Divesiran Is Tolerable and Shows Positive Early Signals in Polycythemia Vera

Divesiran (SLN124), a novel small interfering RNA (siRNA), was safe and displayed signals of efficacy in the treatment of patients with polycythemia vera, according to findings from the phase 1/2 SANRECO trial (NCT05499013).1

Initial results from SANRECO presented during the 2024 ASH Annual Meeting showed that divesiran reduced phlebotomy frequency in patients (n = 21). A total of 79 phlebotomies occurred across all patients prior to dosing; there were 5 phlebotomies during the treatment period and 2 during follow-up among all patients. Divesiran also induced hepcidin in all patients and decreased hematocrit in all cohorts of patients treated.

Additionally, patients did not experience any dose-limiting toxicities. Most treatment-emergent adverse effects (TEAEs) were grade 1 in severity (84%) and there were no TEAEs above grade 2 reported. There were also no treatment-related serious AEs or TEAEs leading to treatment discontinuation.

Divesiran is a first-in-class GalNAc-conjugated siRNA that targets TMPRSS6, a negative regulator of the HJV/BMP/SMAD signaling pathway that induces hepcidin expression. The agent is designed to have a long duration of action, and, notably, it’s target sequence is unique to TMPRSS6 and was selected to maximize TMPRSS6 knock down. Investigators hypothesized that inhibiting TMPRSS6 would raise hepcidin levels and lower iron delivery to the bone marrow, leading to reduced erythropoiesis.

“[Divesiran] is safe and well-tolerated at doses up to 9 mg/kg,” Marina Kremyanskaya, MD, PhD, and her coauthors wrote in a presentation of the data. “[The agent] decreases phlebotomy requirements [and lowered] hematocrit in all patients regardless of baseline levels.”

Kremyanskaya is the medical director for the inpatient oncology unit at The Mount Sinai Hospital and an associate professor of medicine of Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai, both in New York, New York.

SANRECO Study Design and Baseline Characteristics

SANRECO enrolled adult patients with a confirmed diagnosis of polycythemia vera according to revised 2016 World Health Organization criteria.1,2 Eligible patients needed to have undergone at least 3 phlebotomies in the previous 6 months or 5 in the prior 12 months before screening. Patients were also required to have an ECOG performance status of 2 or less, a platelet count of up to 1 million/μL, and a white blood cell count of up to 25,000/ μL.

In phase 1, patients were divided into cohort 1 (n = 6), 2 (n = 8), or 3 (n = 7), and received subcutaneous divesiran at a dose of 3 mg/kg, 6 mg/kg, or 9 mg/kg, respectively, every 6 weeks for 4 doses.1 Follow-up took place for 16 weeks after the last dose.

The primary end points were the incidence of TEAEs and the number of phlebotomies at prespecified intervals.2 Secondary end points included area under the plasma concentration curve and peak plasma concentration at day 127, as well as change in hematocrit, change in transferrin saturation, and change in hepcidin from day 1 to 239.

At baseline, the mean age of patients in the overall population was 55 years (range, 32-71) and the mean hematocrit level was 47% (range, 39%-59%).1 Most patients were male (76%), White (52%), had high-risk disease (57%), and received hydroxyurea as cytoreductive therapy (62%). One patient in cohort 3 received ruxolitinib (Jakafi) as cytoreductive therapy and 7 patients overall did not receive cytoreductives. The baseline number of phlebotomies ranged from 2 to 9.

Additional Safety and Efficacy Data From SANRECO

The most common any-grade TEAEs arising in at least 2 patients in the overall population were injection site reaction (61.9%), anemia (33.3%), fatigue (23.8%), and headache (19.0%). Common any-grade TEAEs in cohort 1 included injection site reaction (83.3%) and anemia (50.0%). Patients in cohort 2 had any-grade injection site reactions (62.5%) and anemia, fatigue, headache, thrombocytosis, and pruitus were reported in 1 patient each (12.5%). The most common any-grade TEAEs in cohort 3 were injection site reaction (42.9%) and anemia (42.9%).

Additional findings from SANRECO demonstrated that divesiran increased ferritin levels in all cohorts. Most patients (n = 18) in the overall population were iron deficient at baseline, which was defined as a maximum ferritin level of 25 μg/L. Additionally, by day 29, platelet counts increased across cohorts with no dose dependency and white blood cell counts were stable.

“Divesiran increases hepcidin resulting in lower hematocrit and number of phlebotomies while increasing body iron content,” the study authors wrote in their conclusion. “These early results support [the] further development of divesiran as a [treatment for] polycythemia vera.”

References

1. Kremyanskaya M, Hoffman R, Chew LP, et al. Initial results from a phase 1/2 study evaluating divesiran, a novel galnac conjugated siRNA, in patients with polycythemia vera (SANRECO). Blood. 2024;144(suppl 1):656. doi:10.1182/blood-2024-205854
2. Study to assess SLN124 in patients with polycythemia vera (SLN). ClinicalTrials.gov. Updated April 22, 2024. Accessed February 25, 2025. https://clinicaltrials.gov/study/NCT05499013