ASH 2024: New Data from Phase II Trials for MDS and MF

The data we presented at ASH supports the differentiated profile of elritercept in both MDS and MF,” said Jasbir S. Seehra, Ph.D., Chair and Chief Executive Officer. “We look forward to commencing enrollment of our Phase III RENEW clinical trial evaluating elritercept in adult patients with transfusion-dependent anemia with very low-, low-, or intermediate-risk MDS soon, so that we can take the next step towards bringing this potential treatment option to patients.”

Clinical Presentations;

• Improvements in Hematological Parameters and Quality of Life (“QoL”) with Elritercept: Results from an Ongoing Phase II Trial in Participants with Lower-Risk MDS; 
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  This ongoing, open-label, two-part, Phase II clinical trial is evaluating elritercept in patients with very low-, low-, or intermediate-risk MDS. As of August 30, 2024 (the “data cut-off date”), 95 patients had received at least one dose of elritercept at the recommended Part 2 dose (“RP2D”) (collectively, the “safety population”). Of these patients in the safety population, 87 had completed at least 24 weeks of treatment or discontinued as of the data cut-off date (collectively, the modified intent-to-treat 24-week population, or the “mITT₂₄ patients”). Data for hematological response and markers of hematopoiesis were presented from exploratory analyses of these mITT₂₄ patients. All data presented from this trial is as of the data cut-off date.

Of the 95 patients in the safety population, 60.0% (n=57) were high transfusion burden (“HTB”) while 24.2% (n=23) were low transfusion burden and 15.8% (n=15) were non-transfused (“NT”).
Elritercept was generally well-tolerated in the safety population. There were four cases of fatal treatment-emergent adverse events (“TEAEs”) in the trial that were all deemed unrelated to treatment. The most commonly reported TEAEs (in ≥15% of patients) were diarrhea, fatigue, COVID-19, dyspnea, dizziness, anemia, nausea and epistaxis. One patient had progressed to acute myeloid leukemia as of the data cutoff date.

55.2% (n=48/87) of the mITT₂₄ patients achieved an overall erythroid response over the first 24 weeks of treatment, which is defined as meeting either modified International Working Group 2006 Hematological improvement-erythroid (“HI-E”) or transfusion independence (“TI”) for at least eight weeks in transfusion-dependent patients who required ≥ 2 red blood cell (“RBC”) units transfused at baseline. The median duration of transfusion independence was 134.1 weeks. Due to ongoing TI responses as of the data cutoff date, the median duration of TI is expected to change as data continues to accumulate. 48.1% (n=13/27) of patients with a TI response had ongoing TI as of the data cutoff date, of which 92.3% (n=12/13) had ongoing TI for greater than 52 weeks.

Additional data from the mITT₂₄ patients include:

• i.  39.1% (n=27/69) of the TI-evaluable patients achieved TI for at least eight weeks over the first 24 weeks of treatment.
• ii. Of the patients with HTB, 31.4% (n=16/51) achieved TI for at least eight weeks during the first 24 weeks of treatment. Eight of those 16 patients (50.0%) achieved TI for at least 24 weeks over the first 48 weeks of treatment.
• iii. Of the TI-evaluable patients with baseline erythropoietin level less than 500 U/L, 47.3% (n=26/55) achieved TI for at least eight weeks over the first 24 weeks of treatment. Of the TI-evaluable patients with baseline erythropoietin level less than 500 U/L and HTB, 38.5% (n=15/39) achieved TI for at least eight weeks over the first 24 weeks of treatment.
   
• The FACIT-Fatigue scale, a measure of self-reported fatigue and its impact upon daily activities and function, was utilized to assess health-related quality of life, including in a subgroup of patients (n=17) achieving TI for at least 24 weeks over the first 48 weeks of treatment. Patients in this subgroup showed clinically meaningful improvements in QoL, and meaningful improvements in FACIT-Fatigue were observed early and generally continued to improve over time in patients with more durable TI responses.

The majority of patients enrolled in this ongoing trial had HTB and/or multi-lineage dysplasia, indicating a difficult-to-treat trial population. Durable TI responses continued to be observed in a broad range of patients with lower-risk MDS, including in those with HTB, which support the potential for elritercept to ameliorate ineffective hematopoiesis across multiple lineages in patients with MDS. These Phase 2 data further support the rationale for the planned Phase 3 RENEW registrational trial of elritercept in transfusion-dependent patients with very low-, low-, and intermediate risk MDS.

• Hematologic Improvement and Fatigue Reduction with Elritercept in Participants with Lower-Risk MDS with Non-Transfusion Dependent Anemia: New Analyses from an Ongoing Phase II Trial;
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  In a subgroup analysis of patients that were non-transfused (“NT”) at baseline, treatment with elritercept showed:
• i. Robust hematological responses observed with 93.3% (n=14/15) of NT patients having an increase greater than 1.0 g/dL and 86.7% (n=13/15) having an HI-E response.
• ii. Durable HI-E responses observed with elritercept treatment with 100% (n=13/13) achieving a continuous response duration of greater than 24 weeks and 76.9% (n=10/13) achieving a cumulative response duration greater than 52 weeks.
• iii. Sustained and durable increases in hemoglobin and soluble transferrin receptor, a marker of erythropoietic activity, were observed in NT participants.
• iv. Overall improvement in mean platelet and neutrophil counts along with decreases in mean ferritin and hepcidin were observed after only one dose and were generally maintained through 48 weeks, demonstrating that elritercept has the potential to address ineffective hematopoiesis across multiple lineages and improve iron utilization and reduce inflammation.
• v.  NT patients achieved meaningful improvements in FACIT-Fatigue scores, with improvements seen early, generally within the first two treatment cycles.
• The data we presented at ASH supports the differentiated profile of elritercept in both MDS and MF,” said Jasbir S. Seehra, Ph.D., Chair and Chief Executive Officer. “We look forward to commencing enrollment of our Phase III RENEW clinical trial evaluating elritercept in adult patients with transfusion-dependent anemia with very low-, low-, or intermediate-risk MDS soon, so that we can take the next step towards bringing this potential treatment option to patients.”
• HematoIgical Improvement and Other Clinical Benefits of Elrtiercept as Monotherapy and in Combination with Ruxolitinib in Participants with Myelofibrosis from the Ongoing Phase II RESTORE Trial;
   
