-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3675 A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes — Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Bone Marrow Failure Syndromes, Workforce, hematopoiesis, Diseases, Biological Processes
Monday, December 13, 2021, 6:00 PM-8:00 PM

David M Ross, MBBS, PhD, FRACP, FRCPA1*, Alejandro Arbelaez, MBBS, FRACP, FRCPA2*, Lynette C.Y. Chee, MBBS, PhD, FRACP, FRCPA3, Chun Yew Fong, MBBS, PhD4, Devendra Hiwase, MBBS, MD, FRACP, FRCPA, PhD5, George Kannourakis, MB.BS, B(Med)Sci, PhD, FRACP6, John Kwan, MBBS, FRACP, FRCPA7*, James Liang, MCBhB, FRACP, FRCPA8*, Anish Puliyayil, MD. DM. FRACP.9*, Hannah Rose, MBBS10*, Shuhying Tan, MBBS11*, Tse-Chieh Teh, MBBS, PhD, FRACP, FRCPA12*, David Alan Westerman, MBBS, FRCPA, FRACP13, Joel Wight, MBBS FRACP FRCPA14, Chris Rovaldi, MSc15*, Elissa M. Furutani, MD16, Adrienne Gaggi16*, Ying Jiang, PhD16*, Jenn Lachey, PhD16, Harveen Dhillon Natarajan16* and Claudia Ordonez, MD16*

1Department of Haematology, Flinders Medical Centre and University, Adelaide, SA, Australia
2Tweed Hospital, Brisbane, AUS
3Department of Clinical Haematology and Bone Marrow Transplant Service, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia
4Department of Clinical Haematology, Austin Health and Olivia Newton John Cancer Research Institute, Melbourne, Australia
5Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia
6Ballarat Onc. & Hem. Services, Ballarat, Australia
7Westmead Hospital, Sydney, NSW, Australia
8Middlemore Hospital, Auckland, New Zealand
9Albury Wodonga Health, Albury-Wodonga Regional Cancer Centre,, Auckland, Australia
10Barwon Health, Geelong, Australia
11St. Vincent, XX, VIC, Australia
12Box Hill Hospital, Victoria, Australia
13Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
14Townsville University Hospital, Douglas, QLD, Australia
15NS Biopharma, Marblehead, MA
16Keros Therapeutics, Lexington, MA

Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia.

KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed.

Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia.

Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study.

Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB <10g/dL or requiring RBC transfusions) are enrolled. In Part 1, ascending dose cohorts receive KER-050 subcutaneously every 4 weeks for 4 doses starting at 0.75mg/kg until a recommended Part 2 dose is determined. Part 2 dose expansion will begin following Part 1, with treatment extended to 2 years. Safety endpoints include incidence of adverse events (AEs); erythroid efficacy endpoints (≥8 weeks duration) include rates of transfusion independence (TI) in transfused participants, reduction in RBC transfusions by ≥4 units or ≥50% reduction in high transfusion burden participants (HTB) and HGB increase ≥1.5g/dL in non-transfused (NT) and low transfusion burden (LTB) participants. Results are reported for efficacy-evaluable participants in cohorts 1 and 2 of Part 1 dose escalation, defined as having ≥8 weeks of HGB and transfusion data.

Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1.

No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML.

In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A).

Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x109/L (mean), range 10.5- 41.6 x109/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%.

Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x109/L (range 104-401 x109/L), and maximum increase from baseline was 130 x109/L (mean), range 32-235 x109/L. No participants required dose reduction due to thrombocytosis.

Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting.

Disclosures: Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH