Initial Results from a Phase 1/2 Study Evaluating Divesiran, a Novel Galnac Conjugated siRNA, in Patients with Polycythemia Vera (SANRECO)

Background Polycythemia Vera (PV), a chronic myeloproliferative neoplasm characterized by excessive production of red blood cells reflected by elevated hematocrit (Hct) levels. Patients (pts) are at an increased risk of developing thromboembolic events which is closely linked to elevated Hct levels (>45%) (Marchioli et al 2013). Hct levels are routinely controlled with phlebotomies (PHL), in combination with cytoreductive therapies. Hepcidin, synthesized by hepatocytes, is the central regulator of iron homeostasis. In PV pts, it is expressed at relatively low levels (Ginzburg et al 2018). We employed a novel approach to alter iron distribution in PV pts using small interfering RNAs (siRNA). siRNAs are targeted precision medicines that engage and silence their mRNA targets via precise Watson-Crick base pairing. Divesiran (SLN124), a liver-targeted GalNAc-conjugated double-stranded 19-mer siRNA increases hepatic hepcidin synthesis and plasma levels by silencing TMPRSS6 (a negative regulator of hepcidin production), and restricting iron availability for erythropoiesis. Previously, in healthy volunteers divesiran was reported to be well-tolerated and resulted in sustained elevations of hepcidin levels, demonstrating durable iron restriction (Porter et al 2023). Here we present initial phase 1 (Ph1) data from the SANRECO trial (NCT05499013), an ongoing Ph1/2 study of divesiran in PV pts. Objective The primary objective is to evaluate the safety and tolerability of divesiran and its effects on the number of PHL. Methods Ph1 is an open-label dose-finding study for PV pts. Eligibility criteria include: PV diagnosis as per 2016 WHO criteria with at least 3 PHL in the 6 months (mo) or 5 PHL in 12 mo prior to screening. Pts treated with PHL alone or on stable doses of cytoreductive therapy (at least 3 mo) are eligible. 3 dosing cohorts, Ct1, Ct2 and Ct3 (3, 6 or 9 mg/kg of divesiran respectively) enrolling up to 8 participants each, receive up to 4 doses of divesiran by subcutaneous injection at 6 weeks intervals (dosing). After the last dose (week 19), pts are followed (observation) for 16 weeks (week 35). A safety review committee reviewed data at each dose level before proceeding to the next. Iron and erythroid biomarkers were assessed throughout the study. Results Nineteen pts were enrolled with a mean age 55 years (range 32 to 71). 14/19 were male, 10/19 white, 9/19 Asian, 11/19 high-risk PV and 12/19 on cytoreductive agents. The study population had a mean baseline Hct of 47% (range 39% to 56%). At the time of the data cut-off, 14 pts had finished the dosing period (4 Ct1, 8 Ct2 and 2 in Ct3), 8 pts had completed the dosing+observation portion of the study (4 in Ct1 and 4 in Ct2). Divesiran was well-tolerated without dose-limiting toxicities. Treatment-emergent adverse events (TEAEs) were reported in 15/19 (79%) pts, the majority (81%) were grade 1. Nine mild self-limiting injection site reactions were observed in 4/19 patients with no dose dependency. No treatment-related serious adverse events, or TEAEs leading to discontinuation, were observed. Plasma concentrations of divesiran were proportional to dose and eliminated by 48 hours after dosing. In the 6 mo prior to dosing, 19 pts had a total of 79 PHL (18 in Ct1, 34 in Ct2 and 27 in Ct3). After dosing with divesiran, pts with a baseline Hct <50% (15/19) did not require additional PHLs or experience thrombotic events. Pts with baseline Hct >50% (4/19) had 6 PHL in total, 4 during dosing (1 Ct1 and 3 Ct2) 2 during observation (1 Ct1, 1 Ct2). Importantly, divesiran induced hepcidin levels 38-fold in Ct1 and 19-fold in Ct2 8 days after dosing and remained elevated to last dose). Serum iron and TSAT were low at baseline reflecting iron deficiency and were further reduced after divesiran dosing, while ferritin levels were increased during the dosing phase. Platelets were 476.7 (47.6) at baseline and 618.0 (82.7), mean (SEM) at peak, while white blood cell counts remained unchanged (baseline 11.1 (1.3), week 19 11.7 (1.9), mean (SEM)). Conclusions Divesiran is the first in class siRNA that increases hepcidin and is being developed for treatment of PV. Ph1 preliminary results suggest that divesiran is safe and well-tolerated. Importantly, divesiran clearly decreased the need for PHL with a convenient dosing regimen (every 6 weeks) suggesting it serves as a potential effective treatment to control erythrocytosis in PV. These findings support further development of divesiran in PV.