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.
| Susan Perrine, MD | |
| 617 335-7002 | |
| [email protected] |
| Melissa Askin, RN | |
| 410 231-1512 | |
| [email protected] |
> 18 Years
Phase 1/Phase 2
Interventional
All
Drug
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
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