sapablursen (ONO-0530) / Ionis, Ono Pharma - LARVOL DELTA

Evaluation of the novel TMPRSS6 antisense inhibitor sapablursen for treatment of polycythemia vera: Results of the imprssion clinical trial (ASH 2025) - P2 | "Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reducedphlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight thepotential of sapablursen as a therapeutic approach in PV and support further development."

Clinical • Hematological Disorders • Myeloproliferative Neoplasm • Polycythemia Vera • KLK7 • TMPRSS6

Deciphera Announces Oral Presentation of Positive Topline Results from Phase 2a Study of Sapablursen in Polycythemia Vera at the 67th American Society of Hematology (ASH) Annual Meeting (Businesswire) - "In both cohorts, the study achieved its primary endpoint of significantly decreasing weekly phlebotomy rate from baseline to weeks 17-37; with a decrease from 0.15 to 0.05 in Cohort A (p<0.0001) and from 0.17 to 0.07 in Cohort B (p=0.0001). In patients who completed the 37-week treatment period, the median number of phlebotomies during the last 20 weeks of treatment (weeks 17-37) decreased to 0 and 1.5 phlebotomies in Cohort A and B, respectively, compared to 5 phlebotomies in the 26 weeks (6 months) prior to treatment for both cohorts....Based on the positive Phase 2a study, Deciphera plans to initiate a Phase 3 study of sapablursen in patients with PV in 2026."

New P3 trial • P2a data • Polycythemia Vera

Sapablursen: Primary completion of P2 trial (NCT05143957) for polycythemia vera in FY2025 (Ono Pharmaceuticals) - Q2 FY2025 Results

Trial primary completion date • Hematological Malignancies • Oncology • Polycythemia Vera

Ionis reports third quarter 2025 financial results… (Businesswire) - "Revenue increased 17% in the third quarter of 2025 and increased 55% in the nine months ended September 30, 2025, compared to the same periods last year, driven by the continued successful launch of TRYNGOLZA and increased royalty revenues. Contributing to the year-to-date increase, Ionis earned a $280 million upfront payment for the global license of sapablursen to Ono Pharmaceutical Co., Ltd. in the second quarter of 2025."

Commercial • Familial Chylomicronemia Syndrome • Myeloproliferative Neoplasm • Polycythemia Vera

Modulators of the Hepcidin Pathway in Polycythemia Vera and Myelofibrosis. (PubMed, Blood) - "Since hepcidin levels are relatively low in PV patients, hepcidin agonists (rusfertide, divesiran, sapablursen) are undergoing clinical development to control PV associated erythrocytosis, thereby reducing the need for therapeutic phlebotomies and myelosuppressive therapeutic options. A number of strategies to lower hepcidin levels (the JAK2 inhibitors pacritinib and momelotinib, anti-hemojuvelin monoclonal antibody DISC-0974C) are currently undergoing clinical development to make systemic iron available for erythropoiesis and alleviate the degree of MF associated anemia. These new therapeutic options that modulate iron trafficking in PV and MF patients represent the application of greater knowledge of iron trafficking to create novel therapeutic options to treat patients with hematological malignancies."

Journal • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Oncology • Polycythemia Vera

Novel Therapies in Essential Thrombocythemia and Polycythemia Vera (SOHO 2025) - P1, P1/2, P2, P3 | "In PV, recommended cytoreductive options include hydroxyurea, pegIGN, ropeginterferon-alpha-2b (ropeginterferon), and ruxolitinib...A novel fully human IgG1 monoclonal antibody against mutant CALR (INCA033989) has demonstrated promising preclinical activity...Another phase 1 trial evaluating JNJ-88549968, a novel bispecific antibody that binds to both mutant CALR and T cells to enhance cytotoxicity, 10 is also enrolling both CALR -mutated ET and MF patients (NCT06150157)...12 A phase 2 trial of bomedemstat in high-risk ET patients who were resistant or intolerant to hydroxyurea demonstrated that 94% (34/36) of patients met hematologic response criteria after a median of 8 weeks, with stable hemoglobin levels and improved white blood cell counts...Novel Therapies in Polycythemia Vera Rusfertide and Hepcidin Mimetics Maintenance of a hematocrit <45% is a core aspect of PV therapy, which can be accomplished with a combination of therapeutic phlebotomy..."

IO biomarker • Chronic Myeloid Leukemia • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • CALR • JAK2 • KLK7 • MPL • TMPRSS6

STUDY DESIGN AND DEMOGRAPHICS OF IMPRSSION, A PHASE 2 OPEN-LABEL CLINICAL TRIAL EVALUATING TMPRSS6 ANTISENSE INHIBITOR SAPABLURSEN, IN POLYCYTHEMIA VERA (EHA 2025) - P2 | "This phase 2 study is designed to assess hematocrit control, reduction in phlebotomy, safety and pharmacokinetics of sapablursen in patients with PV."

Clinical • P2 data • Cardiovascular • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombosis • JAK2 • KLK7 • TMPRSS6

Ono Enters into License Agreement with Ionis Pharmaceuticals for Sapablursen for the Treatment of Polycythemia Vera (Businesswire) - "Ono Pharmaceutical...announced that it has entered into a license agreement with Ionis Pharmaceuticals...for sapablursen, an investigational RNA-targeted medicine for the treatment of polycythemia vera (PV)....Under the agreement, ONO will obtain an exclusive license to develop and commercialize sapablursen worldwide. Ionis will remain responsible for the completion of the ongoing Phase 2 IMPRSSION study, while ONO will be solely responsible for subsequent development, regulatory filings and commercialization. ONO will make an upfront payment of 280 million US dollars, with up to a maximum of 660 million US dollars in additional payments based on the achievement of development, regulatory and sales milestones. ONO will also pay to Ionis royalties in the mid-teens on annual net sales of sapablursen."

Licensing / partnership • Polycythemia Vera

A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2 | N=50 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial primary completion date: Jan 2025 ➔ Jun 2025 | Trial completion date: Dec 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Polycythemia Vera

A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2 | N=50 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Polycythemia Vera

Combination of a TGF-β ligand trap (RAP-GRL) and TMPRSS6-ASO is superior for correcting β-thalassemia. (PubMed, Am J Hematol) - "We used an agent analogous to murine luspatercept (RAP-GRL) and another novel therapeutic, IONIS TMPRSS6-LRx (TMPRSS6-ASO), a hepcidin inducer, to treat non-transfusion-dependent BT-intermedia mice. In contrast, TMPRSS6-ASO improved RBC measurements, ameliorated splenomegaly, and improved iron overload most effectively. Our results provide pre-clinical support for combining TMPRSS6-ASO and luspatercept in treating BT, as these drugs together show potential for simultaneously improving both erythroid and iron parameters in BT patients."

Journal • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • TGFB1 • TMPRSS6

Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) (clinicaltrials.gov) - P2 | N=29 | Terminated | Sponsor: Ionis Pharmaceuticals, Inc. | Phase classification: P2a ➔ P2

Phase classification • Beta-Thalassemia • Genetic Disorders

A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | N=40 ➔ 60

Enrollment change • Polycythemia Vera

A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc.

Trial completion date • Trial primary completion date • Polycythemia Vera

A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Phase classification: P2a ➔ P2

Phase classification • Polycythemia Vera

A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2a | N=40 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Jun 2024 ➔ Dec 2025 | Trial primary completion date: Mar 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Polycythemia Vera

Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) (clinicaltrials.gov) - P2a | N=29 | Terminated | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Oct 2023 ➔ Mar 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2023 ➔ Mar 2023; Favorable safety and tolerability were seen, but efficacy results in the mid-stage study did not meet Ionis' minimum target product profile to justify further development.

Trial completion date • Trial primary completion date • Trial termination • Beta-Thalassemia • Genetic Disorders

A Phase 2a, Randomized, Open-Label Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 702843 Administered to Patients with Phlebotomy Dependent Polycythemia Vera (PD-PV) (clinicaltrialsregister.eu) - P2 | N=48 | Ongoing | Sponsor: Ionis Pharmaceuticals, Inc.

New P2 trial • Polycythemia Vera

A Study to Evaluate IONIS-TMPRSS6-LRx (ISIS 702843) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2a | N=40 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Polycythemia Vera

Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS TMPRSS6-LRx (clinicaltrials.gov) - P2a; N=36; Active, not recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Beta-Thalassemia • Genetic Disorders

A Study to Evaluate IONIS-TMPRSS6-LRx (ISIS 702843) in Patients With Polycythemia Vera (clinicaltrials.gov) - P2a; N=40; Not yet recruiting; Sponsor: Ionis Pharmaceuticals, Inc.

Clinical • New P2a trial • Polycythemia Vera

Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS TMPRSS6-LRx (clinicaltrials.gov) - P2a; N=36; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Trial completion date: Oct 2022 ➔ Oct 2023; Trial primary completion date: Aug 2021 ➔ Aug 2023

Clinical • Trial completion date • Trial primary completion date • Beta-Thalassemia • Genetic Disorders

Safety, Pharmacokinetic and Pharmacodynamic Evaluation of a 2'-MOE Antisense Oligonucleotide-GalNAc3 Conjugate that Targets the Human Transmembrane Protease Serine 6 (TMPRSS6). (PubMed, J Pharmacol Exp Ther) - "ISIS 702843 is a GalNAc3-conjugated 2'-MOE ASO specific for human transmembrane protease, serine 6 (TMPRSS6), and is currently in clinical trials for the treatment of β-thalassemia...Significance Statement This report documents the potency, pharmacology and the overall tolerability profile of a GalNAc-conjugated 2'-MOE ASO specific to TMPRSS6 after chronic treatment in the cynomolgus monkey. Collective analysis of 15 independent GalNAc-conjugated and unconjugated 2'-MOE ASOs shows the consistency in the dose response and character of hepatic and platelet tolerability across sequences that will result in much larger safety margins for the GalNAc-conjugated 2'-MOE ASOs when compared to the unconjugated 2'MOE ASOs given the increased potency."

Clinical • Journal • PK/PD data • Beta-Thalassemia • Genetic Disorders • ASGR • TMPRSS6

Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS TMPRSS6-LRx (clinicaltrials.gov) - P2a; N=36; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting; Initiation date: Feb 2020 ➔ Jul 2020

Clinical • Enrollment open • Trial initiation date • Beta-Thalassemia • Gene Therapies • Genetic Disorders

A study to look at how effective, how safe and how well tolerated a study drug called ISIS 702843 is when given under the skin to patients with Non-Transfusion Dependent β-Thalassemia Intermedia. This study will also look at the movement of ISIS 702843 in the body and how ISIS 702843 affects the body. (clinicaltrialsregister.eu) - P2; N=36; Ongoing; Sponsor: Ionis Pharmaceuticals, Inc.

Clinical • New P2 trial