Dataset Information

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI_Rx in Patients With ESRD.

ABSTRACT:

Introduction

Patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) have an increased risk of thrombotic events and bleeding. Antisense reduction of factor XI (FXI) with IONIS-FXI_Rx is a novel strategy that may safely reduce the risk of thrombotic events.

Methods

This multicenter study enrolled 49 patients receiving HD in 2 parts. First, 6 participants (pharmacokinetics [PK] cohort) received 1 open-label 300 mg dose of IONIS-FXI_Rx both before and after HD. Subsequently, 43 participants were treated in a double-blind, randomized design with 200 mg or 300 mg IONIS-FXI_Rx or placebo for 12 weeks. The PK, pharmacodynamics (PD), and adverse events of IONIS-FXI_Rx were evaluated (ClinicalTrials.gov: NCT02553889).

Results

The PK of IONIS-FXI_Rx was consistent with previous studies and similar whether injected before or after HD. No accumulation of IONIS-FXI_Rx was observed after repeat administration. By day 85, mean levels of FXI activity fell 56.0% in the 200 mg group, 70.7% in the 300 mg group, and 3.9% in the placebo group compared with baseline. FXI antigen levels paralleled FXI activity. Dose-dependent prolongation of activated partial thromboplastin time (aPTT) was observed, with no changes in international normalized ratio (INR). IONIS-FXI_Rx was not associated with drug-related serious adverse events. In the randomized phase of the study, major bleeding events occurred in 0 (0.0%; 200 mg), 1 (6.7%; 300 mg), and 1 (7.7%; placebo) patients and were not considered related to treatment.

Conclusion

IONIS-FXI_Rx reduced FXI activity in patients with ESRD receiving HD. Further studies are needed to determine the benefit-risk profile of FXI as a therapeutic target for patients who require HD.

SUBMITTER: Walsh M

PROVIDER: S-EPMC8820988 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI<sub>Rx</sub> in Patients With ESRD.

Walsh Michael M Bethune Claudette C Smyth Andrew A Tyrwhitt Jessica J Jung Shiangtung W SW Yu Rosie Z RZ Wang Yanfeng Y Geary Richard S RS Weitz Jeffrey J Bhanot Sanjay S

Kidney international reports 20211124 2

<h4>Introduction</h4>Patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) have an increased risk of thrombotic events and bleeding. Antisense reduction of factor XI (FXI) with IONIS-FXI<sub>Rx</sub> is a novel strategy that may safely reduce the risk of thrombotic events.<h4>Methods</h4>This multicenter study enrolled 49 patients receiving HD in 2 parts. First, 6 participants (pharmacokinetics [PK] cohort) received 1 open-label 300 mg dose of IONIS-FXI<sub>Rx</sub> both befor ...[more]

PMID: 35155859

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Project description:BackgroundExperimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.MethodsIn this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.ResultsAround the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.ConclusionsThis study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).

Project description:IntroductionAKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients.Methods/designApproximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire.ConclusionNEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.Trial registrationThe study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).

Dataset Information

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI_Rx in Patients With ESRD.

Introduction

Methods

Results

Conclusion

Publications

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI<sub>Rx</sub> in Patients With ESRD.

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Dataset Information

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXIRx in Patients With ESRD.

Introduction

Methods

Results

Conclusion

Publications

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI<sub>Rx</sub> in Patients With ESRD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI_Rx in Patients With ESRD.