A Case Study Discussion · • Hemophilia is caused by the absence or defect of crucial constituents of the coagulation cascade • Hemophilia A is the most common type of hemophilia

INDIVIDUALIZINGFACTOR THERAPY

A Case Study Discussion

PARTICIPANT GUIDE

Participant Guide

3CME = continuing medical education.

DISCLAIMERS

• This program is presented on behalf of Shire

• I have been compensated by Shire to serve as a speaker for this program

• This is an unbranded presentation, so no specific products will be discussed during this program. In the event the discussion leads to off-topic statements, as the moderator, I will transition back to the approved program

• This is a non-CME program provided by Shire. Statements made by participants are the opinions of participants only and may not reflect those of Shire

• This program may be monitored by Shire for adherence to the program requirements

Participant Guide

5FVIII = factor VIII.

PROGRAM OBJECTIVES• Discuss the role of factor treatment, FVIII, and bypassing agents in

treating hemophilia A patients and patients with inhibitors

• Review treatment considerations and approaches to patient management for hemophilia A patients with and without inhibitors

• Discuss patient management questions that health care professionals commonly encounter

INTRODUCTION:GENERAL

INTRODUCTION: GENERAL

INTR

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A GENERAL INTRODUCTION TO HEMOPHILIA

HALLMARKS OF HEMOPHILIA

EVOLUTION OF FACTOR TREATMENT

• In addition to manufacturing advancements,7 treatment regimens have also evolved, with prophylaxis being recognized as standard of care for patients with severe hemophilia A8

• As compared to on-demand treatment, prophylaxis has been shown to reduce joint bleeding and other bleeding events9

EASY BRUISING IN EARLY CHILDHOOD1

SPONTANEOUS BLEEDING, ESPECIALLY IN JOINTS,

MUSCLES, AND SOFT TISSUES1

EXCESSIVE BLEEDING FOLLOWING TRAUMA

OR SURGERY1

WHOLE BLOOD OR FRESH PLASMA

TREATMENTS2 CRYOPRECIPITATES3

FVIII CONCENTRATES

BECOME COMMERCIALLY

AVAILABLE3

1950 19901970 20101960 20001980 2020

WFH FIRST RECOMMENDS FACTOR PROPHYLAXIS

FOR SEVERE HEMOPHILIA PATIENTS5

BYPASSING AGENT

BECOMES AVAILABLE4

RECOMBINANT FVIII PRODUCTS

BECOME AVAILABLE6

EHL FACTOR PRODUCTS BECOME

AVAILABLE6

Prophylaxis with factor treatment is the standard of care for patients with severe hemophilia A8

1. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 2. Franchini M and Mannucci PM. Orphanet J Rare Dis. 2012;7:24; 3. Jones P. Br J Haematol. 2000;111:719-725; 4. US Food and Drug Administration Web site. User fee billable biologic products and potencies approved under Section 351 of the PHS Act. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm122936.htm. Accessed May 1, 2017; 5. Coppola A and Franchini M. Blood Transfus. 2013;11:327-329; 6. Peyvandi F et al. Lancet. 2016;388:187-197; 7. Carr ME and Tortella BJ. J Blood Med. 2015;6:245-255; 8. Poon MC and Lee A. Thromb J. 2016;14(suppl 1):32; 9. Valentino LA. Haemophilia. 2014;20:607-615.

Participant Guide

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HEMOPHILIA A CASE STUDIES

JESSE, AN ACTIVE ADOLESCENT WITH HEMOPHILIA A

MARK, A HEMOPHILIA A PATIENT ON EHL TREATMENT REQUIRING SURGERY

DANIEL, A HEMOPHILIA A PATIENT WITH A PHARMACOKINETIC-BASED TREATMENT REGIMEN

INTRODUCTION: HEM

OPHILIA A AND B

INTRODUCTION: HEMOPHILIA A AND B

INTR

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TION

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MOP

HILI

A A

AND

B

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AN INTRODUCTION TO HEMOPHILIA A AND B

HEMOPHILIA PATIENTS LACK CRUCIAL FACTORS OF THE COAGULATION CASCADE1

• Hemophilia is caused by the absence or defect of crucial constituents of the coagulation cascade

• Hemophilia A is the most common type of hemophilia and is due to a lack of FVIII

• The next most prevalent type is hemophilia B, which occurs in patients who lack FIX

COAGULATION CASCADE1

Factor treatment replaces what’s missing in the coagulation cascade for people with hemophilia2

1. Retzios AD. Bay Clinical R&D Services, LLC Web site. http://adrclinresearch.com/Issues_in_Clinical_Research_links/The%20New%20Factor%20VIIas_18May2011.pdf. Accessed June 13, 2017; 2. Peyvandi F et al. Lancet. 2015;388:187-197.

