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

• Published in: Blood 2024-11, Vol.144, p.656-656
• Main Authors: Kremyanskaya, Marina, Hoffman, Ronald, Chew, Lee Ping, Sharif, Azizan, Semov, Boyan, Kori, Ahlam Naila, Sia, Hanlon, Grove, Carolyn S., Ng, Ashley P, Kalro, Akash, Raman, Indu, Kasinathan, Ganesh, Oduwole, Olubunmi, Gomez-Palou, Monica, Fok, Henry, Romano, Steve, Rambaran, Curtis, Martinez, Alberto
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-205854

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 base