A Phase 1b/2 Study of the Efficacy and Safety of Combination Hydroxyurea and Dose-Escalated Erythropoietin for Treatment of Anemia in Sickle Cell Disease (ACHiEvE-SCD)

Background. Chronic anemia is a hallmark complication of sickle cell disease (SCD) and is associated with chronic organ damage, poor quality of life, and increased mortality. Therapeutic options for chronic anemia in SCD are limited; hydroxyurea (HU) has a modest effect on hemoglobin (Hb) level, and voxelotor increased Hb by > 1 g/dL in only 51% of subjects in the Phase 3 study. Erythropoiesis-stimulating agents (ESAs) are the standard of care for anemia in chronic kidney disease (CKD), but data on the efficacy and dosing of ESAs in SCD are limited, and there are anecdotal reports of increased pain with ESA treatment. As a result, ESAs are prescribed ad hoc by providers and may be underutilized as a therapeutic option in SCD. Additionally, small case series have suggested that ESAs may synergize with HU to induce fetal Hb (HbF) by increasing stress erythropoiesis. Here, we present the preliminary results of a Phase 1b/2 multicenter, open-label, dose escalation study of epoetin alfa (EPO) for the treatment of anemia in patients (pts) with SCD on HU.

Methods. Pts were recruited from Lagos University Teaching Hospital and University of Pittsburgh. Inclusion criteria included age ≥ 18 years, diagnosis of SCD (HbSS or HbS/β⁰-thalassemia), screening Hb ≤ 9.0 g/dL, on stable-dose HU, and no recent transfusions, voxelotor or ESA treatment. Exclusion criteria included end-stage renal disease on dialysis, untreated iron deficiency, grade 3 hypertension, recent thrombosis or unstable angina. After informed consent, pts initiated EPO 10,000 units three times a week (TIW), escalated by 10,000 units per dose every 2 weeks, up to a maximum dose of 40,000 units TIW, or the minimal effective dose to maintain a target Hb level of 10-11 g/dL. Dose adjustments were made based on clinical judgment and biweekly blood work obtained to assess safety. Specifically, dose escalation was held if Hb > 10 g/dL or dose was reduced if Hb > 11 g/dL or increased by > 2 g/dL over 4 weeks. The primary endpoint was Hb response, defined as a Hb increase of ≥ 1.0 g/dL at 12 weeks of treatment compared to baseline. The study is ongoing with a planned sample size of 15 participants completing 12 weeks of treatment (NCT05451940).

Results. As of July 2024, 15 pts have been enrolled, with 8 completing treatment, 6 in active treatment, and 1 withdrawn prior to completing treatment due to a serious adverse event (SAE) of myelodysplastic syndrome (MDS) unrelated to study drug. All 15 pts had HbSS disease and were African or African American; mean age was 28 years (range 18-50 years); 60% were female; 13% had a diagnosis of CKD. At baseline, mean Hb was 7.4 ± 1.3 g/dL, lactate dehydrogenase (LDH) 376 ± 194 U/L, indirect bilirubin 2.1 ± 1.3 mg/dL, absolute reticulocyte count (ARC) 174 ± 96 x 10⁹/L, mean corpuscular volume (MCV) 98 ± 12 fL, HbF 11.4 ± 5.1%, creatinine 0.69 ± 0.72 mg/dL, and eGFR 130 ± 48 mL/min/1.73m². Mean HU dose was 1303 mg daily, and HU dose remained constant throughout the study.

Among the 8 completers, 87.5% (7/8) had a Hb response of ≥ 1.0 g/dL at 12 weeks, with a mean Hb increase of 2.4 ± 1.3 g/dL (10.3 vs. 7.8 g/dL). There was also a decrease in LDH (-204 ± 183 U/L) and indirect bilirubin (-0.58 ± 0.88 mg/dL) and slight increase in ARC (5.6 ± 84 x 10⁹/L), MCV (2.9 ± 7.2 fL), and HbF (2.2 ± 3.4%), suggesting that concurrent EPO treatment with HU may reduce hemolysis and increase HbF expression without significant reticulocytosis. Mean weekly EPO dose was 17222 units TIW in these 8 pts.

Seven out of 15 pts (46.7%) experienced an adverse event (AE), with none related to EPO treatment. The most common AEs reported were neutrophil count decreased (n=2, Grades 2-3) and priapism (n=2, Grades 1-2). There was one SAE of MDS Grade 4, diagnosed on bone marrow biopsy obtained for longstanding refractory anemia. This pt was withdrawn at 10 weeks; EPO and HU were discontinued due to lack of benefit and regular transfusions were initiated. There was no acute care utilization for vaso-occlusive events (VOEs) during the study and no dose adjustments or treatment discontinuation for pain.

Conclusion. This is the first prospective study of dose-escalated EPO in SCD. Our preliminary results demonstrate the potential efficacy and safety of EPO in combination with HU to treat chronic anemia in SCD. Nearly all participants experienced a Hb response with a relatively low-to-moderate dose of EPO. Subsequent analyses will evaluate the effect of EPO therapy on transfusion burden and other clinical outcomes.

Jonassaint:Expressive Painimation: Current equity holder in private company. DeCastro:Novartis: Research Funding. Novelli:Shield Therapeutics: Consultancy; Chiesi Pharmaceuticals: Consultancy; Novo Nordisk: Consultancy. Xu:GSK: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy.

Erythropoietin (i.e., recombinant human erythropoietin, rHuEPO, or EPO) stimulates erythropoiesis to increase red blood cell production and is FDA-approved for the treatment of anemia in chronic kidney disease and other specific conditions. It is not FDA-approved for use in this study population, although it has been used off-label in sickle cell disease for many years. This study aims to assess the efficacy and safety of using a standardized dosing regimen of EPO to treat anemia in patients with SCD stabilized on hydroxyurea.