Divesiran, a first-in-class GalNAc-conjugated siRNA that silences TMPRSS6 to increase hepcidin production, reduced phlebotomy requirements and improved iron stores and symptom burden in patients with phlebotomy-dependent polycythemia vera (PV), according to data from the phase 1 portion of the SANRECO trial (NCT05499013) presented at the
Among enrolled patients (n = 21), phlebotomies fell from 80 in the 6 months before treatment to 5 during the dosing period and 4 during the 16-week follow-up after the final dose. Ferritin rose from a baseline mean of 28.1 μg/L (SEM, 15.2) to 48.0 μg/L (SEM, 16.2) at week 34 (P = .035), while serum iron and transferrin saturation (TSAT) declined from baseline, consistent with hepcidin-mediated iron restriction.
“Data presented at EHA continue to reinforce divesiran’s potential to transform the treatment paradigm for patients with polycythemia vera,” Curtis Rambaran, MD, chief medical officer at Silence Therapeutics, stated in a news release.2 “In phase 1, we observed sustained hematocrit control, symptom improvement, and robust and durable reductions in phlebotomy burden, which persisted after the final dose.”
The phase 1 portion of SANRECO was an open-label, dose-finding study that enrolled patients with phlebotomy-dependent PV who had received at least 3 phlebotomies in the 6 months, or at least 5 in the 12 months, before screening.1 Patients were allowed to remain on stable doses of cytoreductive therapy.
Divesiran was administered subcutaneously every 6 weeks for 4 doses across 3 dosing cohorts (3 mg/kg, 6 mg/kg, and 9 mg/kg), with up to 8 patients per cohort, followed by a 16-week follow-up period after the last dose.
Among the 21 patients enrolled, the mean age was 56.3 years (range, 32–71), 10 were male, 11 were White, and 10 were Asian. Twelve patients had high-risk PV (age, ≥60 years), and 14 were receiving concurrent cytoreductive therapy. Baseline hematocrit was 47.0% (SEM, 1.2; range, 39%–59%).
Hematocrit declined from baseline to week 24 by a mean of 3.6 percentage points (SEM, 1.7) in the 3-mg/kg cohort, 4.8 percentage points (SEM, 1.2) in the 6-mg/kg cohort, and 4.6 percentage points (SEM, 3.5) in the 9-mg/kg cohort. Among 14 patients with extended follow-up data after the last dose, the median time to first phlebotomy was 287 days.
The majority of patients had improvement in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-10) from baseline through week 34, indicating potential gains in disease-related symptoms and quality of life alongside the hematocrit and phlebotomy findings.
Divesiran was well tolerated across all 3 dosing cohorts, including at doses up to 9 mg/kg, with no dose-limiting toxicities observed. The most common treatment-emergent adverse effects (TEAEs) were mild, transient injection-site reactions. No treatment-related serious adverse effects or TEAEs leading to treatment discontinuation were reported.1,2
