Favorable safety and tolerability were seen, but efficacy results in the mid-stage study did not meet Ionis' minimum target product profile to justify further development.

The purpose was to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of sapablursen administered subcutaneously to participants with non-transfusion dependent β-Thalassemia Intermedia.

This was a multi-center, randomized, open-label study in up to 29 participants. The duration of participation for each subject in the study was approximately 29 months and included an approximately 2-month screening period, a 24-month treatment period, and a 3-month post-treatment period.

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 liver iron concentration (LIC) > 5.0 mg iron (Fe) per gram of dry weight of liver (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, antisense oligonucleotide (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