In this episode I’ll discuss the drug ciraparantag.
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Shout out to Pharmacy Lawrence on Twitter for requesting this topic!
If you are not on Twitter you should consider it. I believe it is the best social media platform to use for education and collaboration with other healthcare providers. For more information listen to episode 69 where I discuss using twitter hashtags for free open access medication education. You can find me on twitter as @PharmacyJoe.
Ciraparantag or PER977 is a broad spectrum anticoagulant reversal agent under fast track review at the FDA.
Ciraparantag is reported to antagonize the effects of all anticoagulants except warfarin and agratroban – even enoxaparin and fondaparinux!
Not much is published on the exact mechanism of action for PER977. According to a letter to the editor published in NEJM November 2014:
PER977 (Perosphere) is a small, synthetic, water-soluble, cationic molecule that is designed to bind specifically to unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen bonding and charge–charge interactions.
PER977 binds in a similar way to the new oral factor Xa inhibitors, edoxaban, rivaroxaban and apixaban, and to the oral thrombin inhibitor, dabigatran. In thromboelastographic studies and rat-tail–transection bleeding assays, PER977 has been shown to reverse anticoagulation with each of the new oral agents.
In nonclinical studies, PER977 did not bind to plasma proteins, including albumin, and showed no binding when tested against several common cardiovascular, antiepileptic, and anesthetic drugs.
Animal data available for this drug is very interesting. In rats overdosed with rivaroxaban, apixaban, edoxaban and dabigatran, ciraparantag reduced bleeding within 30 minutes.
Compare that to 4-factor PCC and idarucizumab which appear to achieve hemostasis in an average of 12 hours. If this fast time to reduction in bleeding translates to humans, perhaps the effect would be strong enough to show actual differences in clinical outcomes with ciraparantag compared to other reversal agents.
The no observable adverse effect level for 14-day intravenous exposure to both rats and dogs was 20 mg/kg/day.
In the first human trial of ciraparantag, it was tested on volunteers who were either untreated or pretreated with 60 mg of edoxaban. A dose of intravenous bolus of 300 mg ciraparantag was found to normalize whole blood clotting time within 10–30 min, and the effect lasted for over 24 h. There are currently 2 active studies on clinicaltrials.gov using ciraparantag in healthy patients. One study is looking at heparin reversal and the other at edoxaban reversal.
The manufacturer’s website indicates ciraparantag is in phase 2 clinical trials, that no procoagulant effect has been found, and that the drug also completely reverses enoxaparin. This last finding is important because the only available agent – protamine – does not completely reverse the effects of enoxaparin.
Ciraparantag received fast track designation in April 2015. According to the FDA:
Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.
As no phase III trials have been registered on clinicaltrials.gov, my guess is that it may be a while before ciraparantag gets reviewed by the FDA. Once a phase III trial is begun, I would expect ciraparantag to get an accelerated approval from the FDA much like idarucizumab did.
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