Marina Kremyanskaya, MD, PhD
Novel RNA-based therapeutic strategies and hepatocyte-directed delivery platforms are generating increasing interest for the management of polycythemia vera, according to Marina Kremyanskaya, MD, PhD.
In an interview with OncLive®, Kremyanskaya, an associate professor and hematologist/oncologist at Mount Sinai Hospital, discussed findings from the ongoing phase 1/2 SANRECO trial (NCT05499013) evaluating divesiran, a GalNAc-conjugated small interfering RNA (siRNA) agent designed to selectively silence gene expression implicated in disease pathophysiology. Findings presented at the 2025 EHA Congress showed that the agent was safe and well tolerated at doses of up to 9 mg/kg. The agent also led to an increase in hepcidin levels, translating to lower hematocrit levels and a decrease in required phlebotomies.
She also noted how novel agents such as divesiran could ultimately expand treatment options beyond cytoreductive therapies and JAK inhibitor–based strategies for patients with suboptimal responses or intolerance to existing standards of care.
Kremyanskaya is an associate professor of medicine, hematology, and medical oncology at Icahn School of Medicine at Mount Sinai in New York, New York.
OncLive: What is the mechanism of action of divesiran?
Kremyanskaya: The mechanism of action of this drug is a novel approach for patients with polycythemia vera. It uses a technology called siRNA. It binds to mRNA of a molecule called TMPRSS6, which is a negative regulator of hepcidin production. When it binds to this molecule in liver cells—hepatocytes—it interferes with the mRNA and leads to its destruction.
As a result, the expression of TMPRSS6 decreases. TMPRSS6 is a negative regulator of hepcidin production; by removing that negative regulator, endogenous hepcidin production goes up. Because of the increased hepcidin in the bloodstream, there is restriction of total iron available to the bone marrow for production of red blood cells. This eventually results in control of erythrocytosis and hematocrit in patients with polycythemia vera.
Divesiran is one of the few agents using the hepcidin-iron pathway. The first drug developed in this space was rusfertide, which is a hepcidin mimetic that [delivers] hepcidin directly. Both work through a similar concept of increasing hepcidin and restricting iron, but divesiran does it indirectly by using siRNA to increase endogenous hepcidin production.
What was the design of the phase 1 portion of the study, and which patients were eligible?
The SANRECO trial is a phase 1/2 study. The data presented here at EHA are from the phase 1 portion. Three different cohorts of patients were enrolled at three dose levels, for a total of 21 patients.
Patients had polycythemia vera diagnosed per WHO 2016 criteria and had to be heavily phlebotomy dependent. That was defined as [either] at least 3 phlebotomies in the 6 months prior to enrollment or 5 phlebotomies in the year prior. These were patients either getting phlebotomies alone or receiving cytoreductive therapy but still needing phlebotomies.
This is a phase 1 study, so the primary end point was safety and tolerability, but efficacy was also assessed.
What safety findings have been observed so far?
The drug was well tolerated. The most common adverse effect [AE] was injection-site reaction. Divesiran is given as a subcutaneous injection every 6 weeks. In the study, patients received an injection every 6 weeks for 4 doses, followed by a 16-week observation period.
Injection-site reactions were self-limited and resolved in all patients. There were no AEs leading to drug discontinuation and no serious AEs related to the study drug.
What preliminary efficacy signals were observed?
The number of phlebotomies these patients required was significantly reduced compared with the period before starting divesiran. Patients entered the study with a wide range of hematocrit [levels]. Interestingly, those who already had controlled hematocrit at baseline did not require any additional phlebotomies while on the study drug. That is an exciting finding—these patients really don’t seem to need phlebotomies once on divesiran.
What are the next steps for this research?
Phase 2 enrollment is ongoing at multiple sites worldwide. The phase 2 study is randomized: one group receives the drug every 6 weeks, one receives it every 12 weeks, and the third group receives placebo. The hope is that enrollment will be completed by the end of this year, and we will have prospective, randomized results.
What potential future clinical implications could this approach have?
As the field develops, we hope these drugs will be available for patients with polycythemia vera who need frequent phlebotomies. Because of the nature of the disease and repeated phlebotomies, many [patients] become iron deficient, leading to symptoms related to iron deficiency. Better hematocrit control could also reduce thrombosis risk.
Reference
Kremyanskaya M, Hoffman R, Ginzburg Y, et al. SANRECO: an ongoing phase 1/2 study evaluating divesiran, a novel GalNAc-conjugated siRNA, in patients with polycythemia vera. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract S224.