Polycythemia Vera
Conditions
Keywords
PV
Brief summary
This is a Phase 1/2, multicenter study with an open-label dose escalation followed by a randomized placebo controlled and double-blind phase of SLN124 in adult patients with Polycythemia Vera (PV) to assess the safety, tolerability, efficacy, pharmacokinetic (PK), and Pharmacodynamic (PD) response of SLN124.
Interventions
DRUGSLN124
SLN124 is a double-stranded small interfering ribonucleic acid (siRNA) targeting transmembrane protease, serine 6 (TMPRSS6) messenger ribonucleic acid (mRNA).
DRUGPlacebo
sodium chloride, solution for injection
Sponsors
Silence Therapeutics plc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Phase 1 is an open-label, dose-finding study. Phase 2 is a randomized, double-blind, placebo-controlled study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase 1 and Phase 2 Inclusion Criteria: * Male and female patients aged 18 years or older. * A confirmed diagnosis of PV according to the revised 2016 World Health Organization criteria: * Suitable phlebotomy history * Must agree to adhere to appropriate contraception requirements * Patients who are not receiving cytoreductive therapy must have been discontinued from any prior cytoreductive therapy for at least 24 weeks before dosing and have recovered from any adverse events due to cytoreductive therapy. * Patients receiving cytoreductive therapy with hydroxyurea, interferon, busulfan or ruxolitinib must have received a stable dose of cytoreductive therapy for at least 12 weeks before dosing and with no planned change in dose. * Patients must have had a dermatological examination within 28 weeks prior to dosing. * Must have an Eastern Cooperative Oncology Group score of 0, 1, or 2.
Exclusion criteria
Phase 1 and Phase 2 * Drug intolerance: 1. History of intolerance to oligonucleotides, or GalNAc, or any component of SLN124. 2. History of intolerance to s.c. injections. * Clinically significant thrombosis (e.g., deep vein thrombosis or splenic vein thrombosis) within 12 weeks of screening. * History of major bleeding events and/or a requirement for blood transfusion therapy owing to bleeding in the last 6 months prior to screening. * Meets the criteria for post-PV myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment * Any investigational drug less than 6 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent. * Any investigational or marketed product using GalNAc targeting less than 48 weeks prior to administration of any investigational agent (excludes patients with PV who participated in Phase 1 of this study). * Clinically significant co-morbidities * Biochemical and hematological parameters: 1. Biochemical evidence of significant liver disease during screening 2. Phase 1: Hematological parameters at screening as follows: platelets \> 1,000,000/µL; or white blood cell (WBC) count \> 25,000/µL; or peripheral blasts \> 1%. b. Phase 2: Hematological parameters at screening as follows: platelets \> 1,000,000/µL; or WBC count \> 30,000/µL; or peripheral blasts \> 1%.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Incidence of treatment-emergent adverse events (AEs) | Day 239 | Safety and tolerability will be reported separately following open-label dose escalation phase and double-blind phase |
| Phase 1: Assessment of the number of phlebotomies at intervals | 6 months prior to dosing to Day 239 | — |
| Phase 2: Proportion of patients who achieve response between week 18 and week 36 (placebo controlled double blind phase) | 18 to 36 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Pharmacodynamic: Change in Transferrin saturation (TSAT) | Day 1 to Day 239 | — |
| Phase 1: Pharmacodynamic: Change in Hepcidin | Day 1 to Day 239 | — |
| Phase 2: Comparison of the effect of SLN124 vs placebo | Over 36 weeks | Number of phlebotomies |
| Phase 2: In the double-blind extension period and in the OLE period: | Week 37 to Week 181 | Assess long-term safety and tolerability of SLN124 |
| Phase 1: Pharmacokinetic: area under the plasma concentration (AUC) | Day 127 | — |
| Phase 2: Assessment of SLN124 PD | Changes from Week 1 to Week 181 | Hepcidin |
| Phase 2: Assessment of QoL | Changes from Week 1 to Week 181 | MPN-SAF-TSS |
| Phase 2: Pharmacodynamic: Change in haematocrit | Changes from Week 1 to Week 181 | — |
| Phase 2: Pharmacodynamic: Change in Hepcidin | Changes from Week 1 to Week 181 | — |
| Phase 2: Assessment of SLN124 Cmax at Day 1 and Day 169 of the trial. | Day 1 and Day 169 | — |
| Phase 1: Pharmacokinetic: peak plasma concentration (Cmax) | Day 127 | — |
| Phase 1: Pharmacodynamic: change in haematocrit | Day 1 to Day 239 | — |
Countries
Australia, Bulgaria, Canada, Germany, Italy, Malaysia, Poland, Spain, United States
Outcome results
None listed