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

Non-transfusion-dependent Thalassemia Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04718844
• Other study ID #: SLN124-002
• Status: Completed
• Phase: Phase 1
• Start date: April 14, 2021
• Est. completion date: May 23, 2023

Study information

• Verified date: January 2024
• Source: Silence Therapeutics plc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: May 23, 2023
• Est. primary completion date: May 23, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• beta-Thalassemia
• Low Risk Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Non-transfusion-dependent Thalassemia
• Preleukemia
• Syndrome
• Thalassemia
• Very-Low Risk Myelodysplastic Syndrome

Intervention

Drug:
• SLN124
SLN124 for subcutaneous (s.c.) injection
• Placebo
Sodium chloride for s.c. injection

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Silence Therapeutics plc

Countries where clinical trial is conducted

Germany,  Israel,  Italy,  Jordan,  Malaysia,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of treatment-emergent adverse events	safety and tolerability will be reported separately following single-dose administration.	Day 84
Primary	Incidence of treatment-emergent adverse events	safety and tolerability will be reported separately following multi-dose administration.	Day 140
Secondary	Pharmacokinetic: peak plasma concentration (Cmax)	Will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Secondary	Pharmacokinetic: area under the plasma concentration (AUC)	Will be reported separately following single-dose and multiple-dose administration.	Day 84 and Day 140
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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