safety, tolerability, pharmacokinetics (pk), pharmacodynamics (pd) and preliminary efficacy of vit-2763 in β-thalassaemia

Conditions: Beta-Thalassemia; Non-transfusion-dependent Thalassemia

Summary: this is a randomised, double-blind, placebo-controlled parallel group trial to investigate the safety, tolerability and efficacy of multiple doses of vit-2763 versus placebo in participants with non-transfusion-dependent beta-thalassemia (ntdt).

the study includes a 12-week treatment period and a safety follow-up period of 4 weeks. about 36 participants (adults and adolescents) are expected to take part in this study at a number of different institutions internationally. adult participants (cohort i) will be randomized to receive either vit-2763 once daily (qd) or twice daily (bid) or placebo, at a dose of 120 mg or 60mg depending on their body weight. following cohort i review, adolescent participants (cohort ii) will be randomized to the same study arms with the same interventions. the study medication will be given as oral capsules, containing 60 mg of vit-2763 or placebo.

Eligibility criteria:
inclusion criteria: * documented diagnosis of ntdt, including a β-thalassemia intermedia-phenotype. * ntdt is defined as subjects having received less than 5 units of red blood cells (rbcs) during the 24-week period prior to randomisation/first drug administration of vit-2763 or placebo (day 1; 1 unit is defined as 200 to 350 ml of transfused packed rbcs and last rbc transfusion must have been received at east 14 days prior to randomisation). * male and female adult ntdt subjects, 18-65 years of age inclusive (cohort i only) at time of screening. * male and female adolescent ntdt subjects, 12-17 years of age inclusive (cohort ii only) at time of screening. * subjects must have a mean baseline hemoglobin (hb) equal to or lower than 11 g/dl, based on at least 2 consecutive measurements with at least 1 week apart within 6 weeks prior to randomisation/baseline. exclusion criteria: * documented diagnosis of transfusion dependent thalassemia (tdt), including a beta-thalassemia major phenotype (including β0/β0, β+/β+, β0/β+ genotype), and mixed compound heterozygous for sickling phenotype variants such as hb s/β- thalassemia, or transfusion dependent non-deletional hb h disease (i.e., hb constant spring) or hb c disease. * subjects on concomitant iron chelation therapy (ict) or subjects on prior ict when discontinued less than 4 weeks prior randomisation. if ict was discontinued at least 4 weeks prior randomization the subject is eligible. * ict naïve subjects or subjects who discontinued ict therapy at least 6 months before the screening visit with serum ferritin lower than 150 ng/ml and/or documented liver iron concentration (lic) equal to or lower than 1 mg/g liver dry weight assessed through magnetic resonance imaging (mri), or subjects on prior ict with serum ferritin lower than 300 ng/ml and/or documented lic lower than 3 mg/g liver dry weight assessed through mri. * subjects with transferrin saturation (tsat) less than 30%. * subjects with documented lic greater than 15 mg/g liver dry weight assessed through mri, or a documented myocardial t2\* less than 20 ms, if available per local practice and retrieved within 24 months prior to randomization. * adult or adolescent subjects with body weight lower than 40.0 kg or greater than 100 kg at screening. * chronic liver disease and/or alanine transaminase (alt), aspartate transaminase (ast) or gamma-glutamyl transpeptidase (ggt) above 3-fold the upper limit of normal (uln) range at screening. * estimated glomerular filtration rate (egfr) less than 30 ml/min/1.73 m2 (according to chronic kidney disease classification stage 4 or higher), and/or significant albuminuria greater than 30 mg/mmol. egfr should be estimated according to chronic kidney disease epidemiology collaboration formula (cki-epi) in adults, and schwartz formula in adolescents. * newly diagnosed folate deficiency anemia and/or vitamin b12 megaloblastic anemia. subjects with known folate deficiency anemia and/or vitamin b12 megaloblastic anemia who are on at least 12 weeks stable replacement therapy are eligible. * any history or clinically important finding of cardiac disorders, such as clinically relevant cardiac arrhythmia, cardiomyopathy, coronary disease, valve disorder, or heart failure according to new york heart association classification 3-4. * subjects with history of partial or total splenectomy within 6 months prior to screening.

Keywords: beta-thalassemia