divesiran (SLN124) / Silence Therap - LARVOL DELTA

SANRECO, AN ON-GOING PHASE1/2 STUDY EVALUATING DIVESIRAN, A NOVEL GALNAC-CONJUGATED SIRNA, IN PATIENTS WITH POLYCYTHEMIA VERA (EHA 2025) - P1/2 | "Divesiran is a first in class siRNA that increases hepcidin and is being developed for treatment of PV. The results show that divesiran is safe and well-tolerated at doses up to 9 mg/kg. Divesiran decreased the need for PHL with a convenient dosing regimen (every 6 wks) suggesting it is a potential effective treatment for PV."

Clinical • P1/2 data • Cardiovascular • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • TMPRSS6

Silence Therapeutics Presents Additional Phase 1 Data Highlighting Promise of Divesiran as the Potential First-in-Class siRNA Treatment for Polycythemia Vera (Businesswire) - P1/2 | N=65 | SANRECO (NCT05499013) | Sponsor: Silence Therapeutics plc | "Silence Therapeutics plc...presented additional data showcasing the SANRECO Phase 1 study of divesiran in patients with polycythemia vera (PV) at the European Hematology Association (EHA) 2025 Annual Meeting....Divesiran increased hepcidin and ferritin, resulting in elevation of iron body content and improved iron deficiency. Divesiran demonstrated similar results in all patient groups, independent of baseline risk or prior and concurrent therapy. White blood cells were not altered over the time-course of the study. Platelets increased, reaching a plateau with no dose dependent effect. Divesiran was well tolerated with no dose-limiting toxicities....'The Phase 2 study is over 50-percent enrolled, and we remain on-track to complete patient enrollment by the end of this year'."

Enrollment status • P1 data • Polycythemia Vera

Divesiran for Polycythemia Vera (PV) (Businesswire) - "Additional Phase 1 results from the SANRECO study of divesiran in PV patients have been accepted for oral presentation during the European Hematology Association (EHA) 2025 Annual Congress being held in Milan, Italy from June 12 – 15, 2025; Advanced patient enrollment into the Phase 2 portion of the SANRECO study of divesiran in PV patients and remain on-track to complete enrollment by year-end 2025."

P1 data • Trial status • Polycythemia Vera

Recent Business Highlights (Businesswire) - "Follow-up has concluded in the SANRECO Phase 1 study of divesiran in PV patients. Data presentations at medical congresses are anticipated in 2025; Enrollment is underway in the SANRECO Phase 2 study of divesiran in PV patients. Full enrollment is anticipated by the end of 2025."

Enrollment status • P1 data • Polycythemia Vera

Exploring the Potential of Targeting Iron Overload and Immune Dysregulation in Myelodysplastic Syndromes (LCC 2025) - "NHD13 and wild-type mice received monthly subcutaneous injections of SLN124 siRNA (3 mg/kg) or the oral iron chelator deferiprone in drinking water (1.25 mg/ml). Conclusion These findings underscore the potential of SLN124 to reduce iron accumulation and inflammation, potentially slowing disease progression in MDS. They also emphasise the need for further research into the pathological effects of iron toxicity and inflammation in managing MDS."

Anemia • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • ASGR • MPO • MUC4 • NLRP3 • TMPRSS6

Initial Results from a Phase 1/2 Study Evaluating Divesiran, a Novel Galnac Conjugated siRNA, in Patients with Polycythemia Vera (SANRECO) (ASH 2024) - P1/2 | "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."

Clinical • P1/2 data • Cardiovascular • Chronic Eosinophilic Leukemia • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • TMPRSS6

Silence Therapeutics Presents Promising Phase 1 Data in Polycythemia Vera Patients at the American Society of Hematology (ASH) Annual Meeting (Businesswire) - P1/2 | N=65 | SANRECO (NCT05499013) | Sponsor: Silence Therapeutics plc | "Additional data presented at ASH 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....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."

P1 data • Trial status • Hematological Malignancies • Oncology • Polycythemia Vera

Silence Therapeutics Announces Positive Results from Ongoing SANRECO Phase 1 Study of Divesiran in Polycythemia Vera Patients (Businesswire) - P1/2 | N=65 | SANRECO (NCT05499013) | Silence Therapeutics plc | "Silence Therapeutics plc...today announced positive results from the ongoing SANRECO Phase 1 repeat dose study of divesiran (SLN124), a siRNA (short interfering RNA) targeting TMPRSS6, in patients with polycythemia vera (PV)...Divesiran is poised to be the first siRNA for PV, and we look forward to advancing development with a phase 2 start planned by year-end...The data being presented today are based on a data cut-off date of March 29, 2024...Of the 16 patients, 8 patients are considered well-controlled and 8 patients have HCT levels over 45% at baseline. To date, divesiran has been observed to be well tolerated with no major safety issues...All patients in the well-controlled group maintained adequate control of HCT levels as per treatment guidelines...Divesiran has received...FDA Orphan Drug Designation for PV."

