Pharmacokinetics of SSP-004184 in the Treatment of Chronic Iron Overload Requiring Chelation Therapy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate SSP-004184AQ in patients with transfusional iron overload whose primary diagnosis is hereditary or congenital anemia. SSP-004184AQ is an iron chelator under development for chronic daily oral administration to patients with transfusional iron overload.

Official Title
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A Phase 2, 24 Week, Open Label, Multi-Center Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SSP-004184 (SPD602) in the Treatment of Chronic Iron Overload Requiring Chelation Therapy

Conditions
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Iron Overload Due to Repeated Red Blood Cell Transfusions

Intervention / Treatment
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* Drug: SPD602


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to sign the approved informed consent. Age: 18-60 years old, inclusive, at Screening. Subjects who have received more than 20 transfusions in their lifetime and who have transfusional iron overload requiring chronic treatment with an iron chelator. N.B.: Sickle Cell Disease subjects receiving regular exchange transfusions and iron overloaded subjects with thalassemia intermedia who are receiving regular transfusions (transfusion dependent thalassemia intermedia) are eligible. Willing to discontinue all existing iron chelation therapies for a minimum period of one to five days prior to first dose of SSP-004184AQ, the 24 week duration of the study and 1 week after last dose for a total of approximately 26 weeks. Willing to fast two hours prior to and one hour after each dose. Serum ferritin >500ng/mL at Screening. Baseline liver iron concentration is greater than or equal to 5mg iron per g (equivalent dry weight, liver)determined by FerriScan® R2 MRI. Mean of the previous three pre-transfusion hemoglobin concentrations is greater than or equal to 7.5g/dL. Adult female subjects should be: Post-menopausal (12 consecutive months of spontaneous amenorrhea), or Surgically sterile, or Females of child-bearing potential must have a negative beta-HCG pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit. Females of child-bearing potential must agree to abstain from sexual activity that could result in pregnancy or agree to use acceptable methods of contraception. Exclusion Criteria: As a result of medical review, physical examination, or Screening investigations, the Principal Investigator (PI) considers the subject unfit for the study. Non-elective hospitalization within the 30 days prior to Baseline testing. Evidence of clinically relevant oral, cardiovascular, gastrointestinal, hepatic, biliary, renal, endocrine, pulmonary, neurologic, psychiatric, immunologic, bone marrow, or skin disorder that contraindicates dosing with SSP-004184AQ. Iron overload from causes other than transfusional siderosis. Evidence of severe renal insufficiency, eg, serum creatinine 1.5X above the upper limit of normal or proteinuria greater than 1 gm per day or a calculated glomerular filtration rate <60mL/min. Severe iron overload including: T2* MRI <10 ms liver iron concentration by FerriScan R2 MRI >30mg/g liver (dw) Known sensitivity to magnesium stearate, croscarmellose sodium or SSP-004184AQ. Platelet count below 100,000/μL or absolute neutrophil count less than 1500/mm3 at Screening. Insufficient venous access that precludes prescribed blood draws for safety laboratory assessments. ALT at Screening >200 IU/L. Use of any investigational agent within the 30 days prior to the Baseline testing. Pregnant or lactating females. Cardiac left ventricular ejection fraction Below the locally determined normal range in the 12 months prior to Screening by echocardiograph or MRI or <50% at Baseline testing by MRI (echocardiograph is acceptable for LVEF if MRI information is not available).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SPD602<br>50 mg/kg/day orally twice daily for 24 weeks | Drug: SPD602<br>* 50 mg/kg/day orally twice daily for 24 weeks<br>* Other names: SSP-004184, deferitazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Liver Iron Concentration (LIC) as Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) | The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using FerriScan R2 standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. | Baseline, 12 and 24 weeks | 
| Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI | The efficacy of SPD602 was assessed by determining LIC and adjusting for transfusional iron intake. Abdominal MRI data were collected by using FerriScan R2 standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. | Baseline, 12 and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in LIC as Assessed by R2* MRI | The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using R2* standard procedures (liver and pancreas) and used to determine LIC. A negative change from baseline indicates that LIC decreased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. | Baseline, 12 and 24 weeks | 
| Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI | The efficacy of SPD602 was assessed by determining LIC and adjusting for transfusional iron intake. Abdominal MRI data were collected by using R2* standard procedures (liver and pancreas) and used to determine LIC. A negative change from baseline indicates that LIC decreased. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. | Baseline, 12 and 24 weeks | 
| Change From Baseline in Cardiac T2* Relaxation Rate, an MRI Parameter Used to Estimate Cardiac Iron Load | The efficacy of SPD602 was assessed by estimating cardiac iron load. T2* data from cardiac MRI were collected by using standard procedures and used as an estimate of cardiac iron load. T2* is an MR relaxation parameter that is reported in milliseconds. Iron within a tissue decreases homogeneity of the magnetic field and shortens the T2* relaxation rate (Anderson, 2001). Low cardiac T2* values are associated with increased risk of heart failure (Kirk, 2009). A negative change from baseline in the T2* relaxation rate indicates that iron load increased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. | Baseline, 12 and 24 weeks | 
| Change From Baseline in Serum Ferritin | Serum ferritin levels were determined from serum biochemistry analyses. A negative change from baseline indicates that serum ferritin decreased. | Baseline, 8 and 16 weeks | 
| Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC | A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the FerriScan R2 according to standard procedures. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. | 12 and 24 weeks | 
| Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Adjusted For Transfusional Iron Intake | A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the FerriScan R2 according to standard procedures, and the results were adjusted for transfusional iron intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. | 12 and 24 weeks | 
| Number of Participants Classified as a Responder by R2* MRI Analysis of LIC | A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the R2* according to standard procedures (liver and pancreas). Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. | 12 and 24 weeks | 
| Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Adjusted For Transfusional Iron Intake | A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the R2* according to standard procedures (liver and pancreas), and the results were adjusted for transfusional iron intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. | 12 and 24 weeks | 
| Number of Participants Classified as a Responder by Serum Ferritin | A responder was defined as a participant whose observed serum ferritin level at the measured time point was less than the baseline value. Serum ferritin levels were determined from serum biochemistry analyses. | 8 and 16 weeks |