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
Study Details
Study Description
Brief 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 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 Myelodysplastic Syndrome will be enrolled. Each subject will receive single or multiple doses of SLN124 or placebo given by subcutaneous (s.c) injection.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- Incidence of treatment-emergent adverse events [Day 84]
safety and tolerability will be reported separately following single-dose administration.
- Incidence of treatment-emergent adverse events [Day 140]
safety and tolerability will be reported separately following multi-dose administration.
Secondary Outcome Measures
- Pharmacokinetic: peak plasma concentration (Cmax) [Day 84 and Day 140]
Will be reported separately following single-dose and multiple-dose administration.
- Pharmacokinetic: area under the plasma concentration (AUC) [Day 84 and Day 140]
Will be reported separately following single-dose and multiple-dose administration.
- Pharmacokinetic: apparent total clearance from plasma after s.c injection (CL/F) [Day 84 and Day 140]
Will be reported separately following single-dose and multiple-dose administration.
- Pharmacodynamic biomarkers: Change in TSAT after s.c injection. [Day 84 and Day 140]
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
- Pharmacodynamic biomarkers: Change in hepcidin after s.c injection. [Day 84 and Day 140]
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
- Pharmacodynamic biomarkers: Change in serum iron after s.c injection. [Day 84 and Day 140]
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
- Pharmacodynamic biomarkers: Change in haemoglobin after s.c injection. [Day 84 and Day 140]
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Universitaetsklinikum Duesseldorf | Düsseldorf | Germany | ||
| 2 | Universitat Leipzig | Leipzig | Germany | ||
| 3 | Rambam Health Care Campus | Haifa | Israel | ||
| 4 | Sheba Medical Center | Ramat Gan | Israel | ||
| 5 | Tel Aviv Sourasky Medical Center | Tel Aviv | Israel | ||
| 6 | Bar-Ilan University - Faculty of Medicine | Zefat | Israel | ||
| 7 | AUSL della Romagna - Ospedale di Ravenna | Ravenna | Italy | ||
| 8 | Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia | Reggio Emilia | Italy | ||
| 9 | Jordan University Hospital | Amman | Jordan | ||
| 10 | King Hussein Cancer Center | Amman | Jordan | ||
| 11 | Irbid Speciality Hospital | Irbid | Jordan | ||
| 12 | Sarawak General Hospital | Kampung Sarawak | Malaysia | ||
| 13 | Hospital Ampang | Kampung Selangor | Malaysia | ||
| 14 | King Chulalongkorn Memorial Hospital | Bangkok | Thailand | ||
| 15 | Mahidol University - Faculty of Medicine - Ramathibodi Hospital | Bangkok | Thailand | ||
| 16 | Mahidol University - Siriraj Hospital | Bangkok | Thailand | ||
| 17 | Faculty of Medicine, Chiang Mai University | Chiang Mai | Thailand | ||
| 18 | University Hospital of Wales | Cardiff | United Kingdom | ||
| 19 | The Leeds Teaching Hospitals NHS Trust - Saint James's University Hospital | Leeds | United Kingdom | ||
| 20 | Hammersmith Medicines Research Ltd (HMR) | London | United Kingdom |
Sponsors and Collaborators
- Silence Therapeutics plc
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SLN124-002