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1277 Oral Roxadustat Demonstrates Efficacy in Anemia Secondary to Lower-Risk Myelodysplastic Syndrome Irrespective of Ring Sideroblasts and Baseline Erythropoietin LevelsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster I
Hematology Disease Topics & Pathways:
Anemias, Adult, Diseases, Non-Biological, Therapies, Biological Processes, erythropoiesis, Study Population, Clinically relevant
Saturday, December 5, 2020, 7:00 AM-3:30 PM

David H. Henry, MD1, John Glaspy, MD, MPH2*, Rosemary Anne Harrup3*, Moshe Mittelman, MD4, Amy Zhou, MD5, Hetty E. Carraway, MD, MBA6, Charles Bradley, Ph.D.7, Gopal Saha, MD7*, Pamela Bartels7*, Robert Leong7* and Peony Yu, MD8*

1Pennsylvania Hospital, University of Pennsylvania, Philadelphia, PA
2UCLA School of Medicine, Los Angeles
3Royal Hobart Hospital, Tasmania, Australia
4Department of Internal Medicine A, Tel Aviv Sourasky Medical Center/Sackler Faculty of Medicine, Tel Aviv, Israel
5Washington University School of Medicine, Saint Louis, MO
6Department of Hematology and Medical Oncology, Leukemia Program, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
7FibroGen Inc., San Francisco
8FibroGen, Inc, San Francisco, CA

Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. In Phase 3 trials, roxadustat increased hemoglobin (Hb) levels and reduced the number of red blood cell (RBC) transfusions vs placebo in patients with anemia of non-dialysis-dependent chronic kidney disease (CKD). In anemia of dialysis-dependent CKD, roxadustat achieved greater mean Hb increase vs epoetin alfa, and reduced IV iron use and RBC transfusions (Coyne, et al. Poster SA-0228 American Society of Nephrology (ASN) 2019; Charytan, et al. Poster SA-0227 ASN 2019)

Low-risk myelodysplastic syndrome (LR-MDS), characterized by symptomatic anemia, is treated with RBC transfusion, erythropoiesis-stimulation agents (ESAs), or luspatercept. Suboptimal response and response durability across MDS subpopulations demonstrates an unmet medical need in LR-MDS. We report a 52-week update of the open-label (OL) phase of a study of roxadustat in anemia in primary MDS patients that determined the starting dose of the ongoing double-blind study phase (NCT03263091).

Methods: The OL phase (N=24) used 3 sequential dose cohorts (1.5, 2.0, and 2.5 mg/kg) thrice weekly (TIW). Eligible patients had very low- to intermediate-risk primary MDS patients per International Prognostic Scoring System-Revised classification, with < 5% bone marrow blasts; baseline Hb < 10.0 g/dL; had low transfusion burden, defined as receiving 1-4 RBC units within 8 weeks before randomization; endogenous EPO levels ≤ 400 mIU/mL; and no 5q(del) cytogenetic abnormality. Red blood cell transfusion was allowed per institutional criteria. Roxadustat doses were titrated every 8 weeks based on Hb response and RBC transfusions. The primary endpoint was transfusion independence (TI) for ≥ 56 consecutive days during the first 28 treatment weeks; follow-up was at 52 weeks. Secondary endpoints included TI ≥ 56 consecutive days anytime during the study, proportion of patients who achieved ≥ 50% reduction in number of RBC transfusion over any 8 weeks vs baseline (BL), cumulative number of patient-exposure-week of TI, cumulative number of pRBC packs transfused, proportion of patients who achieved TI for > 20 weeks. Safety was assessed via adverse events monitoring and patients (%) who progressed to acute myeloid leukemia (AML). Patients with and without ring sideroblasts (RS+/RS-) and BL EPO ≤ 200 mIU/ml and > 200 mIU/ml were assessed for the primary endpoint.

Results: In the OL phase, 24 transfusion-dependent LR-MDS patients were enrolled in 3 starting dose cohorts (Table). Nine patients (38%) achieved TI for ≥ 56 consecutive days within the first 28 and 52 weeks, 3 in cohort 1 (1.5 mg/kg), 1 in cohort 2 (2.0 mg/kg), and 5 in cohort 3 (2.5 mg/kg). When TI was achieved, 78% were receiving 2.5 mg/kg dose, 11% were receiving 2.0 mg/kg dose (started with 1.5 mg/kg) and 11% were receiving 1.5 mg/kg. Four patients (16.7%) remained TI for > 20 weeks (1 at 1.5 mg/kg dose level and 3 at 2.5 mg/kg dose-level) at 52 weeks. The 50% reduction in number of transfusion compared with BL occurred in 13 patients (54.2%) at 28 weeks and 14 (58.3%) at 52 weeks. In patients with TI duration ≥ 56 days (n = 9), the mean (SD) TI duration was 182.9 (153.66) days. In patients with TI duration ≥ 140 days (n = 4), the mean (SD) TI duration was 324.5 (121.22) days. Subgroups met the primary endpoint at week 28 (23.1% and 54.5% MDS-RS+ and -RS-, respectively, and 38.9% and 33.3% BL EPO ≤ 200 mIU/ml and > 200 mIU/ml, respectively); all subgroups maintained TI response to week 52. The overall safety profile was consistent with this patient population. Eight patients reported 8 treatment-emergent serious AEs; none were fatal. No patient progressed to AML.

Conclusion: In this 52-week update, roxadustat 2.5 mg/kg TIW was effective in LR-MDS patients, based on observed response (TI and transfusion reduction), safety profile, and durable 52-week response. The ongoing, 156-patient, double-blind study phase uses a 2.5 mg/kg starting dose. Preliminary data in OL subgroups RS-/RS + and BL EPO ≤ 200 mIU/ml and >200 mIU/ml suggest roxadustat may be effective in these subgroups. These data await confirmation in the ongoing double-blind, placebo-controlled study.

Disclosures: Carraway: BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC). Bradley: FibroGen, Inc.: Current Employment. Saha: FibroGen, Inc.: Current Employment. Bartels: FibroGen, Inc.: Current Employment. Leong: FibroGen Inc.: Current Employment, Current equity holder in private company. Yu: FibroGen, Inc.: Current Employment.

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