Dr Kremyanskaya on the Mechanism of Action of Divesiran in Polycythemia Vera

“The mechanism of action of [divesiran] is that it’s a novel approach for patients with polycythemia vera, but it uses a technology called small interfering RNA, [which] binds to the messenger RNA of this molecule called TMPRSS6.”

Marina Kremyanskaya, MD, PhD, an associate professor of medicine in Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai, detailed the mechanism of action of divesiran (SLN124), a novel agent for the treatment of patients with polycythemia vera (PV).

The phase 1/2 SANRECO trial (NCT05499013) evaluated the novel small interfering RNA, divesiran for the treatment of patients with PV. Divesiran binds to the messenger RNA of the molecule, known as TMPRSS6, Kremyanskaya began. She explained that when divesiran binds to TMPRSS6 in the liver cells and hepatocytes, it leads to destruction and reduces the expression of TMPRSS6, a negative regulator of hepcidin production. This mechanism of action, therefore, removes the negative regulator, and the endogenous production of hepcidin increases, she added. Additionally, due to the increased levels of hepcidin in the bloodstream, the total amount of iron available to the bone marrow is restricted, she continued. This leads to control of erythrocytosis and hematocrit in patients with PV, she concluded.

Of note, the study was completed in February 2025 and included 21 patients who were assigned to 3 cohorts to receive divesiran at either 3 mg/kg (cohort 1; n = 6), 6 mg/kg (cohort 2; n = 8), or 9 mg/kg (cohort 3; n = 7). Patients were eligible for the study if they had a diagnosis of PV according to World Health Organization 2016 criteria, at least 3 phlebotomies in the previous 6 months or 5 in the 12 months prior to screening, platelet levels of 1,000,00/µL or less, and a white blood cell count of 25,000/µL or less. Cytoreductives were also permitted if the patient was on a stable dose 12 weeks before screening without planned dose changes.

Initial results from the study were presented during the 2024 ASH Annual Meeting.