September Horizon Scanning Research & 2016 Intelligence Centre

Ciraparantag for haemorrhage in patients receiving new oral

NIHR HSRIC ID: 10689

Lay summary

Ciraparantag is a new drug to treat bleeding in people taking new oral anticoagulants (NOACs). Anticoagulants are medicines which are given to people to thin the blood and prevent blood clots. Anticoagulation can become a problem when patients experience major bleeding, have a traumatic injury or require emergency surgery. There are currently no licensed treatments that can quickly reverse the effects of NOACs in an emergency.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Haemorrhage: in patients receiving new oral anticoagulants (NOACs).

TECHNOLOGY

DESCRIPTION

Ciraparantag (Aripazine; PER 977) is a water soluble, small molecule that re-establishes normal blood coagulation by directly binding to factor Xa and IIa inhibitors. It is intended for use as a broad-spectrum reversal agent for anticoagulants, including low molecular weight , unfractionated heparin and NOACs that target both factor Xa and IIa. In clinical trials1, ciraparantag was administered via 2 single bolus intravenous (IV) injections on consecutive days, at a dose ranging from 25mg to 300mg per dose, following anticoagulation with .

Ciraparantag does not currently have Marketing Authorisation in the EU for any indication.

INNOVATION and/or ADVANTAGES

If licensed, ciraparantag will address an unmet clinical need for a broad spectrum NOAC reversal agent as well as providing a reversal drug for unfractionated and low molecular weight heparin.

DEVELOPER

Perosphere.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Anticoagulants are that interact with the body’s natural blood-clotting system to treat and prevent abnormal blood clots2. They are widely used to prevent and treat a variety of thromboembolic events3. Anticoagulation becomes a clinical problem when patients experience major bleeding, have a traumatic injury or require emergency surgery3. For decades, was the primary oral in use, however in recent years a number of NOACs have become available as alternatives to warfarin2. NOACs are shorter- acting than warfarin, which takes several days for the anticoagulant effect to wear off. However, unlike warfarin, no specific are currently available to rapidly reverse the anticoagulant effect of NOACs in patients who experience a major bleeding event2.

CLINICAL NEED and BURDEN OF DISEASE

Major bleeding involving intracranial haemorrhages, the gastrointestinal tract, urinary tract or soft tissue occurs in up to 6.5% of patients on anticoagulant therapy, and the annual Horizon Scanning Research & Intelligence Centre

incidence of fatal bleeding is approximately 1% in this population4. NOACs are an option for the treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). It is estimated that 53,040 people in England are eligible to receive NOACs for these indications5. NOACs are also recommended as an option for use after orthopaedic surgery for the prevention of venous thromboembolism. In 2009, around 70,000 elective total knee replacements and 55,000 elective total hip replacements were carried out in England6. NOACs are also recommended as an option to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation. The number of people with atrial fibrillation estimated to be eligible for anticoagulation services, was 800 per 100,000 population in 2011, representing approximately 440,000 people in England7.

In 2014-15, there were 193 hospital admissions in England for haemorrhagic disorder due to circulating anticoagulants (ICD10 D68.3), resulting in 319 finished consultant episodes and 1,409 bed days8.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction (TA388). April 2016. • NICE technology appraisal. Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation (TA355). September 2015. • NICE technology appraisal. Edoxaban for treating and preventing deep vein thrombosis and pulmonary embolism (TA354). August 2015. • NICE technology appraisal. for the treatment of secondary prevention of deep vein thrombosis and/or pulmonary embolism (TA341). June 2015. • NICE technology appraisal. for preventing adverse outcomes after acute management of acute coronary syndrome (TA335). March 2015. • NICE technology appraisal. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation (TA275). February 2013. • NICE technology appraisal. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults (TA245). January 2012.

• NICE clinical guideline. Atrial fibrillation: management (CG180). June 2014. • NICE clinical guideline. Head injury: assessment and early management (CG176). January 2014. • NICE clinical guideline. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing (CG144). June 2012. • NICE clinical guideline. Venous thromboembolism: reducing the risk for patients in hospital (CG92). January 2010. • NICE clinical guideline. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management (CG68). July 2008. • NICE guideline. Sepsis: recognition, diagnosis and early management (NG51). July 2016. • NICE guideline. Routine preoperative tests for elective surgery (NG45). April 2016. • NICE guideline. Major trauma: assessment and initial management (NG39). February 2016. • NICE guideline. Major trauma: service delivery (NG40). February 2016.

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• NICE quality standard in development. Title. Publication anticipated August 2017. • NICE quality standard. Atrial fibrillation (QS93). July 2015. • NICE quality standard. Head injury (QS74). October 2014. • NICE quality standard. Venous thromboembolism in adults: diagnosis and management (QS29). March 2013.

