What is the mechanism of action and clinical use of ciraparantag (PER977)?

Ciraparantag: Mechanism and Clinical Use

Ciraparantag is a broad-spectrum anticoagulant reversal agent that binds multiple anticoagulants through noncovalent hydrogen bonding and charge-charge interactions, but it remains investigational without FDA approval and should not be used in clinical practice at this time. 1

Mechanism of Action

Ciraparantag is a synthetic, water-soluble cationic small molecule consisting of 2 L-arginine units connected with a piperazine-containing linker chain. 1 The drug works through a unique binding mechanism:

• Binds anticoagulants via noncovalent hydrogen bonding and charge-charge interactions, preventing these drugs from binding to their endogenous targets 1
• Originally designed to reverse heparin but was subsequently found to bind direct oral anticoagulants (DOACs) 1, 2
• Does not bind to coagulation factors or other commonly used drugs, providing specificity for anticoagulants 3

Pharmacokinetic Profile

• Onset of action: 5-10 minutes after IV administration 1
• Duration of action: 24 hours 1
• Reaches maximum concentration within minutes with a half-life of 12-19 minutes 3
• Primarily hydrolyzed by serum peptidases into two metabolites with minimal activity 3
• Eliminated almost entirely in urine 3
• Storage advantage: room temperature, unlike idarucizumab and andexanet alfa which require refrigeration 1

Spectrum of Anticoagulant Reversal

Ciraparantag has the broadest reversal spectrum of any agent in development, binding to: 1

• Dabigatran (direct thrombin inhibitor)
• Argatroban
• Oral factor Xa inhibitors (apixaban, rivaroxaban, edoxaban)
• Parenteral factor Xa inhibitors
• Low-molecular-weight heparins
• Unfractionated heparin
• Fondaparinux

This universal binding capacity distinguishes it from agent-specific reversal drugs like idarucizumab (dabigatran only) and andexanet alfa (factor Xa inhibitors only). 1

Clinical Evidence

Phase 2 Studies in Healthy Volunteers

In 80 healthy volunteers given edoxaban 60 mg, ciraparantag doses of 100-300 mg fully reversed whole blood clotting time (WBCT) to within 10% of baseline within 10 minutes. 1 Key findings include:

• Edoxaban induced a 37% prolongation of WBCT, which was reversed within 10 minutes of ciraparantag infusion 1
• Return to baseline hemostasis occurred in 10-30 minutes 4
• Ciraparantag alone (without anticoagulant) had no effect on WBCT, demonstrating it does not cause hypercoagulability 1

For apixaban and rivaroxaban reversal, ciraparantag demonstrated dose-dependent effects: 1

• 60 mg dose reversed apixaban anticoagulation
• 180 mg dose reversed rivaroxaban anticoagulation

Animal Model Data

In rat tail transection and liver laceration models, a single IV dose of ciraparantag significantly reduced blood loss when given either before or after the bleeding injury. 3 This suggests potential efficacy in both prophylactic and therapeutic bleeding scenarios.

Critical Monitoring Limitation

A major practical limitation is that ciraparantag binds citrate, making standard plasma-based coagulation assays (PT, aPTT) impossible to use for monitoring reversal. 1 Instead:

• Whole blood clotting time (WBCT) test was specifically developed for monitoring ciraparantag reversal 1
• This creates logistical challenges for real-world implementation in emergency settings

Current Clinical Status

Ciraparantag remains investigational and is NOT approved by any regulatory authority. 1 The development timeline:

• Phase 2 trials completed in healthy volunteers 1
• Phase 3 clinical trial is being planned but not yet initiated 1
• No clinical data exist in actual bleeding patients, only healthy volunteers 4, 5, 2

Comparison to Available Alternatives

Unlike ciraparantag, two specific reversal agents are already available:

• Idarucizumab (Praxbind) has worldwide approval for dabigatran reversal since 2015 1
• Andexanet alfa received FDA approval for factor Xa inhibitor reversal 1, 5

Potential Clinical Role (When Approved)

If approved, ciraparantag would fill a unique niche as a universal anticoagulant reversal agent, particularly valuable in scenarios where: 5, 2, 6

• The specific anticoagulant is unknown in an emergency bleeding situation
• Multiple anticoagulants may be present (e.g., bridging therapy)
• Heparin reversal is needed in patients with protamine allergy or contraindication
• A single reversal agent is preferred for hospital formulary simplification

Dosing in Clinical Studies

The IV bolus doses studied ranged from 100-300 mg, with higher doses required for more potent anticoagulants: 1

• 100 mg for edoxaban
• 60 mg for apixaban
• 180 mg for rivaroxaban

Safety Profile

Ciraparantag has been generally well tolerated in clinical trials to date, with no reports of immunogenicity or thrombotic complications in healthy volunteer studies. 4, 6 However:

• Long-term safety data are lacking 1
• No data exist on thrombotic risk in actual bleeding patients who receive ciraparantag
• Off-target effects remain a concern that requires further investigation 1

Clinical Implementation Barriers

Several practical challenges must be resolved before clinical use:

• Lack of standard coagulation monitoring due to citrate binding 1
• No comparative studies with other reversal strategies 5, 2
• Unknown efficacy in actual bleeding patients versus healthy volunteers 4, 5
• Uncertain cost-effectiveness compared to agent-specific antidotes

Bottom Line for Current Practice

Do not use ciraparantag—it is not approved and not available for clinical use. For anticoagulant reversal in bleeding emergencies, use:

• Idarucizumab 5 g IV for dabigatran-associated bleeding 1
• Andexanet alfa (dose based on specific factor Xa inhibitor) for apixaban/rivaroxaban bleeding 1
• 4-factor prothrombin complex concentrate as an alternative for factor Xa inhibitor bleeding when andexanet is unavailable 1