A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ISIS 416858 (IONIS-FXIRX, an Antisense Inhibitor of Factor XI), Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis

Evaluation of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ISIS 416858 for up to 204 participants with ESRD receiving chronic hemodialysis as assessed by FXI activity reduction.

Start Date26 Dec 2017

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

[+1]

NCT02553889

/ CompletedPhase 2

A Phase 2, Randomized, Double Blind, Placebo Controlled Study of the Safety, PK, and PD of Multiple Doses of ISIS 416858 (ISIS-FXI RX), Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis

Evaluation of safety, tolerability, PK and PD of ISIS 416858 in patients with end-stage renal disease (ESRD) receiving chronic hemodialysis.

Start Date01 Oct 2015

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

[+1]

EUCTR2012-001836-72-BG

/ Not yet recruitingNot Applicable

An Open-label, Randomized, Active Comparator-Controlled, Adaptive Parallel-group Phase 2 Study to Assess the Safety and Efficacy of Multiple Doses of ISIS 416858 Administered Subcutaneously to Patients Undergoing Total Knee Arthroplasty

Start Date25 Jan 2013

Sponsor / Collaborator

Ionis Pharmaceuticals, Inc.

100 Clinical Results associated with IONIS-FXIRX

100 Translational Medicine associated with IONIS-FXIRX

100 Patents (Medical) associated with IONIS-FXIRX

Literatures (Medical) associated with IONIS-FXIRX

01 Jan 2025·Kidney International Reports

A Systematic Review of Safety and Efficacy of Factor XI/XIa Inhibitors in Patients With ESKD on Hemodialysis

Article

Author: Königsbrügge, Oliver ; Ay, Cihan ; Steiner, Daniel ; Kraemmer, Daniel ; Nopp, Stephan

IntroductionFactor XI/XIa (FXI/XIa) has emerged as a potential target for antithrombotic therapy, driven by preclinical evidence showing the role of FXI/XIa inhibition for preventing thrombosis without impeding hemostasis. This is particularly promising for patients at high risk of both thromboembolic events and bleeding, such as patients with end-stage kidney disease (ESKD) on hemodialysis (HD).MethodsWe systematically searched Embase, MEDLINE, and ClinicalTrials.gov for randomized controlled trials evaluating FXI/XIa inhibitors in patients with ESKD on HD, without restricting inclusion to specific comparators or indications. Interventional treatment arms were pooled, and study results were synthesized by fitting random-effects models, calculating odds ratios (ORs) and 95% confidence intervals (CIs).ResultsFive phases 2 studies encompassing 1270 participants were identified, investigating gruticibart, IONIS-FXI_Rx, osocimab, or fesomersen in the general HD population and using placebo as a comparator. Four studies were fully published and included in the meta-analysis. Use of FXI/XIa inhibitors was associated with an OR of 0.80 (95% CI = 0.47-1.35) for clinically relevant bleeding, 0.51 (95% CI = 0.21-1.28) for major bleeding, and 0.90 (95% CI = 0.49-1.68) for clinically relevant nonmajor bleeding. The ORs for thromboembolic events and all-cause mortality were 0.66 (95% CI = 0.28-1.56) and 0.46 (95% CI = 0.15-1.40), respectively.ConclusionCurrently available evidence does not indicate a significantly increased bleeding risk of FXI/XIa inhibitors in patients with ESKD on HD compared to placebo. Their efficacy and their association with all-cause mortality need to be investigated in sufficiently powered, randomized controlled phase 3 trials.

01 Sep 2024·Drugs

Therapeutic Potential of FXI Inhibitors: Hype or Hope?

