Slide 1
IDARUCIZUMAB: A REQUEST FOR A NEW ICD-10-PCS CODE FOR THE ADMINISTRATION OF IDARUCIZUMAB

- ICD-10 Coordination and Maintenance Committee Meeting

- March 18, 2015

- CMS, Baltimore


Slide 2
AGENDA

- Overview of Idarucizumab

- Coding Issue

- Background
	- Disease State
	- Current Management Options
	- Idarucizumab Phase I/Ib Clinical Trial Data

- ICD-10-PCS Request for Idarucizumab

Slide 3
OVERVIEW OF IDARUCIZUMAB: SPECIFIC REVERSAL AGENT FOR PRADAXA® (DABIGATRAN ETEXILATE MESYLATE)

- Idarucizumab is being developed as a specific reversal agent to Pradaxa: 
	- Dabigatran is an anticoagulant which works by directly inhibiting thrombin, thereby blocking the final step of the coagulation cascade
	- Idarucizumab is a humanized fragment antigen binding (Fab) molecule that specifically binds to dabigatran, preventing it from inhibiting thrombin

- If FDA approved, idarucizumab is expected to be the only specific reversal agent to reverse the anticoagu
	- Require emergency surgery or urgent procedure 
	- Who experience life threatening  or uncontrolled bleeding

- Proposed dosage and administration of idarucizumab is  two consecutive infusions of 2.5 gm iv given either over 5 to 10 minutes each or as a bolus injection

- Idarucizumab has been shown in volunteers to provide immediate, complete, and sustained reversal of dabigatran anticoagulation effect

Slide 4
CURRENT CODES DO NOT DESCRIBE IV INFUSION OF IDARUCIZUMAB

- Issue 
	- Boehringer Ingelheim requests to establish new ICD-10-PCS codes via a new qualifier to more accurately identify idarucizumab administration for reversal of the anticoagulant effect of dabigatran in patients who experience these emergency situations

- New Technology Application 
	- Boehringer Ingelheim submitted a New Technology Add-on Payment application (NTAP) for idarucizumab for fiscal year (FY) 2016

- Food and Drug Administration (FDA) Approval 
	- Boehringer Ingelheim plans to submit a biologic license application (BLA) for idarucizumab to the FDA in the first quarter of 2015
		- If approved, it is expected to be the only FDA approved therapy to specifically reverse the anticoagulant effect of dabigatran 

- In June 2014, FDA granted Breakthrough Therapy Designation for idarucizumab 

Slide 5
OVERVIEW OF PRADAXA (DABIGATRAN ETEXILATE MESYLATE)  

- PRADAXA (dabigatran etexilate mesylate) is an oral direct thrombin inhibitor indicated:
	- In Non-Valvular Atrial Fibrillation (NVAF):
		- To reduce the risk of stroke and systemic embolism
		- Approved October 2010
	- In Deep Vein Thrombosis or Pulmonary Embolism (DVT/PE):
		- For the treatment of patients who have been treated with a parenteral anticoagulant for 5 to 10 days
		- To reduce the risk  of recurrence in patients who have been previously treated
		- Approved April 2014

Slide 6
THE GOAL OF ANTICOAGULATION IN NVAF IS TO REDUCE RISK OF CARDIOEMBOLIC ISCHEMIC STROKE

- Embolus to brain
	- Clot in the left atrium

- Ischemic stroke

Sources: 1) January CT et al. Circulation. 2014;129:1-123; 2) Arboix A, Alió J. Curr Cardiol Rev. 2012;8:54-67

Slide 7
THE GOAL OF ANTICOAGULATION THERAPY IN VTE IS TO REDUCE THE RISK OF SECONDARY OR RECURRENT EVENTS

- Venous Thromboembolism encompasses both DVT and PE
	- PE
		- Symptoms:  range from mild difficulty breathing to hemodynamic instability and shock
	- DVT
		- Symptoms:  pain, swelling, and discoloration of the lower extremities

