fesomersen (IONIS-FXI-LRx) / Ionis - LARVOL DELTA

Factor XI inhibition in hemodialysis patients: the safer anticoagulation? (PubMed, Kidney Int) - "Factor XI inhibition may provide anticoagulation, with a low risk of bleeding, and several factor XI inhibitors, including fesomersen, an antisense oligonucleotide, are under development. Recently, a phase 2 study of fesomersen showed a good safety profile in chronic hemodialysis patients and suggested that clotting rates of the arteriovenous fistula and the dialysis circuit are lower."

Journal • Cardiovascular • Renal Disease

Safety of factor XI inhibitors in patients with end-stage kidney disease on hemodialysis: A meta-analysis of randomized controlled trials (ISTH 2024) - "We identified six RCTs assessing FXI inhibitors in patients with ESKD on hemodialysis, all using placebo as comparator. Of those, one study was still ongoing, resulting in five studies investigating FXI inhibitors (IONIS-FXIRx, xisomab, fesomersen, osocimab) encompassing 1,270 patients included in our meta-analysis (table). FXI inhibitors were associated with an OR of 0.80 (95% CI, 0.49-1.32) for the occurrence of CRB compared to placebo (Fig.)."

Retrospective data • Cardiovascular • Hematological Disorders • Nephrology • Renal Disease • Thrombosis

Pharmacokinetics, pharmacodynamics, and safety of fesomersen, a novel antisense inhibitor of factor XI, in healthy Chinese, Japanese, and Caucasian volunteers. (PubMed, Clin Transl Sci) - "The PK/PD profiles after a single injection were similar among the various ethnic groups. Collectively, the study results suggest that fesomersen has a favorable safety profile and predictable and similar PK and PD profiles across Chinese, Japanese, and Caucasian participants."

Journal • PK/PD data

Drug-Drug Interactions of FXI Inhibitors: Clinical Relevance. (PubMed, Hematol Rep) - "These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa."

Journal • Review • Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • Venous Thromboembolism

A Phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis. (PubMed, Kidney Int) - "Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P = 0.002) and AV-access thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo."

Journal • P2 data • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Ischemic stroke • Myocardial Infarction • Nephrology • Renal Disease • Venous Thromboembolism

Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors. (PubMed, J Med Vasc) - "The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Based on epidemiological data with patients with inherited factor XI (FXI) deficiency and preclinical studies, FXI emerged as the most promising candidate target separating hemostasis from thrombosis. This review summaries the role of FXI and FXIa in hemostasis, provides evidence of initial success with FXI pathway inhibitors in clinical trials (such as IONIS-FXI, fesomersen, osocimab, abelacimab, milvexian, asundexian or xisomab 3G3) and highlights the opportunities and challenges for this next generation of anticoagulants."

Journal • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Venous Thromboembolism

News at XI: Moving Beyond Factor Xa Inhibitors. (PubMed, J Thromb Haemost) - "Currently available DOACs include dabigatran, which inhibits thrombin, and apixaban, edoxaban, and rivaroxaban, which inhibit factor (F) Xa...These new DOACs, which include asundexian and milvexian, inhibit FXIa, which is positioned in the intrinsic pathway of coagulation...These include fesomersen, an antisense oligonucleotide that reduces the hepatic synthesis of FXI, abelacimab, an antibody that binds FXI and blocks its activation, and osocimab, an FXIa inhibitory antibody. Focusing on these new agents, this paper (a) describes the unmet needs in oral anticoagulation therapy, (b) explains why FXI is a promising target for new oral anticoagulants, (c) reviews the phase 2 clinical data with the new agents and describes the ongoing phase 3 trials, and (d) provides perspective on the opportunities and challenges for FXI inhibitors."

Journal • Review • Cardiovascular • Hematological Disorders • Thrombosis • Venous Thromboembolism

Pharmacotherapy for stroke prevention in nonvalvular atrial fibrillation: current strategies and future directions. (PubMed, Expert Opin Pharmacother) - "Several oral (asundexian, milvexian) and parenteral (abelacimab, osocimab, xisomab, IONIS-FXI, fesomersen) factor XIa inhibitors are under development...Non-anticoagulant drugs, such as colchicine, metformin and dronedarone, also being investigated to reduce the burden of NVAF and cardioembolic stroke. Additional clinical data are needed to more clearly define the role of these drugs for stroke prevention in NVAF."

