otamixaban (XRP0673) / Sanofi - LARVOL DELTA

Liver injury from direct oral anticoagulants. (PubMed, World J Hepatol) - "DOACs are increasingly used for various clinical conditions, and DILI secondary to DOACs is a rare but potentially serious complication. Prompt identification and cessation of the offending drug are crucial for the management of DILI. Most patients with DILI secondary to DOACs have a favourable outcome, but a small proportion may progress to liver failure and death. Further research, including post-marketing population-based studies, is needed to better understand the incidence and risk factors for DILI secondary to DOACs."

Journal • Hepatology • Inflammation • Liver Failure

Clinical Significance of Culprit Vessel Occlusion in Patients With Non-ST-Elevation Myocardial Infarction Who Underwent Percutaneous Coronary Intervention. (PubMed, Am J Cardiol) - "We performed a post hoc analysis of the TAO (Treatment of Acute Coronary Syndrome with Otamixaban) randomized trial, which included patients with NSTEMI with systematic coronary angiography within 72 hours...In conclusion, a significant proportion of patients with NSTEMI have a totally occluded culprit vessel at presentation. These patients are at higher risk of early mortality but not at 6 months."

Journal • Acute Coronary Syndrome • Cardiovascular • Myocardial Infarction • Thrombosis

Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19. (PubMed, ACS Infect Dis) - "Of the six molecules advanced for further studies, two are approved drugs in Japan (camostat and nafamostat), two have entered clinical trials (PCI-27483 and otamixaban), while the other two molecules are peptidomimetic inhibitors of TMPRSS2 taken from the literature that have not advanced into clinical trials (compounds 92 and 114). This work demonstrates a suite of assays for the discovery and development of new inhibitors of TMPRSS2."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties. (PubMed, Chem Sci) - "Dominant molecular TMPRSS2-otamixaban interactions are assessed by extensive 109 μs of atomistic molecular dynamics simulations. Our findings suggest that combinations of otamixaban with supplemental camostat or nafamostat are a promising option for the treatment of COVID-19."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Outcomes in non-ST-segment elevation myocardial infarction patients according to heart failure at admission: Insights from a large trial with systematic early invasive strategy. (PubMed, Eur Heart J Acute Cardiovasc Care) - "Non-ST-segment elevation myocardial infarction patients with heart failure at admission still have worse outcomes than those without heart failure, even with systematic early invasive strategy. Further efforts are needed to improve the prognosis of these high risk patients."

Clinical • Journal • Acute Coronary Syndrome • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Myocardial Infarction • Thrombosis

Prevalence, clinical determinants and prognostic implications of coronary procedural complications of percutaneous coronary intervention in non-ST-segment elevation myocardial infarction: Insights from the contemporary multinational TAO trial. (PubMed, Arch Cardiovasc Dis) - P3 | "In a contemporary NSTE ACS population, procedural complications with PCI remain frequent, are difficult to predict based on clinical characteristics, and are associated with worse ischaemic and haemorrhagic outcomes."

Clinical • Journal • Acute Coronary Syndrome • Cardiovascular • Myocardial Infarction

Sex Differences in Ischemic and Bleeding Outcomes in Patients With Non-ST-Segment-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Insights From the TAO Trial. (PubMed, Circ Cardiovasc Interv) - P3 | "In patients with non-ST-segment-elevation acute coronary syndrome with systematic invasive management, ischemic outcomes, bleeding events, and mortality were higher in females. After multivariate analyses, female sex was not an independent predictor of ischemic and bleeding events although noncoronary artery bypass graft related Thrombolysis in Myocardial Infarction major bleeding was higher in females."

Clinical • Journal • Acute Coronary Syndrome • Cardiovascular • Myocardial Infarction

[VIRTUAL] Assay Dependent Reversal of the Oral and Parenteral Anti-Xa Agents By Andexanet Alfa (ASH 2020) - "Introduction: Andexanet alfa (AA, Portola Pharmaceuticals, San Francisco, USA) is an approved reversal agent for the control of potential bleeding associated with apixaban and rivaroxaban. Our results suggest that andexanet alfa is capable of neutralizing the effects of potent parenteral anti-Xa agents such as otamixaban in an assay dependent fashion. The data also points to the varying inhibitory effects of anti-Xa agents which are differentially neutralized by andexanet alfa. These results also underscore that the in-vitro anti-Xa potency of both the oral and parenteral anti-Xa agents does not fully reflect their inhibitory effects on the overall coagulation process."

Outcomes in non-ST-segment elevation myocardial infarction patients according to heart failure at admission: Insights from a large trial with systematic early invasive strategy. (PubMed, Eur Heart J Acute Cardiovasc Care) - "Non-ST-segment elevation myocardial infarction patients with heart failure at admission still have worse outcomes than those without heart failure, even with systematic early invasive strategy. Further efforts are needed to improve the prognosis of these high risk patients."

Clinical • Journal • Acute Coronary Syndrome • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Myocardial Infarction • Thrombosis

Blood transfusion and ischaemic outcomes according to anemia and bleeding in patients with non-ST-segment elevation acute coronary syndromes: Insights from the TAO randomized clinical trial. (PubMed, Int J Cardiol) - "In patients with NSTEMI, blood transfusion was associated with an overall increased risk of ischaemic events. However, this was mainly driven by patients without overt bleeding and those hemoglobin nadir > 9.0g/dl. This suggests possible harm of transfusion in those groups."