Sources: 1) Gay SE. An inside view of venous thromboembolism. Nurse Practioner. 2010; 35 (9): 32-39; 2) Agnelli G, Becattini C.  Acute pulmonary embolism.  NEJM 2010; 363:266-274

Slide 8
UNLIKE WARFARIN, DABIGATRAN DIRECTLY TARGETS THROMBIN* FURTHER DOWNSTREAM IN THE COAGULATION CASCADE

- Steps in Coagulation
	- Initiation
	- Propagation
	- Thrombin Activity

- Coagulation Cascade

- Note: Available pharmacologic alternatives (prothrombin complex concentrates, fresh frozen plasma, factor VIIa) for reversing anticoagulation work by repleting upstream Vitamin K-dependent coagulation factors

*Clinical significance of targeting different parts of the coagulation cascade has not been established

Sources: 1) Adapted with permission from Weitz JI et al. Chest. 2004;126:2655-2865; 2) Furie B et al. N Engl J Med. 2008;359:938-949; 3)  Coumadin® (warfarin sodium) tablets [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co. October 2011. 


Slide 9
PATIENTS ON DABIGATRAN REQUIRING EMERGENCY SURGERY OR URGENT INTERVENTION

- Current instructions for discontinuing therapy in patients on dabigatran before surgical or invasive procedures based on renal function because of the increased risk of bleeding

- Dabigatran half-life in healthy subjects is 12-17 hours

- Longer times may be required for patients undergoing major surgery, spinal puncture, placement of a spinal epidural catheter or port, or in whom complete hemostasis may be required

- If surgery cannot be delayed, there is an increased risk of bleeding

- For patients who require emergency surgery or other urgent medical procedure requiring rapid reversal of dabigatran, delaying the procedure may worsen patient outcomes
	- Potential circumstances: Appendicitis, open fractures, ischemic stroke, acute cholecystitis

- Dabigatran half-life in healthy subjects is 12-17 hours, longer in patients with compromised renal function

Source: US PRADAXA prescribing information

Slide 10
SUMMARY OF CURRENT MANAGEMENT OPTIONS 

- Discontinuation
	- Based on renal function and time to surgical or medical intervention 
	- The half-life of dabigatran in healthy volunteers is 12-17 hours
	- May not be sufficient in certain emergency situations

- Dialysis
	- Four hours to remove approximately 49% of dabigatran from circulation
	- Data supporting hemodialysis is limited
	- Challenges associated with patients who are hemodynamically unstable 
	- May not be emergently available in all centers

- Fresh Frozen Plasma (FFP)
	- FFP has not been evaluated in clinical trials for dabigatran-associated bleeding
	- FFP has been shown to prevent excess hematoma expansion in mice
	- FFP requires a large amount of volume that elderly patients may not tolerate 
	- Risk of transfusion related lung injury5 and contraindicated in IgA-deficient patients

- PCCs/ aPCCs/ FVIIa
	- While there is pre-clinical data that PCCs may be of benefit, they are not a targeted approach and may have significant side effects (e.g. thrombosis)
	- Data limited to in vitro studies, animal bleeding models and healthy human volunteers

Sources: 1) US PRADAXA prescribing information; 2)Nutescu et al. Am J Health Syst Pharm. 2013 Nov 1;70(21):1914-29; 3)South Carolina Rural Health Research Center. Dialysis Availability in Rural America. January 2013; 4)Zhou W et al. Stroke. 2011 Dec;42(12):3594-9; 5) Vamvakas EC and Blajchman. Blood. 2009 Apr 9;113(15):3406-17; 6)  FDA. Octoplas Prescribing Information; 7) Ageno W et al. Chest. 2012;141(2_suppl):e44S-e88S; 8) Van Ryn J et al. Anesthesiology. 2014 Jun;120(6):1429-40; 9) Marlu et al. Thromb Haemost. 2012 Aug;108(2):217-24; 10) Erenberg ES. Circulation. 2011 Oct 4;124(14):1573-9. 


