On December 9, 2024 Silence Therapeutics plc ("Silence" or the "Company") (Nasdaq: SLN), a global clinical-stage company developing novel siRNA (short interfering RNA) therapies, reported additional results from the Phase 1 open label portion of the SANRECO study of divesiran, a siRNA targeting TMPRSS6, in patients with polycythemia vera (PV) were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in San Diego, California (Press release, Silence Therapeutics, DEC 9, 2024, View Source [SID1234648914]).
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"Additional divesiran data presented at ASH (Free ASH Whitepaper) continue to support a compelling profile in PV and highlight the broad potential of our siRNA platform to target both rare and common genetic diseases," said Craig Tooman, President and CEO at Silence. "Based on these very encouraging results, we are committed to advancing divesiran development as the first-in-class siRNA in PV and will prioritize our resources to ensure we are well positioned to progress this very promising program. To this end, we are pleased to have dosed the first subject in the Phase 2 portion of the SANRECO study, which is currently underway."
Initial results from the SANRECO Phase 1 study were presented in June 2024 and showed that all doses of divesiran substantially reduced phlebotomy frequency and lowered hematocrit (HCT) in 16 phlebotomy dependent PV patients regardless of baseline HCT levels. Additional data presented at ASH (Free ASH Whitepaper) further support those findings and included 19 PV patients with a combined history of 79 phlebotomies prior to enrolment. Following divesiran dosing, only five phlebotomies occurred during the 18-week treatment period – all were in patients who entered the study with high baseline HCT levels (over 45%). Two phlebotomies occurred in the 16-week follow-up period following the last administered dose.
Consistent with results reported in June, there was a sustained reduction in HCT during the treatment period and favorable effects on indices of iron metabolism. Hepcidin levels increased and were sustained within physiological levels in all dose groups, demonstrating consistent target engagement. Importantly, divesiran continues to be well tolerated to-date with no dose-limiting toxicities.
"PV patients could benefit from a novel treatment option that effectively manages their condition without causing serious adverse effects," said Marina Kremyanskaya, MD, PhD, Associate Professor of Medicine, Hematology and Medical Oncology, at the Icahn School of Medicine at Mount Sinai. "In the Phase 1 portion of the SANRECO study, divesiran substantially reduced the need for phlebotomy and lowered hematocrit levels following infrequent dosing in a range of PV patients. I’m particularly impressed by the long duration of effect and clean safety/tolerability profile. These data are very exciting and support further development of divesiran in PV."
The ASH (Free ASH Whitepaper) presentation is available on the Company’s website, linked here.
The Phase 1 portion of the SANRECO study has enrolled 21 patients and is ongoing until all patients complete follow-up which is expected to conclude in February 2025. Silence also announced today the first subject has been dosed in the Phase 2 portion of the SANRECO Study. Divesiran has FDA Fast Track and Orphan Drug designation in the US.
SANRECO Phase 1 Study Design
The Phase 1 portion of SANRECO is a 34-week, open-label study evaluating divesiran (3 mg/kg, 6 mg/kg and 9 mg/kg) administered subcutaneously every 6 weeks for four doses, with a 16-week follow-up period following the date of the last administered dose in 21 PV patients. Key inclusion criteria include a PV diagnosis and a history of requiring at least three phlebotomies in the last six months or five in the last year prior to screening. Patients are allowed to be on stable doses of cytoreductive agents. Given the exploratory nature of this Phase 1 study, both well-controlled patients—defined as those with HCT levels at 45% or less – as well as those with HCT levels greater than 45% at baseline on current standard of care treatment were enrolled.
About PV
PV is a rare, myeloproliferative neoplasm – a type of blood cancer—characterized by the excessive production of red blood cells, often resulting in elevated hematocrit levels. Elevated hematocrit above 45-percent is associated with a four-times higher rate of death from cardiovascular or thrombotic events. PV is associated with a range of burdensome symptoms including fatigue, cognitive disturbance and pruritis and additionally, longer term can transform to myelofibrosis and Acute Myeloid Leukemia. The aim of treatment is to maintain hematocrit less than 45%, a level that is associated with a reduced incidence of thrombosis and CV-associated death. The current standard of care includes repeated phlebotomies to reduce hematocrit and/or cytoreductive agents to reduce red blood cell production. There are currently no approved therapies that specifically target red blood cells and hematocrit.
About Divesiran
Divesiran is Silence’s wholly owned siRNA product candidate developed from its proprietary mRNAi GOLD platform that "silences" TMPRSS6 expressed almost exclusively in the liver. TMPRSS6 is a negative regulator of hepcidin, the body’s master regulator of iron metabolism including its absorption, distribution, and storage. By silencing TMPRSS6 in PV patients, divesiran aims to increase hepcidin production and release by liver hepatocytes, leading to the restriction of iron to the bone marrow and, thus, reducing the excessive production of red blood cells, a process dependent on availability of iron.