Clinical • Journal • Acute Coronary Syndrome • Anemia • Cardiovascular • Hematological Disorders • Myocardial Infarction • Reperfusion Injury

A pharmacodynamic comparison of otamixaban and bivalirudin in primates (ISTH 2013) - Abstract # PB 1.49-4; "The anticoagulant effects of otamixaban and bivalirudin exhibit comparable plasma time courses which can be effectively monitored by the ACT suggesting that otamixaban may be useful in surgical or interventional indications. However, the observed differences in the effect of these two types of drugs on the dynamics of clot formation, thrombin generation inhibition and platelet activation inhibition reveals a different balance among the inhibitory effects on the various hemostatic parameters, suggesting that otamixaban may have superior safety and/or efficacy advantages over bivalirudin."

Preclinical • Acute Coronary Syndrome

Prevalence, clinical characteristics and outcomes of procedural complications of percutaneous coronary intervention in non ST-elevation myocardial infarction: insights from the TAO trial (ESC 2018) - "Introduction: Few data are available on procedural complications of percutaneous coronary intervention (PCI) in the contemporary era.Purpose: We sought to describe the prevalence of procedural complications of PCI in a non ST- segment elevation ACS cohort (NSTEACS) and to identify their clinical characteristics and their association with clinical outcomes. TAO (Treatment of Acute Coronary Syndrome with Otamixaban) was an international randomized controlled trial, comparing otamixaban to unfractionated heparin plus eptifibatide in NSTEACS patients undergoing invasive management, in 568 centers in 55 countries from April 2010 to January 2013.All patient who underwent PCI were included in the analysis. In a contemporary population of NSTE-ACS patients, procedural PCI complications are frequent and associated with worse ischemic and hemorrhagic outcomes. They cannot be predicted before the procedure based on clinical characteristics. These results underline the need..."

Clinical • Acute Coronary Syndrome • Biosimilar • Cardiovascular • Hematological Disorders • Reperfusion Injury

Effect of otamixaban versus unfractionated heparin+eptifibatide in patients with unstable angina/non ST elevation myocardial infarction undergoing early invasive strategy (TAO) (clinicaltrials.gov) - P3, N=13,220; Sponsor: Sanofi; Active, not recruiting -> Completed.

Trial completion • Acute Coronary Syndrome

Evaluation of the efficacy and safety of otamixaban versus unfractionated heparin+eptifibatide in patients with non-ST-elevation acute coronary syndromes by PCI in the SEPIA-ACS1 TIMI 42 trial (ACC 2013) - Abstract# 912-5; P2, N=1,769; SEPIA-ACS1 TIMI 42 (NCT00317395); Sponsor: Sanofi; "Regardless of PCI, the pooled doses of OTAM significantly reduced death/MI (RR 0.54, P=0.02) w/o increasing bleeding (RR 1.20, P=0.56) compared to UFH+EPT. The benefit of OTAM in reducing death/MI was consistent regardless of PCI (PCI: RR 0.65; No PCI: RR 0.36; P-interaction=0.32)."

P2 data • Acute Coronary Syndrome

Sanofi provides update on phase 3 studies of two investigational compounds (Sanofi) - P3, N=13,220; TAO (NCT01076764); Sponsor: Sanofi; "In the TAO study...due to efficacy lower than expected, otamixaban did not show superior benefit/risk to the combination of unfractionated heparin...in non-ST elevation acute coronary syndrome...Following the results...company has decided to discontinue the investigational program with otamixaban, an injectable factor Xa inhibitor."

Discontinued • P3 data: top line • Acute Coronary Syndrome

Sanofi: Citi Global Healthcare Conference (Sanofi) - "Otamixaban is the first IV direct and selective factor Xa inhibitor with quick onset/offset; 27% to 42% risk reduction in ACS complications including death and MI in Phase Il"

P2 data • Acute Coronary Syndrome

Anticoagulation with otamixaban and ischemic events in non–ST-segment elevation acute coronary syndromes (JAMA) - P3, N=13,229; TAO (NCT01076764); Sponsor: Sanofi; "Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95% CI, 0.85-1.16]; P = .93)....The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95% CI, 1.63-2.78]; P < .001)."

P3 data • Acute Coronary Syndrome

Sanofi: Citi Global Healthcare Conference (Sanofi) - Anticipated data from P3 TAO study for moderate-to-high risk non-ST-elevation acute coronary syndrome in Q2 2013

Anticipated P3 data • Acute Coronary Syndrome

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art. (PubMed, Semin Thromb Hemost) - "Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59-7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran)...These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or..."

Journal

Sex is not an independent predictor of ischemic outcomes or bleeding in NSTEMI patients undergoing percutaneous coronary intervention. Insights from the TAO trial (ESC 2019) - " The TAO trial randomized moderate to high-risk NSTE-ACS patients with diagnostic coronary angiography planned in the first 72 hours to heparin plus eptifibatide versus otamixaban. In this large international randomized trial of NSTE-ACS with standardized invasive management, women (particularly those younger than 50 years) experienced higher risks of ischemic and bleeding events than men, but the difference was not sustained after adjustment. In this population, sex was not an independent predictor of adverse outcomes in NSTE-ACS. The type of ACS (NSTE-ACS) and routine invasive management in women and men may explain this absence of difference."

Clinical

Activated Clotting Time to Guide Heparin Dosing in Non-ST-Segment-Elevation Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention and Treated With IIb/IIIa Inhibitors: Impact on Ischemic and Bleeding Outcomes: Insights From the TAO Trial. (PubMed, Circ Cardiovasc Interv) - P3; "In the TAO trial, peak procedural ACT ≥250 s was associated with increased bleeding risk in non-ST-segment-elevation acute coronary syndrome patients treated with unfractionated heparin plus GPIs. This threshold was increased to 290 s when performing radial approach."

Clinical • Journal