Silence Therapeutics presented compelling updated Phase 1 data for divesiran, its investigational siRNA therapy for polycythemia vera (PV), at the European Hematology Association (EHA) 2025 Annual Meeting in Milan, Italy. The data reinforce the therapeutic potential of this first-in-class treatment approach for patients with the rare blood cancer.
Phase 1 Results Demonstrate Clinical Promise
The SANRECO Phase 1 study enrolled 21 phlebotomy-dependent PV patients with a combined history of 79 phlebotomies prior to treatment. The results showed that divesiran essentially eliminated the need for therapeutic phlebotomies while maintaining mean hematocrit (HCT) levels at ≤45% across all dose cohorts, regardless of baseline levels.
"The latest data presented at EHA today continue to demonstrate divesiran's potential to maintain rapid and durable control of hematocrit and essentially eliminate the need for phlebotomies in phlebotomy-dependent PV patients," said Marina Kremyanskaya, MD, PhD, Associate Professor of Medicine, Hematology and Medical Oncology, at the Icahn School of Medicine at Mount Sinai.
The therapy demonstrated consistent efficacy across patient populations, showing similar results independent of baseline risk or prior and concurrent therapy. Importantly, divesiran increased hepcidin and ferritin levels, resulting in elevation of iron body content and improved iron deficiency - addressing a key pathophysiological mechanism in PV.
Safety Profile and Dosing Advantages
The safety profile remained favorable throughout the study period. Divesiran was well tolerated with no dose-limiting toxicities observed. White blood cell counts remained stable over the study duration, while platelets increased to a plateau with no dose-dependent effect.
The study evaluated three dose levels (3 mg/kg, 6 mg/kg, and 9 mg/kg) administered subcutaneously every 6 weeks for four doses, followed by a 16-week follow-up period. This dosing schedule suggests the potential for infrequent administration, which could significantly improve patient convenience compared to current standard of care.
Mechanism of Action and Therapeutic Target
Divesiran is developed from Silence Therapeutics' proprietary mRNAi GOLD™ platform and works by "silencing" TMPRSS6, a gene expressed almost exclusively in the liver. TMPRSS6 serves as a negative regulator of hepcidin, the body's master regulator of iron metabolism including absorption, distribution, and storage.
By silencing TMPRSS6 in PV patients, divesiran aims to increase hepcidin production and release by liver hepatocytes, leading to iron restriction to the bone marrow and subsequently reducing the excessive production of red blood cells - a process that depends on iron availability.
Phase 2 Study Progress
The company announced that the SANRECO Phase 2 study has exceeded 50% enrollment and remains on track for full enrollment by year-end 2025. This randomized, double-blind study is evaluating two different divesiran regimens versus placebo in PV patients.
"Divesiran continues to demonstrate a very compelling profile as the first-in-class siRNA for PV," said Craig Tooman, President and Chief Executive Officer at Silence Therapeutics. "We are extremely encouraged by the support we are garnering from the physician community and that's reflected in the positive momentum we're seeing in the SANRECO Phase 2 study."
Addressing Unmet Medical Need
PV is a rare myeloproliferative neoplasm characterized by excessive red blood cell production, often resulting in elevated hematocrit levels. Elevated hematocrit above 45% is associated with a four-times higher rate of death from cardiovascular or thrombotic events. The condition causes burdensome symptoms including fatigue, cognitive disturbance, and pruritus, and can transform to myelofibrosis and acute myeloid leukemia over time.
Current standard of care includes repeated phlebotomies to reduce hematocrit and/or cytoreductive agents to reduce red blood cell production. However, there are currently no approved therapies that specifically target red blood cells and hematocrit, representing a significant unmet medical need.
Divesiran has received FDA Fast Track and Orphan Drug designations for PV, recognizing both the serious nature of the condition and the potential therapeutic benefit of this novel approach.