Review

Author: Occhipinti, Giovanni ; Rollini, Fabiana ; Capodanno, Davide ; Brugaletta, Salvatore ; Franchi, Francesco ; Ortega-Paz, Luis ; Sciarretta, Sebastiano ; Galli, Mattia ; Angiolillo, Dominick J

Significant advancements have shaped the landscape of anticoagulant therapy in the past two decades, including the introduction of direct oral anticoagulants (DOACs), characterized by favorable safety and efficacy profiles and reduced drug-to-drug or food interaction resulting in excellent patient compliance. However, residual concerns still exist with standard-of-care anticoagulant therapy, including the inability to use DOACs in several clinical settings and the need to further reduce the risk of bleeding. Recent improvements in the understanding of the mechanisms behind thrombus formation have led to the awareness that the intrinsic pathway of the coagulation cascade may play an important role in pathological thrombosis, but not in hemostasis. This has represented the rationale for targeting this pathway with factor XI (FXI) inhibitors, with the aim of uncoupling hemostasis and thrombosis. Clinical evidence from patients with FXI deficiency further supports this concept. A number of compounds with different mechanisms of action have been developed to target FXI (i.e., asundexian, abelacimab, Ionis-FXIRx, milvexian, osocimab, and Xisomab 3G). To date, the majority of available trials have not gone beyond completion of phase 2 and results are conflictive making it difficult to appraise the clinical benefit of these compounds in the different clinical settings where they have been tested (i.e., atrial fibrillation, acute ischemic stroke, acute myocardial infarction, end-stage renal disease, total knee arthroplasty). Moreover, the largest phase 3 randomized trial designed to test the efficacy of asundexian over apixaban in patients with atrial fibrillation, the OCEANIC-AF, has been prematurely stopped as a result of the inferior efficacy of asundexian. In this review we discuss the pharmacological properties and available evidence generated thus far for factor XI inhibitors, providing a perspective on the current state of these drugs.

01 Jun 2023·Thrombosis and Haemostasis

Factor XI Inhibitors in Early Clinical Trials: A Meta-analysis

Review

Author: D'Amario, Domenico ; Mehran, Roxana ; Rollini, Fabiana ; Capodanno, Davide ; Tremoli, Elena ; Laborante, Renzo ; Galli, Mattia ; Angiolillo, Dominick J. ; Ortega-Paz, Luis ; Franchi, Francesco ; Gibson, Charles Micheal

Background Phase II randomized controlled trials (RCTs) on factor(F)XI inhibitors have shown promising results but they were burdened by low statistical power for clinical outcomes. Methods We performed a systematic review and meta-analysis of RCT comparing FXI inhibitors versus other anticoagulants (enoxaparin or direct oral anticoagulants, DOACs) or versus placebo on top of antiplatelet therapy. Results Eight RCTs testing FXI inhibitors (ISIS 416858, osocimab, abelacimab, milvexian, asundexian) and enrolling 9,216 patients were included. Compared with enoxaparin, FXI inhibitors were associated with reduced any-bleeding (risk ratio [RR]: 0.49, 95% confidence interval [CI]: 0.31–0.77), no difference in major bleeding (RR: 0.96, 95% CI: 0.41–2.28), and reduced trial-defined efficacy endpoint (RR: 0.62, 95% CI: 0.49–0.79), the latter driven by the high-dose regimens. Compared with DOACs, FXI inhibitors were associated with a trend toward reduced any-bleeding (RR: 0.66, 95% CI: 0.31–1.38) and no difference in major bleeding (RR: 1.03, 95% CI: 0.22–4.78) or in trial-defined efficacy endpoint (RR: 1.23, 95% CI: 0.88–1.70). Compared with placebo, FXI inhibitors were associated with increased any-bleeding (RR: 1.25, 95% CI: 1.08–1.43) and a trend toward increased major bleeding (RR: 1.21, 95% CI: 0.75–1.93), both driven by high-dose regimens, with no difference in trial-defined efficacy endpoint (RR: 1.02, 95% CI: 0.92–1.13). Conclusion Results of this meta-analysis on FXI inhibitors suggest increased safety and efficacy compared with enoxaparin and modest increased safety compared with DOACs. The use of FXI inhibitors in adjunct to antiplatelet therapy versus placebo appears to be associated with a dose-dependent increase in bleeding without any difference in efficacy. Study registration This study is registered in PROSPERO (CRD42022367706).

