A Trial Testing SP-420 in Subjects With Transfusion-dependent β-thalassemia

The goal of this clinical trial is to learn about SP-420 ability to remove iron from organs in subjects with transfusion-dependent β-thalassemia. The main questions it aims to answer are:How efficient is SP-420 in cleaning iron from the liver?How is the safety and tolerability of ascending doses of SP-420?Participants will:Take medication three time weeklyAttend up to 20 site visitsUndergo MRI scans

Inclusion Criteria:Women and men aged ≥18 yearsTransfusion-dependent β-thalassemia including HbE/β-thalassemia requiring iron chelation therapy (β-thalassemia with mutation and/or multiplication of α-globin is allowed)On a stable dose of iron chelation for at least 4 weeks prior to screeningWeight ≥35 kg at screeningWilling to discontinue current iron chelation therapy 7 days (± 3 days) prior to the first dose of SP-420 and for the duration of the trialTransfusion iron overload defined as LIC ≥5 and ≤20 mg/g dw on the R2-MRI obtained within 2 weeks prior to baselineSubject has been treated and followed for at least the past 6 months in a specialised centre that maintained detailed medical records, including transfusion and iron chelation historiesWillingness to participate and signing the informed consent formExclusion Criteria:β-thalassemia with the structural Hb variants HbS and HbCCardiac MRI-T2* score <10 msec obtained within 2 weeks prior to baselineS-ferritin <500 or >4000 ng/mL*Current malignancy with the exceptions of localised basal cell or squamous cell skin cancer or localised prostate cancer or is receiving immunotherapy, chemotherapy, or radiation therapy for a malignancyCurrent myelodysplastic syndromeCurrent biliary disorderALAT >4 times the upper limit of normal, decompensated cirrhosis, or ascites at screeningPast or ongoing history of clinically significant kidney diseaseCreatinine greater than the upper limit of normal at screeningEstimated glomerular filtration rate eGFR <60 mL/min/1.73 m2Urine protein to creatinine ratio >0.5 mg/mg at screeningHeart failure grade II, III and IV by NYHALVEF on MRI <56 % (echocardiography allowed if MRI not available)A QTcF >450 ms, 2nd or 3rd degree atrioventricular block, or incomplete left hemiblock, or the presence of clinically significant abnormalities as determined by the Investigator at screeningHypertransfused defined as more than 6 units/month in average for the last 6 months prior to screeningOngoing symptoms of neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paresthesia at screeningPlatelet count <100×109/L at screeningHistory of hypersensitivity to an iron chelator (investigational or marketed) or excipientsDocumented history of non-compliance to chelation therapy within past 2 yearsReceived another investigational drug within 30 days or investigational antibody within 90 days before screeningTreatment with prohibited medication: iron, aluminium containing antacid therapies, systemic corticosteroids (topical and pulmonary corticosteroids are allowed), oral bisphosphonates, chronic use of high dose NSAIDs (as needed and low dose acetylsalicylic acid are allowed), drugs with known renal toxicity, drugs with known QTc prolongation, potent UGT inducers (e.g. rifampicin, phenytoin, phenobarbital, ritonavir) within 7 days prior to baselineInitiation of treatment with luspatercept within 6 months prior to screening (luspatercept is allowed if initiated and dose is stable at least 6 months prior to screening)Subject unable to undergo trial assessments including MRI, e.g. who are claustrophobic to MRI, have a cardiac pacemaker, ferromagnetic metal implants other than those approved as safe for use in MR scanners (e.g. some types of aneurysm clips, and shrapnel), and subjects who are obese (exceeding the equipment limits)Pregnant or nursing women. In order to avoid pregnancy, women of childbearing potential (premenopausal and not surgically sterile) have to use highly efficient contraception (e.g. intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release)) during the whole trial period and 4 weeks post-dosing. A sterile sole partner or sexual abstinence is also considered acceptable provided it reflects the usual and preferred lifestyle of the participantMen, even if surgically sterilised, (i.e. status post vasectomy), who do not agree to practice effective barrier contraception during the entire trial period, or agrees to completely abstain from heterosexual intercourseAny other laboratory abnormality, medical condition, or psychiatric disorder which, in the opinion of the Investigator, will put the subject's disease management at risk or may result in the subject being unable to comply with the trial requirements