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

Study Overview
=================
Brief Summary
-----------------
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 weekly Attend up to 20 site visits Undergo MRI scans

Official Title
-----------------
An Open-label, Dose-escalation, Dose-finding, and Proof-of-concept Trial of SP-420 in Subjects With Transfusion-dependent β-thalassemia

Conditions
-----------------
Beta Thalassemia Major Anemia

Intervention / Treatment
-----------------
* Drug: SP-420


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women and men aged ≥18 years Transfusion-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 screening Weight ≥35 kg at screening Willing to discontinue current iron chelation therapy 7 days (± 3 days) prior to the first dose of SP-420 and for the duration of the trial Transfusion iron overload defined as LIC ≥5 and ≤20 mg/g dw on the R2-MRI obtained within 2 weeks prior to baseline Subject 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 histories Willingness to participate and signing the informed consent form Exclusion Criteria: β-thalassemia with the structural Hb variants HbS and HbC Cardiac MRI-T2* score <10 msec obtained within 2 weeks prior to baseline S-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 malignancy Current myelodysplastic syndrome Current biliary disorder ALAT >4 times the upper limit of normal, decompensated cirrhosis, or ascites at screening Past or ongoing history of clinically significant kidney disease Creatinine greater than the upper limit of normal at screening Estimated glomerular filtration rate eGFR <60 mL/min/1.73 m2 Urine protein to creatinine ratio >0.5 mg/mg at screening Heart failure grade II, III and IV by NYHA LVEF 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 screening Hypertransfused defined as more than 6 units/month in average for the last 6 months prior to screening Ongoing symptoms of neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paresthesia at screening Platelet count <100×109/L at screening History of hypersensitivity to an iron chelator (investigational or marketed) or excipients Documented history of non-compliance to chelation therapy within past 2 years Received another investigational drug within 30 days or investigational antibody within 90 days before screening Treatment 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 baseline Initiation 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 participant Men, 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 intercourse Any 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>SP-420, 28 mg/kg, three times weekly for 48 weeks | Drug: SP-420<br>* Capsules for oral intake<br>|
| Experimental: Cohort 2<br>SP-420, 56 mg/kg, three times weekly for 48 weeks | Drug: SP-420<br>* Capsules for oral intake<br>|
| Experimental: Cohort 3<br>SP-420, 84 mg/kg, three times weekly for 48 weeks | Drug: SP-420<br>* Capsules for oral intake<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To establish dose-response relationship of SP-420 for 24 weeks in the treatment of subjects with transfusion-dependent β-thalassemia | Total body iron removed by SP-420 from baseline to week 24 | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of SP-420 in clearing iron from the liver after 24 weeks treatment of subjects with transfusion-dependent β-thalassemia | Change in liver iron concentration (LIC) measured by R2-magnetic resonance imaging (MRI) from baseline to week 24 | 24 weeks | 
| To assess the efficacy of SP-420 in clearing iron from the liver after 12 and 48 weeks treatment of subjects with transfusion-dependent β-thalassemia | Change in LIC measured by R2-MRI from baseline to week 12 and week 48 | 12 and 48 weeks | 
| To assess the efficacy of SP-420 on serum (s-) ferritin | Change in s-ferritin from baseline to weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 | up to 48 weeks | 
| To assess the safety and tolerability of ascending doses of SP-420 | Type and incidence of adverse events (AEs) | 48 weeks |