News (Medical) associated with IONIS-FXIRX

03 Aug 2015

·www.biospace.com

Isis Pharma Nabs $65 Million Upfront in Antisense Deal With AstraZeneca PLC

August 3, 2015 By Alex Keown , BioSpace.com Breaking News Staff CARLSBAD, Calif. – Isis Pharmaceuticals, Inc. and AstraZeneca PLC inked a deal to develop antisense therapies for cardiovascular, metabolic and renal diseases, the companies jointly announced this morning. This marks a continued trend for Isis to collaborate with a large pharmaceutical company to develop antisense therapies. As part of the deal, London-based AstraZeneca will pay Isis $65 million in upfront monies, plus milestone payments from any drug from the collaboration AstraZeneca is able to advance through clinical development. California-based Isis will be eligible to earn tiered double-digit royalties on annual net sales for each program, the company said in a statement. B. Lynne Parshall , Isis ’ chief operating officer, said the new collaboration with AstraZeneca will help broaden the application of the company’s antisense technology to targets in the kidney. “This new collaboration with AstraZeneca is committed to finding novel best-in-class therapies for some of the largest, most complex and fastest growing disease segments in the developed world,” Parshall said in a statement. Isis ’ stock was up slightly in pre-market trading following the news of the collaboration with AstraZeneca . The stock closed Friday at $54.93 per share. AstraZeneca’s stock is up slightly in early morning trading, opening at $33.85 per share. Mene Pangalos , vice president of innovative medicines and early development at AstraZeneca , said in a statement that antisense-based therapies have become an important part of the company’s early stage pipeline. Pangalos said the combination of Isis’ antisense drug research and AstraZeneca ’s “expertise in cardiovascular, metabolic and renal disease drug discovery and development” will drive the development of clinical research. Antisense drugs are short, chemically modified, single-stranded nucleic acids (antisense oligonucleotides) that have the ability to target any gene product of interest. Antisense drugs offer opportunities for therapeutic intervention because they act inside the cell to influence protein production by targeting RNA to prevent the production of disease-causing proteins, increase the production of proteins deficient in disease, or target toxic RNAs that are unable to generate proteins, Isis said. Stanley T. Crooke , Isis ’ chief executive officer, told the San Diego Union-Tribune the partnership with AstraZeneca will allow Isis to gain significant experience in kidney therapeutics. “We use transactions with big pharma to move the (antisense) technology into new spaces,” Crooke told the Union-Tribune . “We have experience in the kidney, but one of the objectives in this collaboration is to really learn about ASOs in the kidney, what they can do, what they can’t do, where they can go, and really get into that in depth.” The collaboration with AstraZeneca is another major collaborative deal for Isis . The company also has an antisense alliance with Biogen, Inc. to advance the treatment of neurological and neuromuscular disorders. In April Isis earned $10 million in milestone payments from the Boston-based pharmaceutical company associated with the validation of an undisclosed target to treat a neurological disorder. This is the ninth program to advance, which includes four drugs in development, under Isis’ and Biogen ’s alliance. Isis has four drugs in development with Biogen , including ISIS-SMNRx, ISIS-DMPK-2.5Rx and two drugs to undisclosed targets, the company said. Parshall said to date the Biogen deal has generated $329 million. Also in April Isis inked a deal with Bayer HealthCare to develop and market ISIS-FXIRx, a treatment and preventative for thrombosis. Isis has other collaborative deals with the likes of GlaxoSmithKline , Genzyme Corporation and Roche to develop drugs.

OligonucleotideLicense out/in

04 May 2015

·www.biospace.com

Isis Pharma Inks $155 Million Bayer Deal Just After Good News From Biogen Collaboration

