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 relies on phlebotomy and cytoreductive agents, but is inadequate for hematocrit control and worsens iron deficiency.

• 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.

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

Study Design and Patient Characteristics

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

• 21 patients enrolled as of June 27, 2024, across three dose cohorts; both well-controlled (hematocrit ≤45%) and less-controlled patients (>45%) included, some on stable cytoreductive agents.

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

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

• Key inclusion: PV diagnosis and history of frequent phlebotomies.

Key Efficacy Findings

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

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

• Only 2 phlebotomies occurred during treatment versus 59 in the 6 months prior to study entry.

• Divesiran led to clinically meaningful and consistent reductions in hematocrit across all cohorts, with evidence of dose response and robust elevation of hepcidin, confirming target engagement.

• Ferritin levels increased, indicating improvement in iron-deficient status.