• This ongoing, open-label, two-part Phase II clinical trial is evaluating elritercept administered with or without ruxolitinib in patients with MF who have anemia and were either currently on, failed, or ineligible for ruxolitinib at baseline. Safety data are presented for all patients that received at least one dose of elritercept (n=73) as of the August 30, 2024 data cutoff date. Evaluations of markers of hematopoiesis and anemia over 12 weeks, along with measurements of spleen volume and symptom scores (by the MF-symptom assessment form-Total Symptom Score, or “MF-SAF-TSS”) over 24 weeks, were presented for dose levels 1 through 4 in Part 1 and the RP2D, ranging from 0.75 mg/kg to 5.0 mg/kg (collectively, the “efficacy evaluable patients”). Enrollment of Part 1 of the trial, the dose escalation portion, is complete. Part 2, the dose expansion portion, is open and enrolling with an RP2D of 3.75 mg/kg with the option to up-titrate to 5.0 mg/kg. All data presented from this trial is as of the data cutoff date.
• Elritercept was generally well-tolerated by the safety population. There were six cases of fatal TEAEs in the trial that were each deemed unrelated to treatment. The most commonly reported TEAEs (in ≥15% of patients) were thrombocytopenia and diarrhea. The majority of treatment-related TEAEs were mild to moderate, with 12 patients experiencing Grade 3 or higher treatment-related TEAEs of thrombocytopenia. 93.3% (n=14/15) of patients with a TEAE of thrombocytopenia had baseline platelets below 150 x 10⁹/L.
• Additional data from the efficacy evaluable patients include:
• i. Increases in hemoglobin were observed in 82.8% (n=24/29) of evaluable non-transfusion dependent patients in both arms over a 12-week period within the first 24 weeks, suggesting that elritercept has the potential to address anemia due to MF and ruxolitinib-associated anemia.
• ii. 63.4% (n=26/41) of patients that received at least three RBC units per 12 weeks at baseline in both arms and all dose levels tested showed reductions in transfusion burden over 12 weeks within the first 24 weeks. 24.4% (n=10/41) of the patients who showed reductions in transfusion burdens achieved TI.
  • iii. Additionally, within the subgroup of these patients in the combination arm who received a starting dose of 3.0 mg/kg of elritercept or higher, 62.5% (n=10/16) had reductions of 50% or greater, and 37.5% (n=6/16) achieved TI.
• At week 24, reduction in spleen volume was observed in 40% (n=8/20) of patients with baseline spleen size ≥ 450 cm³ and a week 24 spleen assessment, including three patients who had reductions of 35% or greater. Reductions in spleen volume in the combination arm generally occurred without an increase in ruxolitinib dose.
  • For evaluable patients in the combination arm with a starting dose of 3.0 mg/kg of elritercept or higher, 88% (n=7/8) had some reduction in spleen size at week 24
• At week 24, reduction in disease symptoms was observed in 66.7% (n=18/27) of patients with at least two symptoms with an average score ≥ 3 or an average total score of ≥ 10 on the MF-SAF-TSS questionnaire at baseline and a week 24 MF-SAF-TSS assessment. Five patients had reductions of at least 50%, including three in the monotherapy arm and two in the combination arm.
• The data support the potential of elritercept to ameliorate ineffective hematopoiesis and address cytopenias due to MF and associated with ruxolitinib, and provide broader clinical benefit in patients, as supported by the observed reduction in spleen volume and improvement in total symptom scores.
• About the Ongoing Phase II Clinical Trial of Elritercept in Patients with MDS (NCT04419649);
• Keros is conducting an open label, two-part, multiple ascending dose Phase II clinical trial to evaluate elritercept in patients with very low-, low-, or intermediate-risk MDS who either have or have not previously received treatment with an erythroid stimulating agent.The primary objective of this trial is to assess the safety and tolerability of elritercept in patients with MDS that are RS positive or non-RS. The primary objective of Part 2 of this trial is confirmation of the safety and tolerability of the RP2D (3.75 mg/kg and 5.0 mg/kg). The secondary objectives of this trial are to evaluate the pharmacokinetics, pharmacodynamics and efficacy of elritercept.
• About the Ongoing Phase II Clinical Trial of Elritercept in Patients with MF-Associated Cytopenias (RESTORE trial; NCT05037760);
• Keros is conducting an open label, two-part, multiple ascending dose Phase II clinical trial to evaluate elritercept as a monotherapy and in combination with ruxolitinib in patients with MF-associated cytopenias. The primary objective of this trial is to assess the safety and tolerability of elritercept in patients with MF-associated cytopenias. The primary objective of Part 2 of this trial is confirmation of the safety and tolerability of the RP2D (3.75 mg/kg and 5.0 mg/kg). The secondary objectives of this trial are to evaluate the pharmacokinetics, pharmacodynamics and efficacy of elritercept administered with or without ruxolitinib.