The BENeFiTS Trial in Beta Thalassemia Intermedia

Summary

Beta-thalassemias and hemoglobinopathies are serious inherited blood diseases caused by abnormal or deficiency of beta A chains of hemoglobin, the protein in red blood cells which delivers oxygen throughout the body.The diseases are characterized by hemolytic anemia, organ damage, and early mortality without treatment. Increases in another type of (normal) hemoglobin, fetal globin (HbF), which is normally silenced in infancy, reduces anemia and morbidity. Even incremental augmentation of fetal globin is established to reduce red blood cell pathology, anemia, certain complications, and to improve survival. This trial will evaluate an oral drug discovered in a high throughput screen, which increases fetal globin protein (HbF and red blood cells expressing HbF)and messenger ribonucleic acid (mRNA) to high levels in anemic nonhuman primates and in transgenic mice. The study drug acts by suppressing 4 repressors of the fetal globin gene promoter in progenitor cells from patients. The drug has been used for 50 years in a combination product for different actions - to enhance half-life and reduce side effects of a different active drug- and is considered safe for long-term use. This trial will first evaluate 3 dose levels in small cohorts of nontransfused patients with beta thalassemia intermedia. The most active dose will then be evaluated in larger subject groups with beta thalassemia and other hemoglobinopathies, such as sickle cell disease.

Timeline

Start

2020-10-05

Primary completion

2026-02-28

Completion

2026-02-28

Publications

• Background Boosalis MS, Sangerman JI, White GL, Wolf RF, Shen L, Dai Y, White E, Makala LH, Li B, Pace BS, Nouraie M, Faller DV, Perrine SP. Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice. PLoS One. 2015 Dec 29;10(12):e0144660. doi: 10.1371/journal.pone.0144660. eCollection 2015.
• Background Dai Y, Sangerman J, Luo HY, Fucharoen S, Chui DH, Faller DV, Perrine SP. Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms. Blood Cells Mol Dis. 2016 Jan;56(1):62-9. doi: 10.1016/j.bcmd.2015.10.004. Epub 2015 Oct 27.
• Background Dai Y, Sangerman J, Nouraie M, Faller AD, Oneal P, Rock A, Owoyemi O, Niu X, Nekhai S, Maharaj D, Cui S, Taylor R, Steinberg M, Perrine S. Effects of hydroxyurea on F-cells in sickle cell disease and potential impact of a second fetal globin inducer. Am J Hematol. 2017 Jan;92(1):E10-E11. doi: 10.1002/ajh.24590. Epub 2016 Nov 18. No abstract available.
• Background Chen Z, Luo HY, Steinberg MH, Chui DH. BCL11A represses HBG transcription in K562 cells. Blood Cells Mol Dis. 2009 Mar-Apr;42(2):144-9. doi: 10.1016/j.bcmd.2008.12.003. Epub 2009 Jan 18.
• Background Sedgewick AE, Timofeev N, Sebastiani P, So JCC, Ma ESK, Chan LC, Fucharoen G, Fucharoen S, Barbosa CG, Vardarajan BN, Farrer LA, Baldwin CT, Steinberg MH, Chui DHK. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood Cells Mol Dis. 2008 Nov-Dec;41(3):255-258. doi: 10.1016/j.bcmd.2008.06.007. Epub 2008 Aug 8.
• Background Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet. 2010 Sep;42(9):742-4. doi: 10.1038/ng.637. Epub 2010 Aug 1.
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• Background Franco RS, Yasin Z, Palascak MB, Ciraolo P, Joiner CH, Rucknagel DL. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood. 2006 Aug 1;108(3):1073-6. doi: 10.1182/blood-2005-09-008318.
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• Background Singer ST, Kuypers FA, Olivieri NF, Weatherall DJ, Mignacca R, Coates TD, Davies S, Sweeters N, Vichinsky EP; E/beta Thalassaemia Study Group. Fetal haemoglobin augmentation in E/beta(0) thalassaemia: clinical and haematological outcome. Br J Haematol. 2005 Nov;131(3):378-88. doi: 10.1111/j.1365-2141.2005.05768.x.
• Background Perrine SP, Mankidy R, Boosalis MS, Bieker JJ, Faller DV. Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol. 2009 Jun;82(6):466-76. doi: 10.1111/j.1600-0609.2009.01234.x. Epub 2009 Feb 5.
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• Background Borg J, Papadopoulos P, Georgitsi M, Gutierrez L, Grech G, Fanis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Ijcken W, Ozgur Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patrinos GP, Philipsen S. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010 Sep;42(9):801-5. doi: 10.1038/ng.630. Epub 2010 Aug 1.
• Background Atweh GF, Sutton M, Nassif I, Boosalis V, Dover GJ, Wallenstein S, Wright E, McMahon L, Stamatoyannopoulos G, Faller DV, Perrine SP. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood. 1999 Mar 15;93(6):1790-7.
• Background Centis F, Tabellini L, Lucarelli G, Buffi O, Tonucci P, Persini B, Annibali M, Emiliani R, Iliescu A, Rapa S, Rossi R, Ma L, Angelucci E, Schrier SL. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta-thalassemia major. Blood. 2000 Nov 15;96(10):3624-9.
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• Background Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018 Jul 19;379(3):226-235. doi: 10.1056/NEJMoa1715971.
• Background Minniti CP. l-Glutamine and the Dawn of Combination Therapy for Sickle Cell Disease. N Engl J Med. 2018 Jul 19;379(3):292-294. doi: 10.1056/NEJMe1800976. No abstract available.
• Background Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007 Jan;21(1):37-47. doi: 10.1016/j.blre.2006.07.001. Epub 2006 Nov 7.
• Background Saraf S, Farooqui M, Infusino G, Oza B, Sidhwani S, Gowhari M, Vara S, Gao W, Krauz L, Lavelle D, DeSimone J, Molokie R, Saunthararajah Y. Standard clinical practice underestimates the role and significance of erythropoietin deficiency in sickle cell disease. Br J Haematol. 2011 May;153(3):386-92. doi: 10.1111/j.1365-2141.2010.08479.x. Epub 2011 Mar 21.
• Background Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014 Apr;28(2):233-48. doi: 10.1016/j.hoc.2013.11.009.
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• Background Taher AT, Cappellini MD. How I manage medical complications of beta-thalassemia in adults. Blood. 2018 Oct 25;132(17):1781-1791. doi: 10.1182/blood-2018-06-818187. Epub 2018 Sep 11.
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• Background Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O, Kumasaka N, Takahashi A, Svasti S, Munkongdee T, Mahasirimongkol S, Peerapittayamongkol C, Viprakasit V, Kamatani N, Winichagoon P, Kubo M, Nakamura Y, Fucharoen S. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet. 2010 Mar;127(3):303-14. doi: 10.1007/s00439-009-0770-2.
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• Background Pootrakul P, Sirankapracha P, Hemsorach S, Moungsub W, Kumbunlue R, Piangitjagum A, Wasi P, Ma L, Schrier SL. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassemia. Blood. 2000 Oct 1;96(7):2606-12.
• Background Singer ST, Vichinsky EP, Sweeters N, Rachmilewitz E. Darbepoetin alfa for the treatment of anaemia in alpha- or beta- thalassaemia intermedia syndromes. Br J Haematol. 2011 Jul;154(2):281-4. doi: 10.1111/j.1365-2141.2011.08617.x. Epub 2011 Apr 18. No abstract available.

Drugs

Indications