Roxadustat for the treatment of anemia in patients with lower-risk myelodysplastic syndrome: Open-label, dose-selection, lead-in stage of a phase 3 study

David H Henry, John Glaspy, Rosemary Harrup, Moshe Mittelman, Amy Zhou, Hetty E Carraway, Charles Bradley, Gopal Saha, Katharina Modelska, Pamela Bartels, Robert Leong, Kin-Hung P Yu, David H Henry, John Glaspy, Rosemary Harrup, Moshe Mittelman, Amy Zhou, Hetty E Carraway, Charles Bradley, Gopal Saha, Katharina Modelska, Pamela Bartels, Robert Leong, Kin-Hung P Yu

Abstract

Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.

Trial registration: ClinicalTrials.gov NCT03263091.

© 2021 Wiley Periodicals LLC.

References

REFERENCES

    1. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109(8):1536-1542.
    1. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112(1):45-52.
    1. Chapter 4: red cell transfusion to treat anemia in CKD. Kidney Int Suppl (2011). 2012;2(4):311-316.
    1. Jabbour EJ, Garcia-Manero G, Strati P, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS clinical research consortium. Cancer. 2015;121(6):876-882.
    1. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465.
    1. Pfeilstöcker M, Tuechler H, Sanz G, et al. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016;128(7):902-910.
    1. Alessandrino EP, Amadori S, Barosi G, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica. 2002;87(12):1286-1306.
    1. Bowen D, Hellstrom-Lindberg E. Treatment of anemia in myelodysplastic syndromes. In: Bennett JM, ed. Myelodysplastic Syndromes: Pathobiology and Clinical Management. Marcel Dekker; 2002.
    1. Jabbour E, Kantarjian HM, Koller C, Taher A. Red blood cell transfusions and iron overload in the treatment of patients with myelodysplastic syndromes. Cancer. 2008;112(5):1089-1095.
    1. Bennett JM. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol. 2008;83(11):858-861.
    1. KDIGO. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012;2(4):1-163.
    1. Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005;23(30):7594-7603.
    1. Semenza GL, Agani F, Booth G, et al. Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int. 1997;51(2):553-555.
    1. Kaelin WGJ, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393-402.
    1. Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol. 2010;21(12):2151-2156.
    1. Nangaku M, Kojima I, Tanaka T, Ohse T, Kato H, Fujita T. Novel drugs and the response to hypoxia: HIF stabilizers and prolyl hydroxylase. Recent Pat Cardiovasc Drug Discov. 2006;1(2):129-139.
    1. Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle. 2008;7(1):28-32.
    1. Besarab A, Chernyavskaya E, Motylev I, et al. Roxadustat (FG-4592): correction of anemia in incident dialysis patients. J Am Soc Nephrol. 2016;27(4):1225-1233.
    1. Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015;30(10):1665-1673.
    1. Chen N, Hao C, Liu BC, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019;381(11):1011-1022.
    1. Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381(11):1001-1010.
    1. Chen N, Qian J, Chen J, et al. Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China. Nephrol Dial Transplant. 2017;32(8):1373-1386.
    1. Provenzano R, Besarab A, Sun CH, et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor Roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin J Am Soc Nephrol. 2016;11(6):982-991.
    1. Akizawa T, Ueno M, Shiga T, Reusch M. Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: results from two phase 3 studies. Ther Apher Dial. 2020;24(6):628-641.
    1. Akizawa T, Iwasaki M, Otsuka T, Reusch M, Misumi T. Roxadustat treatment of chronic kidney disease-associated anemia in Japanese patients not on dialysis: a phase 2, randomized, double-blind. Placebo-controlled trial. Adv Ther. 2019;36(6):1438-1454.
    1. Akizawa TYY, Otsuka T, Reusch M. A phase 3, multicenter, randomized, two-arm, open-label study of intermittent oral dosing of roxadustat for the treatment of anemia in Japanese erythropoiesis-stimulating agent-naive chronic kidney disease patients not on dialysis. Nephron. 2020;144(8):372-382.
    1. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study. J Am Soc Nephrol. 2021;32(3):737-755.
    1. Coyne DW, Roger SD, Shin SK, et al. Roxadustat for chronic kidney disease-related anemia in non-dialysis patients. Kidney Int Rep. 2021;6(3):624-635.
    1. Shutov E, Sułowicz W, Esposito C, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant. 2021;36(9):1629-1639.
    1. Charytan C, Manllo-Karim R, Martin ER, et al. A randomized trial of Roxadustat in anemia of kidney failure: SIERRAS study. Kidney Int Rep. 2021;6(7):1829-1839.
    1. Provenzano R, Fishbane S, Szczech L, et al. Pooled analysis of roxadustatfor anemia in patients with kidney failure incident to dialysis. Clin Res. 2021;6(3):613-623.
    1. Barratt J, Andric B, Tataradze A, et al. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant. 2021;36(9):1616-1628.
    1. Provenzano R, Szczech L, Leong R, et al. Efficacy and cardiovascular safety of Roxadustat for treatment of anemia in patients with non-dialysis-dependent CKD: pooled results of three randomized clinical trials. Clin J Am Soc Nephrol. 2021;16(8):1190-1200.
    1. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151.
    1. Cases A, Vera M, Ojeda R, Górriz J. Prolyl hydroxylase inhibitors for the treatment of anemia in chronic kidney disease. Drugs Future. 2018;43:23-33.
    1. Provenzano R, Besarab A, Wright S, et al. Roxadustat (FG-4592) versus Epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am J Kidney Dis. 2016;67(6):912-924.
    1. Provenzano RFS, Szczech L, Leong R, et al. Pooled analysis of roxadustatfor anemia in patients with kidney failure incident to dialysis. Kidney Int Rep. 2021;6:613-623.
    1. Kerkhoff NBH, Westers TM, de Gruijl TD, Kordasti S, van de Loosdrecht AA. Dendritic cells in myelodysplastic syndromes: from pathogenesis to immunotherapy. Immunotherapy. 2013;5(6):621-637.
    1. Li ZL, Tu Y, Liu BC. Treatment of renal anemia with Roxadustat: advantages and achievement. Kidney Dis (Basel). 2020;6(2):65-73.
    1. Fenaux P, Santini V, Spiriti MAA, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018;32(12):2648-2658.
    1. Provenzano R, Shutov E, Eremeeva L, et al. Roxadustat for anemia in patients with end-stage renal disease incident to dialysis. Nephrol Dial Transplant. 2021;36(9):1717-1730.
    1. Platzbecker U, Fenaux P, Adès L, et al. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019;133(10):1020-1030.
    1. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the international working group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere