Clinical trial NCT04432623: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Beta Thalassemia Intermedia
Sickle Cell Disease
Keywords: Non-transfusion dependent beta thalassemia
Sickle cell disease
Lead sponsor: Phoenicia BioScience
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2020-06-16
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Each higher dose level cohort will be enrolled after 2 weeks of treatment in the lower dose level. Additional doses or regimens may be added or expanded.
Primary purpose: TREATMENT

Brief 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.

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.

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

Primary outcomes:
measure: Safety and Tolerability
timeFrame: 12 to 24 weeks
measure: Maximum plasma concentration (Cmax)
timeFrame: 4 weeks
measure: Plasma drug concentration over time
timeFrame: 4 weeks
Secondary outcomes:
measure: F-cells
timeFrame: 12 to 24 weeks
measure: HbF protein per cell
timeFrame: 12 to 24 weeks
measure: Fetal hemoglobin (HbF)
timeFrame: 12 to 24 weeks
measure: Hemoglobin
timeFrame: 16 to 24 weeks
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital at Oakland
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Weston
country: United States
facility: Susan Perrine
state: Massachusetts
city: New York
country: United States
facility: Weil Cornell Medicine
state: New York
city: Toronto
country: Canada
facility: University Health Network and Toronto General Hospital
state: Ontario
Study officials:
affiliation: Phoenicia BioScience
name: Susan Perrine, MD
role: STUDY_DIRECTOR
affiliation: University Health Network, Toronto General Hospital
name: Kevin Kuo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCSF Benioff Children's Hospital at Oakland
name: Sylvia Singer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Hanny D Al-Samkari, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College of Cornell University
name: Sujit Sheth, MD MS
role: PRINCIPAL_INVESTIGATOR
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