Silence Therapeutics Completes Enrollment in Phase 2 Trial of First-in-Class siRNA for Polycythemia Vera
核心洞察
Silence Therapeutics has completed enrollment of 48 patients in the SANRECO Phase 2 study evaluating divesiran, a first-in-class siRNA targeting TMPRSS6 (搜索), for polycythemia vera (搜索) treatment.
The randomized, double-blind, placebo-controlled trial aims to demonstrate divesiran's ability to maintain hematocrit levels below 45% without phlebotomies between weeks 18 and 36.
Phase 1 results showed divesiran's potential to maintain target hematocrit levels with infrequent dosing every six weeks without requiring phlebotomies.
Silence Therapeutics plc has completed patient enrollment in its SANRECO Phase 2 study of divesiran, marking a significant milestone for what the company describes as the first-in-class siRNA therapy targeting polycythemia vera (搜索) (PV). The global, randomized, double-blind, placebo-controlled trial enrolled 48 phlebotomy-dependent PV patients, with initial topline results anticipated in the third quarter of 2026.
Novel Mechanism Targets Iron Metabolism
Divesiran represents a novel therapeutic approach for PV, utilizing Silence's proprietary mRNAi GOLD™ platform to selectively target and silence production of the TMPRSS6 (搜索) protein in liver cells. TMPRSS6 serves as a negative regulator of hepcidin, the body's master regulator of iron metabolism. By increasing hepcidin levels, divesiran aims to redirect iron delivery away from the bone marrow, thereby lowering red blood cell production and potentially reducing the elevated red blood cell count characteristic of PV patients.
The therapy has received FDA Fast Track and Orphan Drug designations for PV, reflecting the significant unmet medical need in this rare disease population.
Addressing Critical Clinical Endpoints
The SANRECO Phase 2 study's primary endpoint focuses on the proportion of patients receiving divesiran compared to placebo who maintain hematocrit (HCT) levels below 45% without phlebotomies between weeks 18 and 36. This endpoint addresses a critical clinical concern, as PV patients face a four-times higher rate of death from cardiovascular or thrombotic events when hematocrit levels exceed 45%.
"The rapid completion of Phase 2 enrollment highlights the growing enthusiasm for divesiran and novel treatment options to address the significant unmet need in PV," said Craig Tooman, President and Chief Executive Officer at Silence. "Despite currently approved treatment options, a serious unmet need exists for patients seeking continuous hematocrit and symptom control, improved quality of life, and more convenient dosing, which we believe divesiran has the potential to address as a first-in-class siRNA."
Promising Phase 1 Results Drive Extended Dosing Intervals
Results from the Phase 1 portion of the SANRECO study demonstrated divesiran's potential to maintain HCT to target levels following infrequent dosing every six weeks without requiring phlebotomies in the target population. Based on the sustained duration of effect observed in Phase 1, the Phase 2 study evaluates two dosing intervals: every six weeks (Q6W) and every 12 weeks (Q12W).
The study design includes a 36-week, placebo-controlled, double-blind period followed by a double-blind extension period and then an open-label extension period. Secondary endpoints encompass safety and tolerability, pharmacokinetics, and quality of life outcomes.
Significant Disease Burden and Treatment Limitations
PV is a rare myeloproliferative neoplasm—a type of blood cancer—characterized by excessive production of red blood cells, often resulting in elevated hematocrit levels. The disease presents with a range of burdensome symptoms including fatigue, cognitive disturbance, and pruritus. Long-term complications include potential transformation to myelofibrosis (搜索) and acute myeloid leukemia (搜索).
Current standard of care relies on repeated phlebotomies to reduce hematocrit and/or cytoreductive agents to reduce red blood cell production. Notably, there are currently no approved therapies that specifically target red blood cells and hematocrit, highlighting the potential significance of divesiran's novel mechanism of action.
The treatment goal remains maintaining hematocrit levels below 45%, a threshold associated with reduced incidence of thrombosis and cardiovascular-associated death. Divesiran's potential to achieve this goal through convenient, infrequent dosing could represent a meaningful advance in PV management.