Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx)

Study Overview
=================
Brief Summary
-----------------
The purpose is to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of sapablursen administered subcutaneously to participants with non-transfusion dependent β-Thalassemia Intermedia.

Detailed Description
-----------------
This is a multi-center, randomized, open-label study in up to 45 participants. The duration of each participant in the study will be approximately 29 months and will include an approximately 2-month screening period, a 24-month treatment period, and a 3-month post-treatment period.

Official Title
-----------------
A Phase 2a, Randomized, Open-Label Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ISIS 702843 Administered Subcutaneously to Patients With Non-Transfusion Dependent β-Thalassemia Intermedia

Conditions
-----------------
Beta Thalassemia Intermedia

Intervention / Treatment
-----------------
* Drug: sapablursen


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willingness to comply with study procedures Clinical diagnosis of Beta-Thalassemia Intermedia with genotypic confirmation Non-transfusion dependent, as defined by: no more than 6 transfusions in the past 12-month period, and no transfusions in the 8-week period prior to Day 1 Mean Hb within the range of 6.0-10.0 g/dL, inclusive at Screening LIC within the range of 3.0-20.0 mg Fe/g dry weight, inclusive If using chelators, must be on a stable dose for at least 3 months with LIC > 5.0 mg Fe/g dry weight and serum ferritin > 300 nanograms per milliliter (ng/mL) Females must be non-pregnant and non-lactating, and either surgically sterile or postmenopausal Males must be surgically sterile, abstinent or using an acceptable contraceptive method Exclusion Criteria: Clinically significant abnormalities in lab values, medical history, or physical examination α-globin gene triplication Symptomatic splenomegaly Platelet count < lower limit of normal (LLN) or > 1,000 x 10^9/L Significant concurrent/recent coagulopathy, history of non-traumatic significant bleeding; history of immune thrombocytopenic purpura (ITP); current use of SC anti-coagulants; history of thrombotic events, including stroke or DVT Clinically significant renal, liver or cardiac dysfunction Uncontrolled hypertension (> 140 mm Hg systolic or > 90 mm Hg diastolic) Fasting blood glucose > 2.0 × upper limit of normal (ULN) Inability to have a magnetic resonance imaging (MRI) scan Known history or positive test for human immunodeficiency virus (HIV), hepatitis C (HCV), or hepatitis B (HBV) Active infection requiring systemic antiviral or antimicrobial therapy Regular excessive use of alcohol Recent start of hydroxyurea (6 months prior to Day 1) Treatment with or recent exposure to another investigational drug, biological agent, ASO, small interfering ribonucleic acid (siRNA), or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer; or treatment with or exposure to: sotatercept (ACE-011), luspatercept (ACE-536), or ruxolitinib within 4 months of Screening hematopoietic stimulating agents or any hypoxia-inducible factor prolyl hydroxylase inhibitors within 8 weeks of Day 1 prior bone marrow transplant, stem cell transplant, or gene therapy Surgery associated with significant blood loss within 4 months of Screening, splenectomy within 12 months of Screening, or splenectomy scheduled during treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sapablursen<br>A single injection of sapablursen at multiple dose levels, administered subcutaneously every 4 weeks | Drug: sapablursen<br>* sapablursen administered subcutaneously<br>* Other names: IONIS TMPRSS6-LRx;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with a ≥ 1.0 grams per deciliter (g/dL) increase from Baseline in hemoglobin (Hb) at Week 27 |  | Baseline and Week 27 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with a ≥ 1.5 grams per deciliter (g/dL) increase from Baseline in hemoglobin (Hb) at Week 53 |  | Baseline and Week 53 | 
| Percentage of participants with a ≥ 1.0 milligram of iron per gram of dry weight of liver (mg Fe/g) decrease from Baseline in liver iron concentration (LIC) at Week 53 |  | Baseline and Week 53 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Thalassaemia, Beta Thalassemia, IONIS TMPRSS6-LRx