Hematological Improvement and Other Clinical Benefits of Elritercept As Monotherapy and in Combination with Ruxolitinib in Participants with Myelofibrosis from the Ongoing Phase 2 Restore Trial

Background: Abnormal JAK and TGF-β superfamily signaling in myelofibrosis (MF) lead to ineffective hematopoiesis (IH), splenomegaly, constitutional symptoms and cytopenia. Anemia is prevalent and is associated with reduced quality of life and survival. JAK inhibitors improve spleen size and symptoms but are associated with dose-limiting cytopenias, exacerbating those caused by IH. Elritercept is an investigational modified activin receptor type IIA ligand trap designed to inhibit activin A and select TGF-β superfamily ligands (activin B, GDFs 8 & 11) to restore IH. Updated results from the ongoing Phase 2 RESTORE trial (NCT05037760) evaluating elritercept in MF are presented, including initial exploration of changes in iron homeostasis markers and specific symptoms.

Methods: Data are presented as of 03Apr24, evaluating elritercept as monotherapy (Arm A) and in combination with ruxolitinib (Arm B) in participants with MF and anemia (transfusion-dependent [TD; ≥6 RBC U/12 wks and ≥1 transfusion within 4 wks before elritercept] or non-TD and hemoglobin [Hgb] <10g/dL). Endpoints include safety, PK/PD, and effects on anemia, spleen size, and symptoms (MPN-SAF-TSS). Baseline and safety data are for participants who received ≥1 dose of elritercept. Anemia, spleen, and total symptom score (TSS) data are for the respective evaluable populations. The recommended Part 2 dose (RP2D) of 3.75 – 5mg/kg SC Q4W was selected, consistent with a parallel Phase 2 study in myelodysplastic neoplasms (MDS), based on the totality of data including safety and PK/PD. Elritercept exposure at the RP2D in MDS and at doses ≥3 mg/kg in RESTORE was similar.

Results: Overall, 23 and 31 participants were enrolled in Arm A and Arm B, respectively, with median treatment duration of 30 wks (Part 1 Dose Escalation: 41 wks, Part 2 Dose Expansion: 10 wks). At baseline, 31% of all participants were TD and most had splenomegaly (volume ≥450 cm³) and symptoms (TSS ≥10). Ferritin and hepcidin levels were elevated, particularly in TD participants, and 59% of all participants had thrombocytopenia (<150x10⁹/L). Treatment-emergent adverse events observed in ≥15% of participants) were thrombocytopenia (19%) and diarrhea (17%). One participant had an asymptomatic Hgb increase (10.2 to 12.1 g/dL) requiring dose reduction, per protocol, that was deemed a dose-limiting toxicity.

A maximum mean increase in Hgb ≥1.0g/dL over 12 consecutive wks during the first 24 wks was observed in 3/8 evaluable non-TD participants in Arm A and 7/12 non-TD participants in Arm B; among participants treated at 3mg/kg or higher in Arm B, 6/10 had a mean increase in Hgb ≥1.0g/dL. Participants with a maximum mean Hgb increase ≥1.0g/dL generally had decreases in hepcidin and ferritin. Platelets were generally maintained or increased, including in participants with baseline thrombocytopenia.

Reduction in 12-wk transfusion burden was observed in 3/5 and 6/10 TD participants in Arms A and B respectively over the first 24 wks. In an expanded population with ≥3 RBC U/12 wks at baseline (TD3), 2/12 participants in Arm A achieved ≥ 12 wks transfusion independence (TI), both at doses < 3 mg/kg. In Arm B, 10/21 TD3 participants had a ≥50% reduction in RBC U/12wks including 6 participants with TI. Among Arm B TD3 participants treated at doses ≥ 3 mg/kg, 8/11 had ≥50% reduction in RBC U/12 wks and 5/11 achieved TI.

Overall, 9/17 evaluable participants showed reduction in spleen size at Wk 24; 3 participants had ≥35% reduction (1 in Arm A, 2 in Arm B). Improvements in TSS were observed in 13/20 evaluable participants at Wk 24 and 3 participants (2 in Arm A, 1 in Arm B) had ≥50% reduction (improvement). Among participants with ≥50% reduction in TSS, dominant items were itching, abdominal discomfort, pain under the left rib, and satiety in Arm A and fatigue, night sweats, and abdominal discomfort in Arm B.

Summary: Elritercept was generally well tolerated with potential to treat multiple aspects of MF. Observed improvements in Hgb and transfusion burden with maintenance or increases of platelets demonstrate potential to address IH and treat MF and ruxolitnib-associated cytopenias. Decreases in ferritin and hepcidin support potential improvements in iron homeostasis and/or inflammation. Data also support potential for elritercept to reduce spleen size and improve TSS as monotherapy and in combination with ruxolitinib. Updated results with additional patients and longer-term data will be presented.