Silence Therapeutics (SLN) Study Result summary

Background and Rationale

• Polycythemia vera (PV) is a rare blood cancer characterized by excessive red blood cell production and elevated hematocrit, increasing thrombotic and cardiovascular risks.

• Current standard of care is inadequate for hematocrit control, with most patients iron deficient at diagnosis and repeated phlebotomy worsening this.

• No approved therapies currently target red blood cells and hematocrit directly in PV.

• Divesiran is an siRNA therapy targeting TMPRSS6 to induce hepcidin, restrict iron, and reduce erythropoiesis, aiming to control hematocrit.

• Divesiran is developed using the mRNAi GOLD platform, with proprietary siRNA and ligand design for targeted liver delivery.

Study Design and Patient Characteristics

• SANRECO is an open-label, multi-cohort, dose-escalation Phase 1 study in PV patients with a history of frequent phlebotomy, evaluating 3, 6, and 9 mg/kg doses every 6 weeks for four doses, with 16 weeks of follow-up.

• 21 patients enrolled as of June 27, 2024, across three dose cohorts; both well-controlled and less controlled patients included, some on stable cytoreductive agents.

• Dosing was subcutaneous on days 1, 43, 85, and 127, with total study duration of 34 weeks.

• Key inclusion: PV diagnosis, history of frequent phlebotomies, and allowance for stable cytoreductive agents.

• Baseline characteristics included a mix of male and female, Asian and Caucasian patients, with no prior thrombotic events.

Efficacy Results

• Divesiran eliminated the need for phlebotomy in all well-controlled patients (hematocrit ≤45%) during treatment, a 100% response rate.

• Of 8 patients with hematocrit >45% at baseline, only 2 required a single phlebotomy each; both had very high baseline hematocrit (53% and 56%).

• Across all patients, only 2 phlebotomies occurred during treatment versus 59 in the 6 months prior to study entry.

• All treated patients maintained or achieved hematocrit ≤45%, regardless of baseline level.

• Divesiran treatment led to early and sustained hepcidin elevation within physiologic range and consistent, clinically meaningful hematocrit reduction.