Image adapted from Retzios AD. Bay Clinical R&D Services, LLC. Web site. http://adrclinresearch.com/Issues_in_Clinical_Research_links/The%20New%20Factor%20VIIas_18May2011.pdf. Accessed June 13, 2017.

INTRINSIC PATHWAY

COMMON PATHWAY EXTRINSIC PATHWAY

Ca++ = Calcium ionPL = PhospholipidsTF = Tissue factor

Blood coagulation

(prothrombin) (thrombin)

FIX FIXa FX

FXa

CLOT

FII FIIa

FXII FXIIa

FXI FXIa

FV FVa

FI FIa

FXIII FXIIIa

fibrin polymer

Ca++-PL

(fibrin)(fibrinogen)

FVIIa FVII

FVIIIaFVIII

TFPITF

TF

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FACTOR ACTIVITY IS REGULATED BY THE NATURAL HEMOSTATIC PROCESSES OF ACTIVATION AND INACTIVATION1-4

DURING A BLEED, FACTOR ACTIVITY IS ACTIVATED, LOCALIZED, THEN INACTIVATED ONCE THE BLEED IS CONTROLLED2,4-7

VWF = von Willebrand factorAPC = activated protein C

1. Lenting PJ et al. Blood. 1998;92:3983-3996; 2. Berg JM et al. In: Biochemistry. 5th ed. New York, NY: WH Freeman; 2002; 3. Hoffman M and Monroe DM. Thromb Haemost. 2001;85:958-965; 4. Johari V and Loke C. Dis Mon. 2012;58:421-423; 5. Stavenuiter F et al. Hematol Educ. 2013;7:365-374; 6. Gale AJ. Toxicol Pathol. 2011;39:273-280; 7. Colvin BT. Vox Sanguinis. 2004;87(suppl 1):S43-S46; 8. Wolberg AS. Haemophilia. 2010;16(suppl 3):7-12.

Inactivation is an important step in the hemostatic process as unchecked thrombin generation could lead to thrombotic risk over time7,8

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1. Franchini M and Mannucci PM. Orphanet J Rare Dis. 2012;7:24; 2. Peyvandi F et al. Lancet. 2016;388:187-197; 3. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 4. Manco-Johnson MJ. N Engl J Med. 2007;357:535-544; 5. National Institutes of Health Clinical Trials Registry Web site. Ongoing and complete clinical trials using factor in patients with hemophilia. https://clinicaltrials.gov/ct2/results/details?term=Factor+VIII&recr=Closed&fund=2. Accessed April 28, 2017; 6. US Food and Drug Administration Web site. User fee billable biologic products and potencies approved under Section 351 of the PHS Act. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ ucm 122936.htm. Accessed May 1, 2017; 7. Valentino LA. Haemophilia. 2014;20:607-615.

FACTOR TREATMENT IS AN ESTABLISHED OPTION WITH A LONG HISTORY OF RESULTS1

FACTOR TREATMENT CAN BE USED IN THE FOLLOWING SCENARIOS2,3

• Extensive experience using factor treatment has shown benefits in managing, controlling, and reducing bleeds1,4

• It is proposed that all bleeding, including subclinical bleeding, can result in irreversible impairments in joint and bone health4

• Factor treatment has also been studied in more than 170 clinical studies and been used for over 50 years, and has demonstrated consistent bleed reduction benefits4-7

ON-DEMANDINFUSED TO CONTROL

BLEEDS ONCE THEY BEGIN

PROPHYLAXISINFUSED ROUTINELY TO

PREVENT BLEEDS

SURGERYINFUSED TO PREVENT/

MANAGE BLEEDS DURING OR AFTER SURGERY

PATIENT CASES: HEM

OPHILIA A-1

PATIENT CASES: HEMOPHILIA A

JESSE, AN ACTIVE ADOLESCENT WITH HEMOPHILIA A

PATI

ENT

CASE

: HE

MOP

HILI

A A

JESS

E

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a Based on a hypothetical patient 1. Chambost H et al. J Pediatr. 2002;141:548-552; 2. Mannucci PM and Tuddenham EG. N Engl J Med. 2001;344:1773-1779.

JESSE, AN ACTIVE ADOLESCENT WITH HEMOPHILIA Aa

PATIENT HISTORY• Diagnosed with severe hemophilia A (FVIII levels <1 IU/dL) after

a circumcision

• No family history of hemophilia

MEDICATION HISTORY• Prescribed standard half-life recombinant FVIII treatment

– As a toddler: FVIII prophylaxis every other day

– 3 years ago treatment changed to FVIII prophylaxis every other day with an increase in dose because of an increase in his activity; his current prophylactic regimen is shown below

Sun Mon Tues Wed Thurs Fri Sat

40 IU/kg 40 IU/kg 40 IU/kg

40 IU/kg 40 IU/kg 40 IU/kg 40 IU/kg

Hemophilia Facts• Roughly one-third of babies born with hemophilia have no family history1,2

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a Based on a hypothetical patient ABR = annual bleed rate; WFH = World Federation of Hemophilia.

