Delving into the Latest Updates on Asundexian with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Factor XIa

Mechanism

factor XIa inhibitors(factor XIa inhibitors)

Therapeutic Areas

Nervous System DiseasesCardiovascular Diseases

Active Indication

Acute Ischemic StrokeIschemic Attack, TransientBrain Ischemia+ [3]

Inactive Indication

Acute myocardial infarctionAtrial FibrillationBlood Coagulation Disorders+ [3]

Originator Organization

Bayer AG

Active Organization

Bayer AG

Inactive Organization

Bayer Healthcare Co., Ltd.

Drug Highest PhasePhase 3

First Approval Date-

RegulationFast Track (US)

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Structure

Molecular FormulaC26H21ClF4N6O4

InChIKeyXYWIPYBIIRTJMM-IBGZPJMESA-N

CAS Registry2064121-65-7

The OCEANIC-AF trial was terminated early due to inferiority of asundexian compared with apixaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation.¹ However, the promisingly low bleeding rates support continued exploration of factor XIa inhibitors. Future efforts should focus on achieving greater factor XIa inhibition and identifying patient populations that may benefit most from these therapies.

01 Oct 2024·American Heart Journal Plus: Cardiology Research and Practice

OCEANIC-AF and the inferior efficacy of asundexian compared to apixaban in patients at high risk with atrial fibrillation: Have we come to the end of the road for factor XIa inhibitors?

Article

Author: Nakhle, Asaad ; Ferdinand, Keith C ; Ferdinand, Keith C.

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.

40

News (Medical) associated with Asundexian

31 Oct 2024

·endpts.com

‘Imitation is best form of flattery’: Regeneron CEO comments on Amgen’s Eylea biosimilar

Regeneron might be ready for competition with its blockbuster drug Eylea, but it’s not clear that investors are. On Thursday morning, the biotech’s leadership fielded question after question about the strength of the eye drug franchise, asking about upcoming competition from Amgen’s biosimilar and mixed revenue results in the third quarter. The company’s overall sales for its Eylea franchise beat the Wall Street expectations by 2% in the third quarter. But the newer version of the drug, Eylea HD, missed by 8%. The stock $REGN was down about 10% in reaction to the results. Things may not get much better three months from now. Last week, Amgen announced it was preparing to launch an Eylea biosimilar years early after winning a legal case against Regeneron in an appeals court. Regeneron has long dominated the market, with the company delivering “somewhere in the neighborhood” of 100 million Eylea injections, CEO Leonard Schleifer said on Thursday’s earnings call. “They say imitation is the best form of flattery, so we’re glad to be flattered by Amgen that they’re spending their time imitating our products,” Schleifer said on the call. “We’re spending our money trying to bring new products to market, which we think is what this industry really is built for. Biosimilars are fine, but we think the industry is built, and Regeneron is best built, to bring innovative products to market.” Regeneron has never been shy about its lack of interest in developing biosimilars, even as other large biotechs have pursued the market. Schleifer and CSO George Yancopoulos co-founded Regeneron in the late 1980s and remain atop the drugmaker’s board, making them one of the longest-standing scientist-led biotechs in the industry. “We know that there is a biosimilar in the market for Eylea, not Eylea HD. And we know it will be competitive, but we think we’ll be able to compete,” Schleifer said. Regeneron has more than 40 drugs in clinical development, Schleifer emphasized on the call. It did cull one asset in the quarter, however: REGN6569, a GITR monoclonal antibody in Phase 1 for solid tumors, a company spokesperson confirmed to Endpoints News . Meanwhile, Regeneron said it could move two factor XI inhibitors into pivotal trials early next year and plans to report proof-of-concept results before the end of this year. Factor XI drugs aim to take advantage of genetic data showing patients with factor XI deficiency — which in some cases can cause a form of bleeding risk — have reduced incidence of myocardial infarction, stroke and other cardiovascular problems. The factor XI field has had its ups and downs. Bayer stopped a large Phase 3 in atrial fibrillation last year but is still pushing ahead with asundexian in other late-stage testing . Johnson & Johnson and Bristol Myers Squibb’s milvexian is also in late-stage testing, as is Blackstone-backed Anthos Therapeutics . Regeneron’s factor XI work includes an A2 domain-focused asset codenamed REGN9933 and a catalytic domain drug called REGN7508. “Our A2 domain antibody is not a complete blocker of factor XI. It actually is more like a complete factor XII blocker. It’s expected to not have as profound an effect on the coagulation pathways but to have a much milder safety profile,” Yancopoulos said on the call. “In contrast, we believe that our catalytic domain antibody is the best-in-class blocker of factor XI. It will come with the best ability to control coagulation among all agents that are attacking this pathway.” The company also said it anticipates finishing enrollment in its Phase 2 obesity trial, which is focused on preserving muscle mass in patients on Novo Nordisk’s semaglutide. Regeneron plans to have results in the second half of 2025 for the study, which is testing an anti-myostatin called trevogrumab in addition to semaglutide with and without the anti-activin A known as garetosmab. “The simplest regulatory will be just by increasing the actual weight loss and then you’ll be able to show secondary endpoints that you’re doing better on composition of weight loss as well,” Yancopoulos said. “That said, we are going to be measuring metabolic parameters and we’re also going to be measuring functional outputs as well.”