Journal • Atrial Fibrillation • Cardiovascular • Ischemic stroke

Ionis announces positive results from fesomersen development program (PRNewswire) - P2b | N=307 | RE-THINc ESRD (NCT04534114) | Sponsor: Bayer | "The RE-THINC ESRD study evaluated fesomersen in patients with end-stage renal disease (ESRD) on hemodialysis. In the study, fesomersen achieved its primary endpoint, demonstrating no increase in the incidence of the composite of major bleeding and clinically relevant non-major (CRNM) bleeding with 24 weeks of treatment. Fesomersen also achieved dose-dependent and sustained median reductions in steady-state FXI levels of 53.1%, 72.2% and 86.6% in the 40 mg, 80 mg, and 120 mg doses of fesomersen, respectively, administered once every 4 weeks....'We are very pleased with the efficacy and safety data seen in the Phase 2b study of fesomersen in patients with ESRD, which we believe supports continued advancement of this potential novel anti-thrombotic therapy for patients with renal and cardiovascular diseases."

P2b data • Cardiovascular • Thrombosis

Antithrombotic Treatment With Fesomersen vs. Placebo in Patients With ESKD on Hemodialysis (ESKD-HD) (KIDNEY WEEK 2022) - "Conclusion Fesomersen did not significantly increase the risk of bleeding in patients with ESKD-HD. Incidences of HD circuit clotting and AV-access thrombosis diminished significantly with decreasing FXI levels."

Clinical • Late-breaking abstract • Cardiovascular • Hematological Disorders • Myocardial Infarction • Venous Thromboembolism

Ionis announces positive topline results from Phase 2b clinical study of fesomersen, a potential novel anti-thrombotic treatment (PRNewswire) - P2 | N=307| RE-THINc ESRD (NCT04534114) | Sponsor: Bayer | "Phase 2b RE-THINC ESRD study of fesomersen met its primary endpoint in patients with end-stage renal disease on hemodialysis....Fesomersen, a novel Factor XI antisense inhibitor designed to prevent thrombosis, was safe and well-tolerated in the study with up to 48-week treatment....Ionis Pharmaceuticals...today announced positive topline results of the Phase 2b RE-THINC ESRD study of fesomersen, formerly IONIS-FXI-LRx, in patients with end-stage renal disease (ESRD) on hemodialysis...Data from the study show that fesomersen, administered monthly at 40 mg, 80 mg and 120 mg for up to 48 weeks, was safe and well-tolerated. Fesomersen also demonstrated substantial and statistically significant reductions in Factor XI activity levels."

P2b data • Hematological Disorders • Renal Disease

RE-THINc ESRD: Factor XI LICA to Reduce Events Such as Heart Attack and Stroke in Patients Whose Kidneys Are no Longer Able to Work as They Should and Require Treatment to Filter Wastes From the Blood: Focus is on the Safety of BAY2976217 and the Way the Body Absorbs, Distributes and Removes the Study Drug (clinicaltrials.gov) - P2 | N=307 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Chronic Kidney Disease • Myocardial Infarction • Nephrology • Renal Disease

Fesomersen: Data from P2b trial for thrombosis in H2 2022 (Ionis Pharmaceuticals) - FY 2021 Results

P2b data • Thrombosis

RE-THINc ESRD: Factor XI LICA to Reduce Events Such as Heart Attack and Stroke in Patients Whose Kidneys Are no Longer Able to Work as They Should and Require Treatment to Filter Wastes From the Blood: Focus is on the Safety of BAY2976217 and the Way the Body Absorbs, Distributes and Removes the Study Drug (clinicaltrials.gov) - P2; N=305; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Chronic Kidney Disease • Myocardial Infarction • Nephrology • Renal Disease

PK/PD modelling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "IONIS-FXI (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI and has been investigated in healthy volunteers and end-stage renal disease (ESRD) patients. FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes...The model was then used to predict dose dependent steady-state FXI activity following repeat once-monthly doses of FXI-LICA in a virtual ESRD patient population. Under the assumption of similar ASGPR expression in ESRD patients and healthy volunteers, doses of 40mg, 80mg, and 120mg FXI-LICA are expected to cover the target range of clinical interest for steady-state FXI activity in the Phase 2b study of FXI-LICA in ESRD patients undergoing hemodialysis."

