Ciraparantag (aripazine) / Norgine, Azurity Pharma - LARVOL DELTA

Study of Ciraparantag for Reversal of Anticoagulation Induced by Edoxaban, Apixaban or Rivaroxaban in Healthy Adults (clinicaltrials.gov) - P2 | N=41 | Terminated | Sponsor: AMAG Pharmaceuticals, Inc. | N=108 ➔ 41 | Recruiting ➔ Terminated; Sponsor decision unrelated to safety

Enrollment change • Trial termination

Correction of the effect of direct oral and parenteral anticoagulants in hemorrhagic stroke (PubMed, Zh Vopr Neirokhir Im N N Burdenko) - "Early hemostatic therapy and reversal of anticoagulant effects in patients with hemorrhagic stroke significantly reduce the risk of adverse outcomes. This problem is being studied. Regular literature review with creation of updated clinical guidelines is needed."

Journal • Review • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Thrombocytopenia

Study of Ciraparantag for Reversal of Anticoagulation Induced by Edoxaban, Apixaban or Rivaroxaban in Healthy Adults (clinicaltrials.gov) - P2 | N=108 | Recruiting | Sponsor: Perosphere Pharmaceuticals Inc, a wholly owned subsidiary of AMAG Pharmaceuticals, Inc. | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date

Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants? (PubMed, Thromb Res) - "Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote...However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes."

Journal • Review

Latest advances in the reversal strategies for direct oral anticoagulants. (PubMed, Fundam Clin Pharmacol) - "With the validation of specific and nonspecific antidotes, DOACs could supplant traditional oral anticoagulants. This progress represents a significant advancement in anticoagulation therapy. However, ongoing research is crucial to address remaining safety concerns of the specific reversion agents of DOACs in clinical practice."

Journal • Review • Cardiovascular • Hematological Disorders • Thrombosis

Study of Ciraparantag for Reversal of Anticoagulation Induced by Edoxaban, Apixaban or Rivaroxaban in Healthy Adults (clinicaltrials.gov) - P2 | N=108 | Recruiting | Sponsor: Perosphere Pharmaceuticals Inc, a wholly owned subsidiary of AMAG Pharmaceuticals, Inc. | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date

Comparison of Cardiovascular and Respiratory Toxicity of Heparin Antidotes: Protamine Sulfate, PER977 and Heparin-Binding Copolymer (HBC) (ISTH 2023) - "HBC with dose escalation most significantly reduced blood pressure and increased perfusion of paw vessels, which was accompanied by complement system activation and secretion of NO and angiotensin 1-7. We observed the respiratory disturbances and increased angiotensin II and thromboxane B2 production after protamine and HBC infusion. Protamine-induced hypotension and vasodilatation were accompanied by the release of prostacyclin metabolite and angiotensin 1-7 (Figure 1A-G)."

Cardiovascular • Hypotension

Direct oral anticoagulants improve podocyte health and reverse hypercoagulopathy in an experimental model of glomerular disease (ISTH 2023) - "IVC ligation experiments were performed on day 10 to investigate in vivo effects of DOAC treatment with or without ciraparantag, an investigational DOAC antidote. Both DOACs significantly improved proteinuria, decreased podocyte injury, and reduced ETP. DOAC-Stop reversed 30% of the dabigatran effect on ETP, suggesting that 70% of the effect was due to its antiproteinuric effect. Similarly, rivaroxaban had both a direct anticoagulant and an indirect antiproteinuric effect on ETP (49% and 51% of total effect, respectively)."

Cardiovascular • Glomerulonephritis • Hematological Disorders • Infectious Disease • Nephrology • Renal Disease • Thrombosis

"Translation, Ciraparantag is coming soon!" (@puppy_chow1)

"👍🏻👍🏻 Also Ciraparantag - Universal antidote 😎 (against Heparin, LMWH and DOACs) - acts by formation of hydrogen bonds" (@DigambarPanchal)

When and How to Use Reversal Agents for Direct Oral Anticoagulants? (PubMed, Curr Cardiol Rep) - "Specific (idarucizumab for dabigatran and andexanet alfa for direct factor Xa inhibitors) and non-specific (prothrombin complex concentrates) reversal agents are effective in neutralizing the anticoagulant effect of DOACs. New investigational antidotes such as ciraparantag and VMX-C001 offer an alternative to andexanet alfa in reversing the anticoagulant activity of direct oral factor Xa inhibitors, but more clinical data are needed before they could be licensed for use. Specific reversal agents are recommended for use in clinical situations within their licensed indications (i.e.: reversal of DOACs in patients with severe uncontrolled or life-threatening bleeding or in need of emergency surgery or other invasive procedures), while non-specific reversal agents may be used when specific antidotes are not available or indicated."

