A Study Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124 in Adults With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome

A Randomised, Single-blind, Placebo-controlled, Phase 1, Single-ascending and Multiple-dose Study in Adult Subjects With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome to Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124.

This study will investigate the safety and tolerability of SLN124 in patients with Thalassaemia or patients with Very Low- and Low-risk Myelodysplastic Syndrome (MDS) after single ascending s.c. doses and multiple doses in healthy male and female subjects. Up to 7 cohorts of 56 patients with Thalassaemia and up to 7 cohorts of 56 patients with MDS will be enrolled. Each subject will receive single or multiple doses of SLN124 or placebo given by subcutaneous (s.c) injection.

Study Overview

• Status: Completed
• Conditions: Non-transfusion-dependent Thalassemia; Low Risk Myelodysplastic Syndrome; Very-Low Risk Myelodysplastic Syndrome
• Intervention / Treatment: Drug: SLN124; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany
    • Universitaetsklinikum Duesseldorf
  • Leipzig, Germany
    • Universität Leipzig
• Israel
  • Haifa, Israel
    • Rambam Health Care Campus
  • Ramat Gan, Israel
    • Sheba Medical Center
  • Tel Aviv, Israel
    • Tel Aviv Sourasky Medical Center
  • Zefat, Israel
    • Bar-Ilan University - Faculty of Medicine
• Italy
  • Ravenna, Italy
    • AUSL della Romagna - Ospedale di Ravenna
  • Reggio Emilia, Italy
    • Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia
• Jordan
  • Amman, Jordan
    • Jordan University Hospital
  • Amman, Jordan
    • King Hussein Cancer Center
  • Irbid, Jordan
    • Irbid Speciality Hospital
• Malaysia
  • Kampung Sarawak, Malaysia
    • Sarawak General Hospital
  • Kampung Selangor, Malaysia
    • Hospital Ampang
• Thailand
  • Bangkok, Thailand
    • King Chulalongkorn Memorial Hospital
  • Bangkok, Thailand
    • Mahidol University - Faculty of Medicine - Ramathibodi Hospital
  • Bangkok, Thailand
    • Mahidol University - Siriraj Hospital
  • Chiang Mai, Thailand
    • Faculty of Medicine, Chiang Mai University
• United Kingdom
  • Cardiff, United Kingdom
    • University Hospital of Wales
  • Leeds, United Kingdom
    • The Leeds Teaching Hospitals NHS Trust - Saint James's University Hospital
  • London, United Kingdom
    • Hammersmith Medicines Research Ltd (HMR)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult with alpha- or beta-thalassaemia or compound heterozygous haemoglobin E/beta-thalassaemia or adult with very low- or low-risk MDS according to the 2016 revision to the World Health Organisation classification.
• All subjects must agree to adhere to appropriate contraception requirements.
• Subjects must provide written informed consent and be able to comply with all study requirements.
• Body mass index ≥18 kg/m2 and ≤35 kg/m2 at screening.
• At least one of: a) Mean ferritin >250 μg/L based on a minimum of 2 measurements ≥1 week apart within 20 days before the planned dosing day, in the absence of active significant infection; b) Mean TSAT >40% measured on a minimum of 2 occasions ≥1 week apart within 20 days before the planned dosing day; c) Liver iron >3 mg Fe/g dry weight, measured according to local procedures.
• Mean baseline haemoglobin concentration ≥5 g/dL and ≤11 g/dL, based on a minimum of 2 measurements ≥1 week apart, within 20 days before the planned dosing day.

