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

Ionis Pharmaceuticals

Status and phase: Terminated; Phase 2

Conditions: Beta Thalassemia Intermedia

Treatments: Drug: sapablursen

Study type: Interventional

Funder types: Industry

Identifiers

NCT04059406

ISIS 702843-CS2

2019-003505-96 (EudraCT Number)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 29 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

---

29 participants in 3 patient groups

Cohort A: Sapablursen

Experimental group

Description:

Subjects initially received 30 mg/0.3 mL of sapablursen by (subcutaneous) SC injection once every four weeks up to Week 105. After the protocol Amendment 2 the dose was increased to a maximum of 160 mg once every 4 weeks.

Treatment:

Drug: sapablursen

Cohort B: Sapablursen

Experimental group

Description:

Subjects initially received 50 mg/0.5 mL of sapablursen by SC injection once every four weeks up to Week 105. After the protocol Amendment 2 the dose was increased to a maximum of 160 mg once every 4 weeks

Treatment:

Drug: sapablursen

Cohort C: Sapablursen

Experimental group

Description:

Subjects initially received 80 mg/0.8 mL of sapablursen by SC injection once every four weeks up to Week 105. After the protocol Amendment 2 the dose was increased to a maximum of 160 mg once every 4 weeks.

Treatment:

Drug: sapablursen