Slide 11
IDARUCIZUMAB GRANTED FDA BREAKTHROUGH THERAPY STATUS
	
- FDA granted Breakthrough Therapy Status Designation for idarucizumab in June, 2014

- Boehringer Ingelheim is currently planning to submit BLA to FDA in Q1, 2015; Priority Review has been requested

- Phase Ia/Ib Pharmacokinetic studies completed in Healthy Volunteers
	- Data will be used as basis for BLA submission to FDA 

- Phase III RE-VERSE AD study enrolling  
	- Approximately 500 sites planned globally
	- Approximately 100 sites planned for the US
	- Anticipated target enrollment 200-300 patients
	- Patients who require an emergency or urgent procedure or who have uncontrolled or life threatening bleeding 
	- Estimated completion date July 2017

- If approved, idarucizumab is expected to be the first specific reversal agent to reverse the anticoagulant effect of dabigatran in cases where an emergent surgery or urgent procedure is required or for life-threatening or uncontrolled bleeding

Slide 12
IDARUCIZUMAB SPECIFICALLY TARGETS DABIGATRAN TO REVERSE ITS ANTICOAGULANT EFFECT 

- Development
	- Monoclonal mouse antibody developed with high dabigatran binding affinity
	- Monoclonal antibody then humanized and directly expressed as a Fab fragment in hamster cells

- Properties
	- Potent binding affinity ~350 times higher than binding of dabigatran to thrombin
	- No prothrombotic or anticoagulant effects expected
	- Terminal half life (4.5-9 hours)
	- Intravenous administration
	- Each patient will receive a total dose of 5000mg, using two vials containing 2500mg/vial 
	- Full effect apparent by end of infusion

- Expected low risk of adverse reactions
	- No Fc receptor binding
	- No endogenous targets
	- No transmission of bloodborne pathogens

Sources: 1) Glund S et al. Presented at AHA, Dallas, TX, USA, 16–20;November 2013; 2)Schiele F et al. Blood. 2013;121:3554-62


Slide 13
1321.1 HEALTHY VOLUNTEER STUDY: IMMEDIATE, COMPLETE, AND SUSTAINED REVERSAL OF DABIGATRAN ANTICOAGULATION EFFECT

- Fab infusion results in immediate, complete, and sustained reversal of dabigatran anticoagulation in healthy volunteers	

Source: 1) Glund S et al. Presented at AHA, Dallas, TX, USA, 16–20;November 2013


Slide 14
1321.1 HEALTHY VOLUNTEER STUDY: SAFETY

- Adverse events
	- Similar frequencies in placebo, dabigatran alone, and idarucizumab groups
	- Mild or moderate in severity
	- None leading to discontinuation
	- No severe, serious, or fatal adverse events
	- No immunogenic reactions detected 

- Laboratory
	- Transient, dose-dependent increases in urinary protein excretion immediately after Idarucizumab dosing reflecting competition with endogenous proteins for renal tubule re-uptake transporter
		- Returned to normal 4-12 hours after treatment
	- Low level of persistent newly developed ADAs observed (1 of 118 volunteers) 

- Infusion of up to 8 g idarucizumab was well tolerated, both alone and in combination with dabigatran

Source: 1) Glund S et al. Presented at AHA, Dallas, TX, USA, 16–20;November 2013; Abstract 17765

Slide 15
PHASE IB: SUSTAINED REVERSAL AFTER 5 GRAMS OF IDARUCIZUMAB IN ELDERLY AND RENALLY IMPAIRED VOLUNTEERS

- Median peak dabigatran exposure was comparable to exposure in patients with NVAF

- Dabigatran-prolonged clotting times (dTT, ECT, aPTT and TT) were reversed to baseline immediately after end of idarucizumab infusion

- Sustained reversal observed after idarucizumab 5 g in healthy subjects (45–64 years), the elderly, and subjects with mild or moderate renal impairment

Slide 16
PHASE IB: RE-ADMINISTRATION OF DABIGATRAN 24 HOURS AFTER IDARUCIZUMAB APPLICATION LEADS TO RESTORATION OF ANTICOAGULATION

- Healthy subjects (45–64 years) received 5 g idarucizumab or placebo

- 24 h later, dabigatran treatment was restarted

- Dabigatran-mediated anticoagulation was restored to levels comparable to initial levels

