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

Phase 2

Terminated

Conditions: Beta Thalassemia Intermedia

Interventions: Drug: sapablursen

Registration Number: NCT04059406

Lead Sponsor: Ionis Pharmaceuticals, Inc.

Brief Summary: 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.

Detailed 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 29

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort A: Sapablursen	sapablursen	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.
Cohort B: Sapablursen	sapablursen	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
Cohort C: Sapablursen	sapablursen	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.

Primary Outcome Measures

Name	Time	Method
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	Blood hemoglobin

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With a ≥1.5 g/dL Increase From Baseline in Hb at Week 53	Week 53	Blood hemoglobin
Percentage of Participants With a ≥1.0 Milligrams of Iron Per Grams of Dry Weight of Liver (mg Fe/g) Decrease From Baseline in Liver Iron Concentration (LIC) at Week 53	Week 53	Liver iron content

Trial Locations

Locations (19): Aghia Sophia General Children's Hospital
🇬🇷
Athens, Attica, Greece
Royal Prince Alfred Hospital
🇦🇺
Camperdown, New South Wales, Australia
Monash Medical Centre
🇦🇺
Clayton, Victoria, Australia
Royal Perth Hospital
🇦🇺
Perth, Western Australia, Australia
Koutlimbaneio & Triantafylleio General Hospital of Larissa
🇬🇷
Larissa, Thessaly, Greece
University General Hospital of Patras
🇬🇷
Patra, Peloponnese, Greece
Chronic Care Center
🇱🇧
Hazmiyeh, Lebanon
Maharaj Nakorn Chiang Mai Hospital
🇹🇭
Chiang Mai, Thailand
Siriraj Hospital
🇹🇭
Bangkok, Thailand
Srinagarind Hospital
🇹🇭
Khon Kaen, Thailand
Thammasat University Hospital
🇹🇭
Pathum Thani, Thailand
King Chulalongkorn Memorial Hospital
🇹🇭
Pathum Wan, Thailand
Songklanagarind Hospital
🇹🇭
Songkhla, Thailand
Hacettepe Üniversitesi Tıp Fakültesi
🇹🇷
Ankara, Turkey
Naresuan University Hospital
🇹🇭
Phitsanulok, Thailand
Cukurova Üniversitesi Tıp Fakültesi
🇹🇷
Adana, Turkey
Ege Universitesi Tip Fakultesi
🇹🇷
İzmir, Turkey
Akdeniz University Faculty of Medicine
🇹🇷
Antalya, Turkey
İstanbul Üniversitesi - Istanbul Tıp Fakültesi
🇹🇷
Topkapı, Turkey