Phase 1Phase 2Phase 3

03 Sep 2024

·endpts.com

Researchers seek answers as they spell out Phase 3 failure of Bayer’s next-gen anticoagulant

Researchers reported Sunday that atrial fibrillation patients who received Bayer’s experimental anticoagulant were significantly more likely to experience a stroke or systemic embolism compared to those who got Eliquis. The company in November announced that it stopped its 14,810-person OCEANIC-AF study early due to asundexian’s inferior efficacy, a concerning result for what Bayer called a landmark clinical trial program. In the Phase 3 clinical trial, 98 patients who received asundexian had a stroke or systemic embolism compared to 26 in the control arm who got the anticoagulant Eliquis, also known as apixaban. That resulted in a hazard ratio of 3.79 — an outcome that no drug developer ever wants to see. Atrial fibrillation is a type of irregular and often fast heartbeat. People with atrial fibrillation take anticoagulants as a form of stroke prevention, but the currently marketed anticoagulants — direct-acting oral anticoagulants, or DOACs — come with a risk of bleeding. Bayer and other drug companies have now turned to a class of experimental treatments called factor XI inhibitors, which they hope could provide the same level of stroke and blood clot prevention without the bleeding risk. On the safety front, 17 patients experienced major bleeds on asundexian compared to 53 on Eliquis. Johnson & Johnson and Bristol Myers Squibb are developing a factor XI inhibitor called milvexian and have put together a similarly massive clinical trial program. Meanwhile, Novartis and Blackstone-backed Anthos Therapeutics are developing a once-monthly antibody treatment also targeted at factor XI. Both are in late-stage trials. The OCEANIC-AF trial results were shared at the European Society of Cardiology’s annual meeting and published in the New England Journal of Medicine . The co-authors of the NEJM study, led by Duke professor of medicine Jonathan Piccini, floated several possibilities as to why asundexian led to higher levels of stroke or blood clots compared to Eliquis. They started with the most straightforward explanation, writing that “it is possible that factor XIa inhibition with asundexian does not lead to effective stroke prevention as compared with apixaban in patients with atrial fibrillation.” The study authors also suggested that “escape mechanisms may play an important role, especially in patients with atrial fibrillation being transitioned from ongoing oral anticoagulation.” The basis for targeting factor XI comes from data that show people with natural factor XI deficiency may have a lower risk for stroke and blood clots. Another potential explanation was that the once-daily 50 mg of asundexian is not a high enough dose. In a Phase 2 trial, the 50 mg dose led to a 92% to 94% reduction in factor XI activity, but perhaps “complete or near complete (>99%) suppression of factor XIa may be required,” the researchers wrote. They concluded by adding that the incidence of stroke in the control arm was significantly lower than predicted or seen in the key trial behind Eliquis’ approval over a decade ago. “The findings of the OCEANIC-AF trial are probably attributable to a combination of these factors,” the study authors wrote. Bayer is running a separate Phase 3 study called OCEANIC-STROKE, but announced in November it is reevaluating plans for a third Phase 3 study called OCEANIC-AFINA.