Orphan drug • P1/2 data • Hematological Malignancies • Oncology • Polycythemia Vera

Silence Therapeutics Reports Third Quarter 2024 Financial Results and Recent Business Highlights (Businesswire) - "R&D Highlights:...Results from the Phase 1 portion of the SANRECO Phase 1/2 study of divesiran in polycythemia vera (PV) patients have been selected for oral presentation at the American Society of Hematology (ASH) Annual Meeting..."

P1 data • Polycythemia Vera

Silence Therapeutics Reports First Quarter 2024 Results and Highlights Pipeline Progress (Businesswire) - "Silence Therapeutics...reported its financial results for the first quarter ended March 31, 2024 and reviewed recent business highlights...Advanced the SANRECO phase 1 study of divesiran in polycythemia vera (PV) patients: Emerging data from the open-label study continue to look promising; On-track to report phase 1 data by the end of June 2024....Research and development (R&D) expenses were £9.2 million, a decrease of £3.4 million compared to the first quarter of 2023. The was primarily due to a decrease in contracted R&D expenses of £2.5 million resulting from the completion of the divesiran phase 1 study in thalassemia patients and timing of manufacturing activities for divesiran compared to the same period in 2023."

Commercial • P1 data • Trial status • Hematological Disorders • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

Silence Therapeutics Reports Full Year 2023 Financial Results and Recent Business Highlights (Businesswire) - "Advanced enrollment in the SANRECO phase 1/2 study of divesiran in PV patients. Emerging data from the ongoing phase 1 open label portion of the study continue to look promising; On-track to report phase 1 data in the second quarter of 2024."

Enrollment status • P1 data • Hematological Malignancies • Oncology • Polycythemia Vera

Silence Therapeutics Achieves $10 Million Milestone Payment from AstraZeneca Collaboration Following the Initiation of Phase 1 Trial (Businesswire) - "Silence Therapeutics plc...today announced that the initiation by AstraZeneca of a phase 1 clinical trial of the first product candidate under its siRNA (short interfering RNA) collaboration, has triggered a $10.0 million milestone payment to Silence...'In addition to this great achievement under our collaboration with AstraZeneca, we are also pleased with the continued advancement of our proprietary pipeline with encouraging clinical data now emerging from our zerlasiran program in high Lp(a) and divesiran program in polycythemia vera.'"

Clinical • Licensing / partnership • Cardiovascular • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

Silence Therapeutics Announces Oversubscribed $120 Million Private Placement (Businesswire) - "Silence Therapeutics plc...today announced an oversubscribed private placement of 5,714,286 of the Company’s American Depositary Shares...'The financing provided by this blue-chip syndicate of investors, both new and existing, with whom we’ve had longstanding relationships, allows us to advance our divesiran (SLN124) PV program through Phase 2 and into the next phase of development.'...'The extended cash runway also positions us well as we continue Phase 3 readiness activities for zerlasiran (SLN360), and progress partnering discussions for this program.'....Silence intends to use the net proceeds from the Private Placement for advancement of its ongoing clinical development for divesiran (SLN124) and continued progression of zerlasiran (SLN360) manufacturing and clinical activities as well as working capital and general corporate purposes."

Financing • Cardiovascular • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

GEMINI II: A Study Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124 in Adults With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=44 | Completed | Sponsor: Silence Therapeutics plc | Active, not recruiting ➔ Completed | Trial completion date: Sep 2023 ➔ May 2023

Trial completion • Trial completion date • Beta-Thalassemia • Genetic Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Iron Chelation Efficiency in Human Hepatocytes Is Enhanced By Exogenous Hepcidin (ASH 2023) - "Here we have examined whether application of exogenous hepcidin to a human hepatocyte cell line HepG2 can increase the chelation efficiency of deferiprone and whether this effect is also seen with other iron chelators such as deferasirox and deferoxamine. Two mechanisms for enhanced chelation are possible in this model; the first is by increased iron loading of hepatocytes incubated with hepcidin and secondly through the blocking by hepcidin of labile intracellular iron egress through ferroportin channels, thereby increasing the magnitude of chelatable intracellular iron pools. Future work in primary human hepatocytes will examine whether manipulation of intracellular hepcidin levels by SLN124 has similar chelation-enhancing effects."