• NICE diagnostic guidance. Atrial fibrillation and heart valve disease: self-monitoring coagulation status using point-of-care coagulometers (the CoaguChek XS system and the INRatio2 PT/INR monitor (DG14). September 2014.

NHS England Policies and Guidance

• NHS England. 2013/14 NHS Standard Contract for specialised vascular services (Adults). A04/S/a.

Other Guidance

• All Wales Medicines Strategy Group. All Wales advice on the role of oral anticoagulants. 20169. • NHS Clinical Knowledge Summary. Anticoagulation – oral. October 201510. • European Heart Rhythm Association. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. 201311. • Scottish Intercollegiate Guidelines Network. Antithrombotics: indications and management (SIGN 219). October 201212. • Agency for Healthcare Research and Quality. Guideline for the management of bleeding on (Pradaxa). 201213.

CURRENT TREATMENT OPTIONS

Guidelines recommend that patients with substantial bleeding are transfused with blood, platelets and clotting factors in line with local protocols for managing this acute medical emergency14. Prothrombin complex concentrate is given to patients who are taking warfarin and actively bleeding.

Currently, there are no licensed broad-spectrum reversal agents for NOACs or for low molecular weight heparin.

EFFICACY and SAFETY

Trial NCT02207257, PER977-02-001; ciraparantag vs placebo; phase II. Sponsor Perosphere, Inc. Status Ongoing. Source of Trial registry1, manufacturer. information Location USA. Design Randomised, placebo-controlled. Participants n=69 (planned); aged 18-65 years; healthy volunteers. Schedule All participants receive edoxaban 60mg oral in the morning on days 1-4. Participants randomised to receive ciraparantage IV at 25mg, 50mg, 100mg or 300mg, or placebo IV on days 3-4, approximately 3 hrs following dose of edoxaban. Follow-up Observed in hospital for 24 hrs and followed up 1 wk later.

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Primary Whole blood clotting time as a measure of edoxaban anticoagulation reversal. outcome/s Secondary ; safety coagulation measures; safety and tolerability. outcome/s Key results Ciraparantag at 100mg and 300mg IV produced 100mg and 300mg produced complete and sustained reversal of anticoagulationa. Adverse Not reported. effects (AEs) Expected Currently being prepared for publication. reporting date

ESTIMATED COST and IMPACT

COST

The cost of ciraparantag is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 ClinicalTrials.gov. Study of PER977 administered to subjects with steady state edoxaban dosing and re-anticoagulation with edoxaban. https://clinicaltrials.gov/ct2/show/NCT02207257?term=nct02207257&rank=1 Accessed 23 August 2016. 2 Wadhera RK, Russell CE and Piazza G. Warfarin versus novel oral anticoagulants. How to choose? Circulation 2014;130(22):e191-e193.

a Information from manufacturer.

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3 NHS Choices. Anticoagulant medicines. http://www.nhs.uk/Conditions/Anticoagulant- medicines/Pages/Introduction.aspx Accessed 23 August 2016. 4 American College of Emergency Physicians. Focus on: reversal of anticoagulation. https://www.acep.org/Clinical---Practice-Management/Focus-On--Reversal-of-Anticoagulation/ Accessed 6 September 2016. 5 National Institute for Health and Care Excellence. Implementing the NICE guidance on apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. Technology appraisal costing statement TA341. London: NICE; June 2015. 6 National Institute for Health and Clinical Excellence. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults: costing statement TA245. London: NICE; January 2012. 7 National Institute for Health and Clinical Excellence. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation: costing statement TA275. London: NICE; February 2013. 8 Health & Social Care Information Centre. Hospital episode statistics for England. Admitted patient care, 2014-15. www.hscic.gov.uk 9 All Wales Medicines Strategy Group. All Wales advice on the role of oral anticoagulants. Llandough: AWMSG; February 2016. 10 Clinical Knowledge Summaries. Anticoagulation – oral. http://cks.nice.org.uk/anticoagulation- oral#!topicsummary Accessed 23 August 2016. 11 Heidbuchel H, Verhamme P, Alings M et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. European Heart Journal 2013;34(27)2094-2106. 12 Scottish Intercollegiate Guidelines Network. Antithrombotics: indications and management. National clinical guideline 129. Edinburgh: SIGN; October 2012. 13 Agency for Healthcare Research and Quality. Guideline for the management of bleeding on dabigatran (Pradaxa). USA: AHRQ; February 2009. 14 National Institute for Health and Clinical Excellence. Acute upper gastrointestinal bleeding in over 16s: management. Clinical guideline CG141. London: NICE; June 2012.

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