Phase 3Phase 2Clinical Result

02 Sep 2024

·firstwordpharma.com

ESC24: Bayer details extent of asundexian fail in atrial fibrillation trial

Full results from the OCEANIC-AF study reveal the extent to which Bayer's oral factor XIa inhibitor asundexian fell short when put up against leading factor Xa inhibitor Eliquis (apixaban) in preventing strokes and systemic embolism in patients with atrial fibrillation (AF). The results were unveiled at the European Society of Cardiology (ESC) Congress on Sunday.The Phase III study was stopped prematurely last year on the advice of an independent data monitoring committee due to the "inferior efficacy" of asundexian, triggering a 20% share drop for Bayer when the announcement was made in November.Higher risk of stroke, embolismPreventing strokes in AF patients using with direct-acting oral anticoagulants often comes with a risk of bleeding. It was hoped that asundexian, which targets the XIa clotting factor, might reduce the risk of strokes while causing less bleeding.The OCEANIC-AF trial included 14,810 high-risk patients with AF randomised to receive asundexian at a dose of 50 mg once daily or standard-dose Eliquis. However, according to results detailed at the ESC conference and also simultaneously published in the NEJM, stroke or systemic embolism occurred in 98 patients (1.3%) receiving asundexian, compared to just 26 patients (0.4%) on Eliquis.Cardiovascular deaths happened in 48 (0.6%) patients taking asundexian and 44 (0.6%) of those in the Eliquis arm. Deaths from any cause were slightly lower with Bayer's drug, occurring in 60 (0.8%) patients from the asundexian group and 71 (1.0%) of those given Eliquis.Lower bleeding riskAlthough then drug did appear to less likely to cause major bleeding. Seventeen (0.2%) of patients taking asundexian experienced major bleeding in the trial, versus 53 (0.7%) who had been given Eliquis."Our results show that the dose of asundexian tested was inferior for stroke or systemic embolism compared with apixaban," stated principal investigator Manesh Patel. "We could speculate that near-total factor XIa suppression may be needed to prevent thrombus formation." Prior to the presentation, Jefferies analysts also suggested that the dose of asundexian used in the trial may have been too low to achieve the necessary levels of factor XIa inhibition.Researchers writing in the NEJM paper on OCEANIC-AF highlighted an earlier trial – PACIFIC-AF – in which asundexian at a dose of 50 mg once daily resulted in a 94% reduction in factor XI activity at peak concentrations. "However, to effectively prevent thrombus formation, complete or near complete (>99%) suppression of factor XIa may be required," the authors wrote.The failure of asundexian in the OCEANIC-AF trial was a significant setback for Bayer, with analysts having suggested previously that the AF indication represented around €4 billion ($4.4 billion) of the €5.5 billion ($6.1 billion) peak sales estimate for the drug. The late-stage programme also includes the OCEANIC-STROKE trial, which is testing asundexian for preventing stroke caused by a clot in people after an acute ischaemic stroke or high-risk transient ischaemic attack, a so-called mini stroke. The study is expected to wrap in October of next year.

Clinical ResultPhase 3

100 Deals associated with Asundexian

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Ischemia	Phase 3	-	Bayer AG	31 Aug 2022
Embolism	Phase 3	-	Bayer AG	31 Aug 2022
Stroke	Phase 3	-	Bayer AG	31 Aug 2022
Systemic embolism	Preclinical	KR	Bayer AG	05 Dec 2022
Systemic embolism	Preclinical	GR	Bayer AG	05 Dec 2022
Systemic embolism	Preclinical	LV	Bayer AG	05 Dec 2022
Systemic embolism	Preclinical	CZ	Bayer AG	05 Dec 2022
Systemic embolism	Preclinical	FI	Bayer AG	05 Dec 2022
Systemic embolism	Preclinical	RO	Bayer AG	05 Dec 2022
Systemic embolism	Preclinical	CO	Bayer Healthcare Co., Ltd.	05 Dec 2022