Journal • Review

Anticoagulation for Atrial Fibrillation: A Review of Current Literature and Views. (PubMed, Cardiol Rev) - "Since early 2010s, direct oral anticoagulants (DOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban have been introduced and approved for anticoagulation of atrial fibrillation. One major concern and disadvantage for DOACs was lack of reversal agents, which have largely been ameliorated by the approval of Idarucizumab for dabigatran and Andexanet alfa for both apixaban and rivaroxaban, with Ciraparantag as a universal reversal agent for all DOACs undergoing Fast-Track Review from FDA. In this article, we will be providing a broad review of anticoagulation for atrial fibrillation with a focus on risk stratification schemes and anticoagulation agents (warfarin, aspirin, DOACs) including special clinical considerations."

Journal • Review • Atrial Fibrillation • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Immunology • Ischemic stroke • Ventricular Tachycardia

Reversal agents for severe bleeding associated with direct oral anticoagulants (PubMed, G Ital Cardiol (Rome)) - "Idarucizumab has been approved for dabigatran reversal and andexanet alfa was recently granted approval for the reversal of apixaban or rivaroxaban in patients with life-threatening or uncontrolled bleeding events. Other reversal agents (e.g. ciraparantag for heparins and DOACs) are under development. Non-specific prohemostatic agents (e.g. prothrombin complex concentrate) can counteract the anticoagulant action of DOACs in emergency situations, when specific reversal agents are unavailable. However, specific reversal agents are efficacious and safe and should be preferred when available."

Journal

Reversal of direct oral anticoagulants: what about new treatments available? (PubMed, Rev Med Suisse) - "Recently, we have seen the emergence of specific antidotes to DOAC, such as idarucizumab and andexanet alfa, effective on anti-II and anti-Xa DOAC respectively. These new molecules have shown excellent biological efficacy, hence supporting their use in clinical practice, however they are not routinely used, mainly due to limited availability and high cost. Ciraparantag, an antagonist of DOAC and heparins currently in phase III trials, could become a key molecule in the future considering encouraging preliminary results."

Journal

A short review of ciraparantag in perspective of the currently available anticoagulant reversal agents. (PubMed, Drug Discov Today) - "Ciraparantag, a synthetic small molecule that inactivates heparins and DOAC, is a promising new reversal agent that has been investigated in phase 2 trials. In this short review we provide an overview of the preclinical and clinical evidence of ciraparantag, and compare strengths and weaknesses of ciraparantag and the currently available anticoagulant reversal strategies."

Journal • Review

"The next DOAC reversal agent? Ciraparantag!" (@Bloodman)

"Ciraparantag as a potential universal anticoagulant reversal agent - Editorial https://t.co/ADLNNO4thY" (@JerroldLevy)

"Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects https://t.co/oxOz1za2WG" (@JerroldLevy)

Clinical

Study of Ciraparantag for Reversal of Anticoagulation Induced by Edoxaban, Apixaban or Rivaroxaban in Healthy Adults (clinicaltrials.gov) - P2 | N=108 | Recruiting | Sponsor: Perosphere Pharmaceuticals Inc, a wholly owned subsidiary of AMAG Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting | N=72 ➔ 108 | Trial completion date: Jun 2021 ➔ Dec 2022 | Trial primary completion date: Jun 2021 ➔ Dec 2022

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date

"Ciraparantag as a potential universal anticoagulant reversal agent #EHJ #cardiotwitter @escardio https://t.co/QuQTEJ4aiw" (@ehj_ed)

Ciraparantag as a potential universal anticoagulant reversal agent. (PubMed, Eur Heart J) - No abstract available

Journal

Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects. (PubMed, Eur Heart J) - "Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated."

Clinical • Journal • Thrombosis

Ciraparantag: the next anticoagulant airbag? (PubMed, Blood) - No abstract available

Journal

[VIRTUAL] Reversal of Anticoagulation By Ciraparantag: Time to Onset and Duration of Effect (ASH 2020) - "Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including direct oral anticoagulants (DOACs), enoxaparin, and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. In healthy subjects at steady-state levels of anticoagulation, ciraparantag single IV doses were well tolerated and produced rapid reversal of anticoagulation in high proportions of subjects within 15 minutes of administration (the first timepoint assessed) at doses ≥60 mg for apixaban and at a dose of 180 mg for rivaroxaban which were maintained throughout the 24-hour measurement period. Figure. Proportion of subjects with WBCT reversed to within 10% above baseline at 15 minutes and 30 minutes after dosing"

Mood Disorders • Thrombosis

[VIRTUAL] Design of a Randomized, Controlled Study to Evaluate Reversal of Anticoagulation of Ciraparantag in Healthy Adults: Whole Blood Clotting Time Assessed By Automated and Manual Methods (ASH 2020) - "Phase 2 clinical studies have shown that ciraparantag reverses anticoagulation in healthy volunteers treated with edoxaban, enoxaparin, apixaban, or rivaroxaban as assessed by manual whole blood clotting time (WBCT). Further details of the design of this study will be provided. The results of this study will inform dose selection for the future Phase 3 clinical trial and will provide data on the use of the PoC coagulometer for assessment of ciraparantag for reversal of anticoagulation."

Clinical • Mood Disorders • Thrombosis