Study in Beta-thalassaemia or Myelodysplastic Syndrome Patients to Investigate the Safety and Tolerability of SLN124

Study Overview
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Brief Summary
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The primary purpose of this study is to determine the safety and tolerability of SLN124 for the treatment of non-transfusion-dependent (NTD) β-thalassaemia and low risk myelodysplastic syndrome.

Official Title
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Phase 1b Single Ascending and Multiple Dose First-in-man Study in Adult Patients With Non-transfusion-dependent Beta-thalassaemia or Low Risk Myelodysplastic Syndrome to Investigate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Response of SLN124

Conditions
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Non-transfusion-dependent Thalassemia, Low Risk Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: SLN124 is a GalNAc conjugated double stranded fully modified siRNA. Sodium chloride 0.9% w/v is used as Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18yrs; BMI 18-35 kg/m2 β-thalassaemia intermedia or compound heterozygous HbE/β-thalassaemia Non-transfusion dependent: ≤ 5 units red cells in last 6 months and transfusion-free for ≥8 weeks Hb between 5 & 11 g/dL Ferritin > 250 µg/L and /or liver iron ≥ 3mg Fe/g dry weight and TSAT >40% Exclusion Criteria: Haemoglobin S/β-thalassaemia, homozygous β-0 thalassaemia or α thalassaemia ALT/AST > 1.5 x upper limit normal or cirrhosis eGFR < 60 mL/min/1.73m2 Platelets <100 or > 1000 x 109/L Untreated B12/folate deficiency Iron chelation therapy unless stable for ≥8 weeks Daily NSAID, therapeutic dose anticoagulant, ESA ≤12 weeks or stable dosing of hydroxyurea ≤ 6 months Significant cardiac disease (MI in 6 months, NYHA class III-IV heart failure, long QT) HIV or active hepatitis B/C or malignancy within 5 year

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multiple Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: SLN124 is a GalNAc conjugated double stranded fully modified siRNA. Sodium chloride 0.9% w/v is used as Placebo<br>* IMP will be provided as a solution to be injected by qualified clinical staff in patient's abdomen, upper arms or front of the thighs.<br>|
| Experimental: 0.3 mg/kg<br> | Drug: SLN124 is a GalNAc conjugated double stranded fully modified siRNA. Sodium chloride 0.9% w/v is used as Placebo<br>* IMP will be provided as a solution to be injected by qualified clinical staff in patient's abdomen, upper arms or front of the thighs.<br>|
| Experimental: 1.0 mg/kg<br> | Drug: SLN124 is a GalNAc conjugated double stranded fully modified siRNA. Sodium chloride 0.9% w/v is used as Placebo<br>* IMP will be provided as a solution to be injected by qualified clinical staff in patient's abdomen, upper arms or front of the thighs.<br>|
| Experimental: 3.0 mg/kg<br> | Drug: SLN124 is a GalNAc conjugated double stranded fully modified siRNA. Sodium chloride 0.9% w/v is used as Placebo<br>* IMP will be provided as a solution to be injected by qualified clinical staff in patient's abdomen, upper arms or front of the thighs.<br>|
| Experimental: 10.0 mg/kg<br> | Drug: SLN124 is a GalNAc conjugated double stranded fully modified siRNA. Sodium chloride 0.9% w/v is used as Placebo<br>* IMP will be provided as a solution to be injected by qualified clinical staff in patient's abdomen, upper arms or front of the thighs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| # of participants with all AEs as assessed by CTCAE V4.0 included injection site reaction, will be measured from baseline to post dose follow up |  | Up to two months | 
| 12 lead electrocardiogram parameters included PR, QTcF and QTcB will be measured from baseline to post dose follow up |  | Up to two months | 
| clinical chemistry, haematology, urinalysis, liver function tests (included ALT, AST, GGT) will be measured from baseline to post dose follow up |  | Up to two months | 
| height, weight, blood pressure, heart rate, respiration rate and temperature will be measured from baseline to post dose follow up |  | Up to two months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers will be measured from baseline to post dose follow up | serum hepcidin level (ng/ml), ferritin level (ug/L), Transferrin saturation (%), iron level (umol/L), haemoglobin and reticulocyte count will be analysed by central laboratory. | Up to two months | 
| Pharmacokinetic of SLN124 in plasma from baseline to post dose follow up | Peak Plasma Concentration (Cmax) will be analysed by central laboratory. | Up to two months | 
| Pharmacokinetic of SLN124 in plasma from baseline to post dose follow up | Area under the plasma concentration versus time curve (AUC) will be analysed by central laboratory. | Up to two months |