The BENeFiTS Trial in Beta Thalassemia Intermedia

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

Overview

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.

Detailed 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.

Interventions

• Drug Benserazide Only Product
  Investigational drug

Primary outcome measures

• Safety and Tolerability [Time frame: 12 to 24 weeks]
• Maximum plasma concentration (Cmax) [Time frame: 4 weeks]
• Plasma drug concentration over time [Time frame: 4 weeks]

Secondary outcome measures (4)

• F-cells [Time frame: 12 to 24 weeks]
• HbF protein per cell [Time frame: 12 to 24 weeks]
• Fetal hemoglobin (HbF) [Time frame: 12 to 24 weeks]
• Hemoglobin [Time frame: 16 to 24 weeks]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• UCSF Benioff Children's Hospital at Oakland — Oakland
• Massachusetts General Hospital — Boston
• Susan Perrine — Weston
• Weil Cornell Medicine — New York

Canada · 1 center

• University Health Network and Toronto General Hospital — Toronto

Publications

• 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. PMID 26713848
• 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. PMID 26603726
• 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. PMID 27766663
• 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. PMID 19153051
• 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. PMID 18691915
• 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. PMID 20676097
• Cao H, Stamatoyannopoulos G, Jung M. Induction of human gamma globin gene expression by histone deacetylase inhibitors. Blood. 2004 Jan 15;103(2):701-9. doi: 10.1182/blood-2003-02-0478. Epub 2003 Aug 14. PMID 12920038
• 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. PMID 16861353

Identifiers

NCT: NCT04432623 · PB04-001 · R33HL147845

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