Beta-Thalassemia • Genetic Disorders • Hematological Disorders • TMPRSS6

Silence Therapeutics Highlights Recent Company Progress and Reports Third Quarter 2023 Financial Results (Businesswire) - "Anticipated Milestones: SLN124 data from the phase 1 portion of the SANRECO PV study expected in mid-2024....During the three-month period ending September 30, 2023, research and development expenditures were £8.9 million compared to £8.8 million for the same three-month period in 2022. Research and development expenditures increased for the nine-month period ending September 30, 2023 to £34.1 million from £27.2 million for the same period in 2022. This was largely due to an increase in contracted research and development expenses as we continue to advance the SLN124..."

Commercial • P1 data • Hematological Malignancies • Oncology • Polycythemia Vera

GEMINI II: A Study Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124 in Adults With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=44 | Active, not recruiting | Sponsor: Silence Therapeutics plc | Recruiting ➔ Active, not recruiting | N=112 ➔ 44 | Trial completion date: Jan 2023 ➔ Sep 2023 | Trial primary completion date: Nov 2022 ➔ May 2023

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Beta-Thalassemia • Genetic Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers. (PubMed, Am J Hematol) - "In all SLN124 groups, a dose-related effect was observed across iron metabolism markers, and across erythroid markers, SLN124 resulted in increased plasma hepcidin levels, peaking around Day 29, and consequent dose-related sustained reductions in plasma iron and transferrin saturation with decreased reticulocyte production, MCHC, and MCV. Results suggest duration of action lasting up to 56 days after a single SLN124 dose, on hepcidin and hematological parameters of iron metabolism (serum iron and TSAT)."

Journal • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • TMPRSS6

A Phase 1 Study to Evaluate the Safety, Tolerability, PK and PD of SLN124 in Healthy Volunteers (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Silence Therapeutics plc | Active, not recruiting ➔ Completed

Trial completion

Silence Therapeutics Announces Publication in Blood Demonstrating Role for Iron Regulation in Polycythemia Vera (Businesswire) - "Silence Therapeutics plc...announced publication of human genomic and in vivo preclinical data linking iron regulation to polycythemia vera (PV) in the latest issue of Blood, the medical journal of the American Society of Hematology (ASH)...The study further demonstrated in a mouse model of PV that hepcidin, a master regulator of iron availability whose expression is influenced by HFE, governs the red blood cell (erythroid) phenotype in PV."

Preclinical • Polycythemia Vera

Silence Therapeutics Reports Fourth Quarter and Full Year 2022 Results (Businesswire) - "In January 2023, we opened sites for enrollment in the SANRECO phase 1/2 clinical program of SLN124 in polycythemia vera patients."

Trial status • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

[VIRTUAL] NON-CLINICAL SAFETY OF SLN124, A GALNAC CONJUGATED 19-MER DOUBLE-STRANDED SIRNA TARGETING TMPRSS6 FACILITATING EVALUATION IN CLINICAL STUDIES (EHA 2021) - P1 | "Conclusion The non-clinical safety profile of SLN124 is consistent with the known GalNAc siRNA safety profile and supportive of clinical entry, with PK/PD modelling supporting 1 mg/kg as an appropriate safe starting dose. Two clinical studies are underway: NCT04559971 in healthy volunteers and NCT04718844 in non-transfusion dependent b-thalassaemia and VL and LR-MDS patients."

Clinical • Beta-Thalassemia • Myelodysplastic Syndrome • TMPRSS6

SLN124, a GalNAc Conjugated 19-Mer Double-Stranded SiRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study (ASH 2021) - P1 | "The encouraging efficacy signal on serum iron and transferrin saturation and the expected benign safety profile of SLN124 supports further development. The GEMINI II trial ( NCT04718844) is currently recruiting and wil l evaluate single and multiple doses of SLN124 in patients with thalassemia and myelodysplastic syndromes."

Clinical • P1 data • Anemia • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Hepatology • Myelodysplastic Syndrome • Oncology • TMPRSS6

Study to Assess SLN124 in Patients With Polycythemia Vera (clinicaltrials.gov) - P1/2 | N=65 | Recruiting | Sponsor: Silence Therapeutics plc | Not yet recruiting ➔ Recruiting | Initiation date: Oct 2022 ➔ Jan 2023

Enrollment open • Trial initiation date • Polycythemia Vera

Silence Therapeutics Announces FDA Fast Track Designation for SLN124, a Novel Investigational siRNA Therapy for the Treatment of Polycythemia Vera (Businesswire) - "Silence Therapeutics plc...announced that the U.S. Food and Drug Administration ('FDA') has granted Fast Track Designation to SLN124, a novel siRNA targeting the TMPRSS6 gene, for the treatment of polycythemia vera ('PV'). The Company plans to start a phase 1/2 study in PV patients this year."

Fast track designation • Trial initiation date • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera