sapablursen (IONIS-TMPRSS6-Lrx) / Ionis, Ono Pharma - LARVOL DELTA

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

Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS TMPRSS6-LRx (clinicaltrials.gov) - P2a; N=36; Not yet recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Trial completion date: Feb 2023 ➔ Oct 2022; Initiation date: Nov 2019 ➔ Feb 2020; Trial primary completion date: May 2021 ➔ Aug 2021

Clinical • Trial completion date • Trial initiation date • Trial primary completion date

Bench to bedside strategies demonstrate Ionis' foremost expertise in RNA-targeted therapeutics at DIA/FDA Oligonucleotide Conference (Ionis Pharmaceuticals Press Release) - "Ionis Pharmaceuticals, Inc....will give presentations highlighting antisense medicines for neurological diseases and two LIgand Conjugated Antisense (LICA) medicines...IONIS-TMPRSS6-LRx at the DIA/FDA Oligonucleotide-Based Therapeutics Conference in North Bethesda, Maryland, Oct. 28-30, 2019."

Clinical data

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

Clinical • New P2a trial

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 702843 Administered Subcutaneously to Healthy Volunteers (clinicaltrials.gov) - P1; N=36; Completed; Sponsor: Ionis Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Feb 2019 ➔ Sep 2018; Trial primary completion date: Feb 2019 ➔ Sep 2018

Clinical • Trial completion • Trial completion date • Trial primary completion date