The BENeFiTS Trial in Beta Thalassemia Intermedia

Sickle Cell Disease Clinical Trial

— PB04-001  

Official title:

A Phase 1b Sequential Open Label Dose-Ranging Study of Safety, Pharmacokinetics, and Preliminary Activity of Benserazide in Subjects With Beta Thalassemia Intermedia and Sickle Cell Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04432623
• Other study ID #: PB04-001
• Secondary ID: R33HL147845
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 5, 2020
• Est. completion date: February 28, 2025

Study information

• Verified date: April 2024
• Source: Phoenicia BioScience
• Contact: Susan Perrine, MD
• Phone: 617 335-7002
• Email: sperrine[@]bu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

The study will first evaluate 3 doses of the investigational drug which are considered safe with chronic use in a combination therapeutic used widely for a different disease in Europe and Canada. The doses to be studied are human equivalent doses of doses that are active in nonhuman primates in inducing high level fetal globin messenger ribonucleic acid (mRNA), protein, and proportions of red blood cells expressing fetal globin protein (F-cells). Additive effects are observed with hydroxyurea in sickle cell patients' cells in vitro.

The study will first evaluate the study therapeutic in male and female patients who are 18 years and older. After a screening period to obtain baseline medical and laboratory data, the study drug will be taken by mouth once per day, every other day. The first dose will be taken in a clinical unit, and thereafter will be taken at home for 12 weeks. Laboratory tests, physical exams, and tolerability will be assessed 6 times over 4 months, including for one month after completion of dosing.

The cohorts will be enrolled sequentially. Each new cohort will begin after the prior lower dose cohort has received 2 weeks of treatment without serious adverse events related to the study drug. The dose that increases fetal globin assays to the highest degree will be evaluated in a larger group of subjects with beta thalassemia intermedia and a groups with sickle cell disease. Other regimens or test doses may be added as needed to identify an active dose and regimen. The study drug is expected to be safe when added to most other medications used to treat thalassemia.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: February 28, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Beta thalassemia intermedia (BTI) or (NTDT, Non-Transfusion Dependent Thalassemia) with at least one documented beta thalassemia mutation, including HbE beta thalassemia or an established diagnosis of sickle cell disease

• >18 years of age at time of consent

• Average of 2 total hemoglobin (Hgb) levels between 6.0 and 10.0 g/dL in the preceding 6 months

• Able and willing to give consent and comply with all study procedures

• If female and of childbearing potential, must have a documented negative pregnancy test prior to entry and agree to use one or more locally medically accepted methods of contraception

Exclusion Criteria:

• Red blood cell (RBC) transfusion within 2 months prior to administration of study medication

• Participating in a chronic transfusion program

• Pulmonary hypertension requiring oxygen therapy

• Use of erythropoiesis stimulating agents within 90 days of first dose

• Transaminases > 3 times upper limit of institution normal (ULN)

• Total and direct bilirubin > 3 times institution ULN unless due solely to hemolysis

• Known infection with HIV or hepatitis C (untreated)

• Fever > 38.5°C in the week prior to first administration of study medication

• History of osteoporosis or osteomalacia with a fragility fracture

• Received other investigational systemic therapy within 30 days prior to first dose

• Narrow angle glaucoma

• Currently pregnant or breast feeding a child

• Known current drug or alcohol abuse

• Taking monoamine oxidase inhibitors

• Other co-morbidity that substantially increases subject risk for the study per Investigator discretion

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Beta Thalassemia Intermedia
• beta-Thalassemia
• Sickle Cell Disease
• Thalassemia

Intervention

Drug:
• Benserazide Only Product
Investigational drug

Locations

Country	Name	City	State
Canada	University Health Network and Toronto General Hospital	Toronto	Ontario
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Weil Cornell Medicine	New York	New York
United States	UCSF Benioff Children's Hospital at Oakland	Oakland	California
United States	Susan Perrine	Weston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Phoenicia BioScience	National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (33)

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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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Perrine RP, Brown MJ, Clegg JB, Weatherall DJ, May A. Benign sickle-cell anaemia. Lancet. 1972 Dec 2;2(7788):1163-7. doi: 10.1016/s0140-6736(72)92592-5. No abstract available. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

Sripichai O, Makarasara W, Munkongdee T, Kumkhaek C, Nuchprayoon I, Chuansumrit A, Chuncharunee S, Chantrakoon N, Boonmongkol P, Winichagoon P, Fucharoen S. A scoring system for the classification of beta-thalassemia/Hb E disease severity. Am J Hematol. 2008 Jun;83(6):482-4. doi: 10.1002/ajh.21130. — View Citation

Steinberg MH, Rodgers GP. Pharmacologic modulation of fetal hemoglobin. Medicine (Baltimore). 2001 Sep;80(5):328-44. doi: 10.1097/00005792-200109000-00007. No abstract available. — View Citation

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. — View Citation

Tanabe O, McPhee D, Kobayashi S, Shen Y, Brandt W, Jiang X, Campbell AD, Chen YT, Chang Cs, Yamamoto M, Tanimoto K, Engel JD. Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. EMBO J. 2007 May 2;26(9):2295-306. doi: 10.1038/sj.emboj.7601676. Epub 2007 Apr 12. — View Citation

Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5. doi: 10.1073/pnas.0711566105. Epub 2008 Feb 1. — View Citation

Wang X, Thein SL. Switching from fetal to adult hemoglobin. Nat Genet. 2018 Apr;50(4):478-480. doi: 10.1038/s41588-018-0094-z. — View Citation

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* Note: There are 33 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	12 to 24 weeks
Primary	Maximum plasma concentration (Cmax)	drug concentration (ng/ml)	4 weeks
Primary	Plasma drug concentration over time	Area under the curve	4 weeks
Secondary	F-cells	% Red blood cells containing HbF	12 to 24 weeks
Secondary	HbF protein per cell	Mean fluorescent intensity (MFI)	12 to 24 weeks
Secondary	Fetal hemoglobin (HbF)	% and absolute (g/dl)	12 to 24 weeks
Secondary	Hemoglobin	gram/dl	16 to 24 weeks