May 4, 2015 By Mark Terry , BioSpace.com Breaking News Staff Carlsbad, Calif.-based Isis Pharmaceuticals, Inc. inked a $155 million deal with Bayer HealthCare to develop and market ISIS-FXIRx, a treatment and preventative for thrombosis. The deal is structured so that Isis will receive an upfront payment of $100 million, with another $55 million when the program moves out of a Phase II study. Additional milestone payments are included, as well as tiered royalties. Bayer will take on global clinical development, as well as global regulatory and commercialization responsibilities. ISIS-FXIRx targets Factor XI, a chemical produced by the liver that is a major component in blood clotting. Individuals with high levels of Factor XI are at increased risk of heart attacks and strokes. In a Phase II trial, patients treated with ISIS-FSIRx had a seven-fold lower rate of venous thromboembolic events (VTEs) than patients treated with enoxaparin. “This first-in-class FXI inhibitor perfectly complements our in-house thrombosis pipeline and is an innovative development candidate for a variety of anti-coagulation needs,” said Joerg Moeller , member of the Bayer HealthCare Executive Committee and Head of Global Development in a statement. “We believe the novel mechanism of Factor XI inhibition may offer an additional pathway for treating patients for whom there are currently no suitable therapeutic options available.” Isis is on a roll, having announced on April 30 that it had earned a $10 million milestone payment from Biogen related to the validation of an unidentified target used to treat a neurological disorder. The two companies signed a broad strategic alliance in 2012, which has successfully advanced nine programs, including four drugs that are in development. “Together with Biogen, Inc. , we have made significant progress advancing multiple programs,” said B. Lynne Parshall , chief operating officer of Isis in a statement. “In our pipeline, we have four drugs in development with Biogen , including ISIS-SMNRx, ISIS-DMPK-2.5Rx and two drugs to undisclosed targets. In addition, we have a number of earlier stage programs, like this one, that we will be advancing this year. To date, we have generated $329 million in payments from our broad collaboration with Biogen .” Which including the $155 million from Bayer , makes a whopping $484 million. ISIS will release its first quarter earnings tomorrow, May 5. Analyst are projecting earnings per share of ($0.21) and revenue of $52.74 million for the quarter. Zacks analysts have downgraded ISIS shares from “buy” to “hold.” Based on a research note from March 17, analysts at Janney Montgomery Scott set a “neutral” rating. Analysts at TheStreet upgraded their rating from “sell” to “hold” on March 5. The company’s stock has been on an overall increase since May 20, 2014, when it sold for $23.58. It peaked on April 19, 2015 with a price of $77.08. ISIS stock is currently selling for $61.00. Will Hungry Pfizer Make a Play for Struggling GlaxoSmithKline? Almost a year after its $119 billion offer for AstraZeneca PLC fell apart in the face of massive opposition from regulators and internal dissent, global drugmaker Pfizer Inc. is once again being floated as a potential buyer of another marquee-name British pharmaceutical company: GlaxoSmithKline . We at BioSpace want to know your thoughts: With cash to burn, will Pfizer go hunting for Glaxo? var _polldaddy = [] || _polldaddy; _polldaddy.push( { type: "iframe", auto: "1", domain: "biospace.polldaddy.com/s/", id: "will-hungry-pfizer-make-a-play-for-struggling-glaxo", placeholder: "pd_1430715615" } ); (function(d,c,j){if(!document.getElementById(j)){var pd=d.createElement(c),s;pd.id=j;pd.src=(' '==document.location.protocol)?' ':' ';s=document.getElementsByTagName(c)[0];s.parentNode.insertBefore(pd,s);}}(document,'script','pd-embed'));

Phase 2License out/in

100 Deals associated with IONIS-FXIRX

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Kidney Failure, Chronic	Phase 2	Canada	Ionis Pharmaceuticals, Inc.	01 Oct 2015
Venous Thromboembolism	Phase 2	-	Bayer AG	-
Thrombosis	Discovery	Spain	Ionis Pharmaceuticals, Inc.	-
Thrombosis	Discovery	Canada	Ionis Pharmaceuticals, Inc.	-
Thrombosis	Discovery	Austria	Ionis Pharmaceuticals, Inc.	-
Thrombosis	Discovery	Canada	Bayer AG	-
Thrombosis	Discovery	Austria	Bayer AG	-
Thrombosis	Discovery	Spain	Bayer AG	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03358030 (EMERALD, CTgov)	Phase 2	Kidney Failure, Chronic	213	Placebo (Placebo)	qqjrblgflr(ibotfnnnfh) = heohxdvbey xxvqyybnvu (fzcqdhjuui, oqyukyqwpt - jbhyzejgck) View more	-	20 Jan 2023
				ISIS 416858 (Cohort A: ISIS 416858, 200 mg)	qqjrblgflr(ibotfnnnfh) = vsuhjpjsfh xxvqyybnvu (fzcqdhjuui, thkgnadknj - bsabxdvdnb) View more

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