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


OCEANIC-AF (NEWS) Manual	Phase 3	Atrial Fibrillation	-	asundexian	ajszqcdosd(hvwxwytdis) = Bayer is stopping a pivotal clinical trial for its experimental treatment for atrial fibrillation at the recommendation of an independent committee that concluded the drug would not be more effective than a Bristol Myers Squibb and Pfizer product widely used to treat the heart condition. ibjjuzmbut (vmomrlmztk )	Negative	20 Nov 2023
				Eliquis
NCT04304508 (PACIFIC-STROKE, CTgov)	Phase 2	Thrombosis \| Acute Ischemic Stroke	1,808	Asundexian (BAY2433334) (Asundexian 10 mg)	ulzashgtxx(kpcebjjhzq) = cnimiwhtib kfpiqzgavn (fpgqdbpfnt, uyaynhnenw - gaodeprlbl) View more	-	19 Apr 2023
				Asundexian (BAY2433334) (Asundexian 20 mg)	ulzashgtxx(kpcebjjhzq) = qoaaypnaeh kfpiqzgavn (fpgqdbpfnt, qmgqymbosf - vblnpvjahb) View more
NCT04304534 (PACIFIC-AMI, CTgov)	Phase 2	Acute myocardial infarction	1,601	Asundexian (BAY2433334) (Asundexian 10 mg)	adtbncppuk(nfusvcdben) = vkaboxzyzx uccgooqkeu (dfvjoqhvgo, rlrmwykkde - ytnyzkfrdm) View more	-	05 Apr 2023
				Asundexian (BAY2433334) (Asundexian 20 mg)	adtbncppuk(nfusvcdben) = fmqgimiryn uccgooqkeu (dfvjoqhvgo, yrttqnyvaf - dmgtvvawtq) View more
NCT04218266 (PACIFIC-AF, CTgov)	Phase 2	Complication \| Atrial Fibrillation	755	Apixaban+Asundexian (BAY2433334) (Asundexian 20 mg)	tzceiubcqf(lwpethopdd) = zrvqzwnzbd hrbpguxjic (lcvfmzvpor, jboyowctvt - lidbwpmlqw) View more	-	27 Oct 2022
				Apixaban+Asundexian (BAY2433334) (Asundexian 50 mg)	tzceiubcqf(lwpethopdd) = npvqmrrbli hrbpguxjic (lcvfmzvpor, fzyzfzkcwr - orqyxlvpqs) View more
NCT04304508 (PACIFIC-Stroke, Pubmed \| Lancet)	Phase 2	Acute Ischemic Stroke	1,808	Asundexian 10 mg	iyjrqtzbbi(hjrqdhonxu) = lnwortbica sofcvdiaim (wkynmcpjgb, 0.79 - 1.24) View more	Negative	02 Sep 2022
				Asundexian 20 mg	iyjrqtzbbi(hjrqdhonxu) = xkokcxctmr sofcvdiaim (wkynmcpjgb, 0.93 - 1.43) View more
ESC2022	Not Applicable	-	59	Asundexian	ckorhjzijb(ykasztxqiu) = qjyotfyomv izlohislvu (hftwsjilxn )	-	29 Aug 2022
NCT04304534 (Pubmed)	Phase 2	Acute myocardial infarction	1,601	Asundexian 10 mg	(evlcroizah) = svxphyqqdg lbadajbzhx (lxrmlcfkjg ) View more	Positive	27 Aug 2022
				Asundexian 20 mg	(evlcroizah) = pvoqjbkxer lbadajbzhx (lxrmlcfkjg ) View more
NCT04218266 (PACIFIC-AF, Pubmed \| Lancet)	Phase 2	Atrial Fibrillation	862	Asundexian 20 mg	(ddypnjptht) = The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. fwiurbxzmw (tetmczmaqk )	Positive	01 Apr 2022
				Asundexian 50 mg
ISTH2020	Phase 1	-	-	BAY 2433334	(zipvysllpy) = wxzrtrwkae zqaymneuuq (yylwirfrxe )	-	12 Jul 2020