Clinical • Journal • PK/PD data • Chronic Kidney Disease • Nephrology • Renal Disease • ASGR • MUC4

RE-THINc ESRD: Factor XI LICA to Reduce Events Such as Heart Attack and Stroke in Patients Whose Kidneys Are no Longer Able to Work as They Should and Require Treatment to Filter Wastes From the Blood: Focus is on the Safety of BAY2976217 and the Way the Body Absorbs, Distributes and Removes the Study Drug (clinicaltrials.gov) - P2; N=288; Recruiting; Sponsor: Bayer; Trial completion date: Sep 2022 ➔ May 2022; Trial primary completion date: May 2022 ➔ Jan 2022

Trial completion date • Trial primary completion date • Cardiovascular • Chronic Kidney Disease • Myocardial Infarction • Nephrology • Renal Disease

Ionis reports third quarter 2020 financial results and recent business achievements (Ionis Pharmaceuticals Press Release) - "Third Quarter 2020 and Recent Pipeline Highlights: IONIS-FXI-LRx advanced into Phase 2b development in patients with end-stage renal disease...IONIS-ENAC-2.5 Rx Phase 2 study in patients with cystic fibrosis....Dosing completed in the IONIS-ENAC-2.5 Rx Phase 2 study in patients with cystic fibrosis."

Enrollment closed • Trial status • Renal Disease

RE-THINc ESRD: Factor XI LICA to Reduce Events Such as Heart Attack and Stroke in Patients Whose Kidneys Are no Longer Able to Work as They Should and Require Treatment to Filter Wastes From the Blood: Focus is on the Safety of BAY2976217 and the Way the Body Absorbs, Distributes and Removes the Study Drug (clinicaltrials.gov) - P2; N=288; Recruiting; Sponsor: Bayer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Cardiovascular • Chronic Kidney Disease • Myocardial Infarction • Nephrology • Renal Disease

RE-THINc ESRD: Factor XI LICA to Reduce Events Such as Heart Attack and Stroke in Patients Whose Kidneys Are no Longer Able to Work as They Should and Require Treatment to Filter Wastes From the Blood: Focus is on the Safety of BAY2976217 and the Way the Body Absorbs, Distributes and Removes the Study Drug (clinicaltrials.gov) - P2; N=288; Not yet recruiting; Sponsor: Bayer

Clinical • New P2 trial • Cardiovascular • Chronic Kidney Disease • Myocardial Infarction • Nephrology • Renal Disease

Ionis up after cardio-renal pipeline update (SeekingAlpha) - "Ionis Pharmaceuticals (IONS +1.3%) is slightly ahead of the broad market advance following its update on its cardio-renal franchise. Highlights: Company expects to file at least 10 marketing applications through 2025....Licensee Bayer to launch Phase 2b study evaluating anti-thrombotic IONIS-FXI-Lrx in patients with end-stage renal disease on dialysis this year."

Trial initiation date

IONIS-FXI-LRx: Initiation of P2b RE-THINc ESRD (NCT04534114) trial in patients with end stage renal disease in 2020 (Ionis Pharmaceuticals) - Cardio-Renal Franchise Webcast

Trial initiation date • Renal Disease

Ionis Pharmaceuticals to hold cardio-renal franchise webcast (Ionis Pharmaceuticals Press Release) - "Ionis Pharmaceuticals, Inc....announced today that it will host a live webcast on Wednesday, September 2nd at 10:00 a.m. Eastern Time to review its cardio-renal franchise. The approximately 90-minute webcast will include presentations...The agenda for the webcast will be as follows: Thrombosis: IONIS-FXI-LRx."

Clinical • Live event

Ionis reports second quarter 2020 financial results and recent business achievements - "Ionis Pharmaceuticals, Inc....today reported its financial results for the second quarter of 2020 and recent business highlights....Upcoming Catalysts: Initiate a Phase 2 study of IONIS-FXI-LRx in patients with clotting disorders."

New P2 trial

Factor XI LICA to reduce thrombotic events such as heart attack and stroke in patients whose kidneys are no longer able to work as they should and require treatment to filter wastes from the blood. Focus is on the safety of BAY2976217, and the way the body absorbs, distributes and gets rid of the study dug given as multiple doses (clinicaltrialsregister.eu) - P2; N=340; Ongoing; Sponsor: Bayer AG

Clinical • New P2 trial • Cardiovascular • Chronic Kidney Disease • Myocardial Infarction • Nephrology • Renal Disease

Ionis, Akcea confirmation with hypertriglyceridemia results (SeekingAlpha) - "In the fourth quarter of 2019, Ionis expects to recognize substantially all of the $250 million upfront payment...$10 million from Bayer for advancing IONIS-FXI-LRx. This will add to the cash balance but will produce a lump that will be hard to push beyond for Q1 2020."

Financing