- Similar results after administration of 2.5 g idarucizumab (data not shown)

Slide 17
IDARUCIZUMAB IN COMBINATION WITH DABIGATRAN WAS WELL TOLERATED

- Infusion of up to 5 g idarucizumab in combination with dabigatran was well tolerated in male and female subjects (aged 45–64 years), elderly subjects, and subjects with mild or moderate renal impairment 

- No clinically relevant drug-related adverse events (AE)*

- No relevant changes in any of the investigated safety parameters

- No AEs detected indicative of immunogenic reactions

- A dose-dependent, transient increase in urine protein and low-weight proteins was observed due to renal clearance of idarucizumab
	- Values returned to normal range within 4–24 h

Slide 18
PHASE III STUDY POPULATION AND ENDPOINTS (EXPECTED COMPLETION JULY 2017)

- Inclusion criteria
	- Group A –Patient’s taking dabigatran who have overt bleeding judged by the physician to require a reversal agent
	- Group B-Patients who are taking dabigatran who may not be bleeding, but do require an emergency surgery or procedure (within 8 hours) for a condition other than bleeding

- Primary Endpoint
	- Maximum reversal of anticoagulant effect of dabigatran based on central laboratory determination of dTT or ECT, at any time point from the end of the first infusion up to 4 hours after the last infusion

- Secondary Endpoints
	- Reversal of Activated Partial Thromboplastin Time (aPTT) and Thombin time (TT) up to 4 hours
	- Duration of reversal up to 24 hours
	- Occurrence of major bleeding (for group B only) intraoperatively and up to 24 hours post-surgery
	- Time to cessation of bleeding (for Group A only) 
	- Minimum unbound sum (free) dabigatran up to 4 hours 
	- Reversal of anticoagulation as measured by diluted Thrombin Time (dTT) or Ecarin Clotting Time (ECT) after the first infusion and before the start of the second

Reference: : NCT02104947 Clinical trials.gov 

Slide 19
BOEHRINGER INGELHEIM REQUESTS TO ESTABLISH NEW ICD-10-PCS CODES

- Boehringer Ingelheim proposes to add new Qualifier R Idarucizumab to Section 3, Body System E, Operation 0, as shown below
	- Administration: 3 Administration
	- Body System: E Physiological Systems and Anatomical Regions
	- Operation: 0 Introduction: Putting in or on a therapeutic, diagnostic, nutritional, physiological, or prophylactic substance except blood or blood products
	- Body System/Region: 3 Peripheral Vein, 4 - Central Vein
	- Approach: 3 Percutaneous
	- Substance: G Other Therapeutic Substance
	- Qualifier: C Other Substance, N Blood Brain Barrier Disruption, 4 Glucarpidase, ADD R Idarucizumab

- A unique code for the administrations of idarucizumab will aid in the tracking and monitoring of dabigatran reversals needed; additionally, as idarucizumab is under consideration for NTAP payment, a unique code will facilitate claims processing and payment adjustments for qualifying cases

Slide 20
SUMMARY

- If FDA approved, idarucizumab is expected to be the only specific reversal agent to reverse the anticoagulant effect of dabigatran in patients who:
	- Require emergency surgery or urgent procedure 
	- Experience life threatening  or uncontrolled bleeding

- ICD-10-PCS does not currently allow specific identification of the intravenous administration of idarucizumab

- Boehringer Ingelheim proposes to add new Qualifier R Idarucizumab to Section 3, Body System E, Operation 0
	- Administration: 3 Administration
	- Body System: E Physiological Systems and Anatomical Regions
	- Operation: 0 Introduction: Putting in or on a therapeutic, diagnostic, nutritional, physiological, or prophylactic substance except blood or blood products
	- Body System/Region: 3 Peripheral Vein, 4 - Central Vein
	- Approach: 3 Percutaneous
	- Substance: G Other Therapeutic Substance
	- Qualifier: C Other Substance, N Blood Brain Barrier Disruption, 4 Glucarpidase, ADD R Idarucizumab