over the last several years in designing this phase 3 study to take advantage of the differentiated profile that we've seen. Where we can see that differentiated profile is really in the high transfusion burden population in terms of the response rates as well as the durability of the effect. And so we do plan to enroll majority of patients that have high transfusion burden. And importantly, we're including both RS and non-RS in this population. So the phase 3, again, with a successful outcome, potentially could be broad label for both the RS and non-RS population.
I think that fits really with how physicians are thinking about treatment. They're not living in an RS, non-RS world anymore. They think about transfusion burden and the anemia and fatigue that's associated with that, and so that's how we've designed the phase 3 study.
So Tyler, with respect to enrollment, we've not given guidance as to how far along the recruitment we are at this point in time. If you recall, we guided that it's 75% of the sites will be outside of the US. It is a global study, and therefore, everything is dependent upon, you know, this rolling filings with different countries and then different sites being activated. We're really pleased with how it has progressed, and to the point where here we are toward the end of the second quarter, and we're guiding to fourth quarter completion of enrollment. I think that should tell you that we're very excited with the progress that we've made, and it, it, it...
We feel confident with being able to complete the enrollment in the fourth quarter. Exactly when, it's always hard to tell, because many factors come into play and but we will provide guidance as soon as we are there.
Thank you. Next question is coming from Jason Zemansky from Bank of America. Your line is now live.
Good morning. Congratulations on the progress, and thanks so much for taking our questions. Two, if we may. It seems that there was a pretty stark difference between responders and non-responders, at least in terms of durability, according to your KM curve. Any sense of what's driving that or any insights behind that? And then secondarily, congratulations. It looks like FDA was willing to go along with kind of opening up the population to the broadest measures there. But I'm curious, was there anything that you can share regarding their openness or willingness to look at, particularly those with and without ring sideroblasts in terms of giving them comfort there? Thanks so much.
Yeah. Thanks for that question. I think the general comment I'll make first was that we really had a very, very good discussion with the FDA. And, you know, the study that was proposed was one that the FDA accepted. So with that general comment, I'm gonna let Chris and Dina address the specific points.
Sure. Thanks, Jason. So again, great question in terms of other insights, in terms of the patient profile that leads to response and non-response. I think the one factor that we've identified in the phase 2 study as it relates to erythropoietic response is the baseline in endogenous EPO levels. And so as you can see the way we've presented the data, we've presented the full population, but also those patients with EPO levels less than 500. What we know is that as EPO levels increase, and as they get to a certain level, 500 and greater, you tend to lose the ability to have an erythropoietic response. That's well known based on the years of experience with ESAs, luspatercept, and even some of the imetelstat experience.
So as we looked at our data, really, the endogenous EPO levels help define patients that are responding or non-responding erythropoietically. We have not seen any characteristics yet that help inform the durability of response, but that is something we continue to look for in our phase 2 data set.
Great. Thanks for the color.
Thank you. Next question today is coming from Matt Phipps from William Blair. Your line is now live.
Thanks for taking my question, and congrats on the updates and FDA feedback. I was curious, in the MDS trial, how many patients end up getting up titrated to that five mg per kg level? And I assume you'll use similar criteria and ability to titrate in the phase III trial? And also, just will you include any Rytelo-experienced patients? Thank you.
Thanks, Matt. Dena, why don't you answer that?
Great. Thanks for the question, Matt. So, in the phase 2 trial, close to 60%, sixty percent of the patients was actually just under 59% uptitrated to five mg per kg. So it was a little bit more than half of the patients. And with respect to your second question, we do not plan to include ESA-experienced patients in our phase 3 trial.
Thank you. As a reminder, that's star one to be placed into question queue. Our next question is coming from Julian Harrison from BTIG. Your line is now live.
Good morning. Thank you for taking my questions. I'm curious if you can share the median time from diagnosis to enrollment, both for your phase II MDS and MF trials. Also, if you've identified any mutations that look predictive of response in either trial, that would be helpful to know. And then finally, can you remind us why you believe COMMANDS is not a good reference point for your phase II MDS results?
Thanks, Julian, for that question. Chris? Dina? In that order.
Sure. Why don't I start with the time since diagnosis in the phase II study, it's nearly two years. Again, it's an evolving time since diagnosis as the study's been continually enrolling. I think we look at the Medalist data as being a better comparable study. And when you think about cross-trial comparisons, obviously it's difficult to make those trial comparisons. But in our phase II experience, we had elevated EPO levels, elevated number of patients that are transfusion-dependent, those that have high transfusion burden. Those two factors really contribute to the ability to respond therapeutically. And, you know, I think when you look at the Medalist experience, you see that the majority of patients, 2/3, are high transfusion burden, similar to the phase II experience. EPO levels are elevated, similar to the Medalist experience.
Importantly, nearly 80% of the patients that we've enrolled in our phase II have multilineage dysplasia, indicating a more severe bone marrow state, and that is more comparable to the phase III experience with MEDALIST. When we move into the first-line setting, the lower EPO, lower transfusion burden, as low, as well as lower multilineage dysplasia.
Thank you. We've reached the end of our question and answer session. I'd like to turn the floor back over for any further closing comments.
Thanks, operator. I want to thank you all on the call this morning and your thoughtful questions. We're pleased with the advancement we continue to make at Keros, and we look forward to continued progress across the pipeline. Thank you, everybody. Have a good day.
Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time and have a wonderful day. We thank you for your participation today.