Exclusion criteria

• Adult with haemoglobin S/alpha-thalassaemia or haemoglobin S/beta-thalassaemia or adult with secondary MDS, i.e., MDS that is known to have arisen because of chemical injury or treatment with chemotherapy and/or radiation for another disease.
• History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc, or intolerance to s.c. injections.
• Known infection with HIV, or active infectious hepatitis A, B, or C virus.
• Any conditions which, in the opinion of the Investigator, would make the subject unsuitable for enrolment in the study or could interfere with the subject's participation in, or completion of the study.
• History or clinical evidence of alcohol or illegal drug misuse within 2 years before screening.
• Currently using ESA, or plan to use ESA at any point during the study.
• Require daily treatment with 1 or more non-steroidal anti-inflammatory drugs during the study period. Paracetamol will be permitted for use as an antipyretic and/or analgesic.
• Treatment, or change in treatment with prohibited medications as specified in the protocol
• Treatment with ICT where the subject has not been on a stable dose for at least 8 weeks before screening or it is planned to initiate ICT therapy during the study.
• Clinically significant cardiac disease
• Clinically significant pulmonary disease

For subjects with thalassaemia:

• Treatment, or change in treatment with prohibited medications as specified in the protocol
• currently and anticipated to receiving more than 5 units of RBCs during the 24 weeks to 6 weeks period before first dose of study drug.

For subjects with very low / low-risk MDS:

• Previous allogeneic or autologous stem cell transplantation.
• Currently or planned to receive treatment with a corticosteroid for MDS within 8 weeks before screening.
• Currently or planned to receive treatment with haematopoietic growth factors (e.g., eltrombopag, romiplostim) within 8 weeks before screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

18

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1.0mg/kg - Thalassaemia	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 3.0mg/kg - Thalassaemia	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 6.0mg/kg - Thalassaemia	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Placebo Comparator: Placebo - Thalassaemia	Drug: Placebo; Sodium chloride for s.c. injection
Experimental: Xmg/kg - Thalassaemia	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 1.0mg/kg - Myelodysplastic Syndrome	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 3.0mg/kg - Myelodysplastic Syndrome	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 10.0mg/kg - Myelodysplastic Syndrome	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: Xmg/kg - Myelodysplastic Syndrome	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 3.0mg/kg - Thalassaemia multi dose	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 10.0mg/kg - Thalassaemia multi dose	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: Xmg/kg - Thalassaemia multi dose	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 3.0mg/kg - Myelodysplastic Syndrome multi dose	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: 10.0mg/kg - Myelodysplastic Syndrome multi dose	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Experimental: Xmg/kg - Myelodysplastic Syndrome multi dose	Drug: SLN124; SLN124 for subcutaneous (s.c.) injection
Placebo Comparator: Placebo - Thalassaemia multi dose	Drug: Placebo; Sodium chloride for s.c. injection
Placebo Comparator: Placebo - Myelodysplastic Syndrome	Drug: Placebo; Sodium chloride for s.c. injection
Placebo Comparator: Placebo - Myelodysplastic Syndrome multi dose	Drug: Placebo; Sodium chloride for s.c. injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events	safety and tolerability will be reported separately following single-dose administration.	Day 84
Incidence of treatment-emergent adverse events	safety and tolerability will be reported separately following multi-dose administration.	Day 140

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic: peak plasma concentration (Cmax)	Will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Pharmacokinetic: area under the plasma concentration (AUC)	Will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Pharmacokinetic: apparent total clearance from plasma after s.c injection (CL/F)	Will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Pharmacodynamic biomarkers: Change in TSAT after s.c injection.	safety and tolerability will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Pharmacodynamic biomarkers: Change in hepcidin after s.c injection.	safety and tolerability will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Pharmacodynamic biomarkers: Change in serum iron after s.c injection.	safety and tolerability will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Pharmacodynamic biomarkers: Change in haemoglobin after s.c injection.	safety and tolerability will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140

Collaborators and Investigators

• Sponsor: Silence Therapeutics plc

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2021
• Primary Completion (Actual): May 23, 2023
• Study Completion (Actual): May 23, 2023

Study Registration Dates

• First Submitted: January 19, 2021
• First Submitted That Met QC Criteria: January 19, 2021
• First Posted (Actual): January 22, 2021

Study Record Updates

• Last Update Posted (Actual): January 3, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Precancerous Conditions; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Syndrome; Myelodysplastic Syndromes; Preleukemia; Thalassemia; beta-Thalassemia
• Other Study ID Numbers: SLN124-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No