Polycythemia vera is a rare myeloproliferative neoplasm characterized by elevated red blood cell production and hematocrit levels, increasing the risk of thrombotic and cardiovascular events. Approximately 60 percent of patients are symptomatic at diagnosis, experiencing burdens such as fatigue, pruritus, and cognitive impairment. The disease carries a risk of progression to myelofibrosis or acute myeloid leukemia, highlighting the need for therapies that offer both hematologic control and symptom management.

A total of 21 patients were enrolled, with a mean age of 56.3 years (range: 32–71). Of these, 16 (76%) were male, 11 (52%) were White, and 10 (48%) were Asian. Eleven patients (52%) were classified as high-risk polycythemia vera based on age >60 years, and 14 (67%) were receiving cytoreductive therapy (CRT). The patient population had a baseline hematocrit (HCT) of 47.0% (±1.2%; mean ± standard error of the mean [SEM]; range: 39%–59%). At the data cut-off, 17 patients had completed the dosing period, and 16 had completed the study. Divesiran was well tolerated, with no dose-limiting toxicities observed. Treatment-emergent adverse events (TEAEs) occurred in 19 of 21 patients (91%), the majority of which were Grade 1. The most common TEAE was injection site reactions (ISRs), reported in 13 of 21 patients. In the six months prior to dosing, patients underwent a total of 80 phlebotomies. Following divesiran administration, none of the patients with baseline HCT <45% (8 of 21) required phlebotomies or experienced thrombotic events. Among patients with baseline HCT ≥45% (13 of 21), a total of 7 phlebotomies were performed—5 during the dosing period and 2 during follow-up. Mean hemoglobin levels decreased by Day 169 by 1.04 g/dL (±0.56) in Cohort 1, 1.95 g/dL (±0.40) in Cohort 2, and 2.42 g/dL (±1.91) in Cohort 3. 

Divesiran induced a peak mean hepcidin increase of more than 40-fold from baseline across all cohorts, indicating clear target engagement. Serum iron and transferrin saturation (TSAT), which were low at baseline, were further reduced following divesiran dosing, while ferritin levels gradually increased throughout the study. Platelet counts rose from a baseline mean of 463 (±46) to a peak of 612 (±72) on Day 29. White blood cell counts remained stable, with baseline values of 11.2 (±1.3) and 11.9 (±1.9) on Day 127 (mean ± SEM).

KOL insights: 

“The latest data presented at EHA further reinforce the potential of divesiran to deliver rapid and sustained hematocrit control while effectively eliminating the need for phlebotomies in patients with phlebotomy-dependent polycythemia vera. These early results also point to the promise of infrequent dosing and a favorable safety profile. I’m encouraged by the consistency observed across the Phase I dataset and look forward to seeing this therapy advance through clinical development.”– Expert Opinion

Conclusion: 

Current treatment for polycythemia vera relies on repeated phlebotomies and cytoreductive agents, yet no approved therapies directly modulate red blood cell production or provide targeted hematocrit control. The first and main program to go over in Silence Therapeutics’ pipeline, currently is the use of divesiran for the treatment of patients with polycythemia vera.

Divesiran is Silence’s wholly owned first-in-class siRNA product candidate designed to inhibit TMPRSS6 expression to raise hepcidin and reduce iron delivery to the bone marrow. It was well tolerated at doses up to 9 mg/kg, with primarily mild adverse events and no serious toxicities observed. The therapy led to significant reductions in hematocrit and hemoglobin levels, substantially decreased the need for phlebotomy, and maintained hematologic control even in patients already considered well-managed. Reflecting its potential clinical benefit and unmet need in this setting, Divesiran has received both Fast Track from the US Food and Drug Administration.