1. Broderick CR et al. JAMA. 2012;308:1452-1459; 2. World Federation of Hemophilia. Guidelines for the Management of Hemophilia, 2nd ed. Montreal, Quebec: World Federation of Hemophilia; 2012; 3. Den Uijl IE et al. Haemophilia. 2011;17:849-853.


CURRENT SITUATION• Jesse, now 12 years old, and his parents are in for their biannual

appointment with his physician/hematologist

• They would like to talk about changes in his life and discuss different treatment options – He has been on the same prophylactic regimen for 3 years; his mom makes sure he

performs his infusions, and his current ABR is 5

– Jesse wants to play tennis, but has a target joint in his elbow

• Jesse and his family are interested in an EHL treatment

What aspects of Jesse’s life or situation would you consider prior to making a decision?

How would you decide if Jesse is a good candidate for an EHL treatment?

How would you determine the dose?

How would your approach change if Jesse were playing a different sport with a higher risk of bleeding?

Hemophilia Facts• In children and adolescents, vigorous activity is transiently associated with a moderate

relative increased risk of bleeds1

• WFH guidelines recommend prophylactic factor treatment prior to engaging in activities with a higher risk of injury2

• For severe hemophilia patients (FVIII levels <1 IU/dL), it has been shown that joint bleeding may occur at a younger age compared with patients with moderate hemophilia (FVIII levels 1-5 IU/dL)3

Participant Guide

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a Based on a hypothetical patient PK = pharmacokinetics.

1. Berntorp E and Andersson NG. Semin Thromb Hemost. 2016;42:518-525; 2. Collins PW et al. J Thromb Haemost. 2010;8:269-275.


JESSE’S HEMATOLOGIST ADJUSTS HIS DOSING SCHEDULE TO BETTER ACCOMMODATE HIS ACTIVITIES AND LIFESTYLE• Based on the results of Jesse’s PK assessment, his new dose is

determined to be 50 IU/kg with twice-weekly dosing scheduled to better coincide with practices and tournaments (see graph1)

JESSE HAS A BREAKTHROUGH BLEED DURING PRACTICE• As this was a breakthrough bleed the day before his next infusion with

EHL treatment, Jesse infused another dose to control the bleed

FVIII half-life may vary from patient to patient2

This chart is a visual representation only. It does not show actual patient data. Not all activities shown are appropriate for all patient types. Discuss what activities your patients plan to engage in and an appropriate plan of treatment

How would you explain EHL treatment to Jesse and his family?

What are your recommendations for patients with breakthrough bleeds on a prophylactic regimen?

FVIII dosing

100

80

60

40

20

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FVIII dosing

Mon0 Tues Wed Thurs Fri Sat Sun

Tennis tournament

Tennis practice

Targ

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Fact

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aBased on a hypothetical patient

1. Valentino LA. Haemophilia. 2014;20:607-615; 2. Collins PW et al. J Thromb Haemost. 2010;8:269-275; 3. Berntorp E and Andersson NG. Semin Thromb Hemost. 2016;42:1-8; 4. Seuser A et al. Haemophilia. 2007;13:47-52.

This chart is a visual representation only. It does not show actual patient data. Not all activities shown are appropriate for all patients. Discuss an appropriate plan of treatment based on the activities your patients plan to engage in.


KEY TAKEAWAYS • Factor treatment allows for individualized dosing1

• Prophylaxis regimens can be adjusted according to a patient’s changing lifestyle, activities, and PK profile2,3

ACHIEVING AN INDIVIDUAL PEAK FACTOR LEVEL4,a PATIENT CASES: HEM

OPHILIA A-2

Targ

et P

eak

Fact

or L

evel

s, %

Golf (Low risk)

Golf (Low risk)

Running (Medium risk)

Tennis (Medium risk)

Dosing Regimen

100

80

60

40

20

0

0


MARK, A HEMOPHILIA A PATIENT ON EHL TREATMENT REQUIRING SURGERY

PATI

ENT

CASE

: HE

MOP

HILI

A A

MAR

K

Participant Guide

33aBased on a hypothetical patient

MARK, A HEMOPHILIA A PATIENT ON EHL TREATMENT REQUIRING SURGERYa

PATIENT HISTORY• 58-year-old male

• Developed 2 target joints: his left ankle and left elbow

• Has severe end-stage arthropathy in his ankle

• Reports pain in his ankle despite no bleeding episodes on his current medication

MEDICATION HISTORY• Prescribed on-demand treatment for much of his life

• Started prophylaxis with standard rFVIII 5 years ago

• One year ago, switched to an EHL prophylaxis regimen (45 IU/kg twice weekly)

What other information would you like to know about Mark?

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a Based on a hypothetical patient MASAC = Medical and Scientific Advisory Council.

1. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 2. National Hemophilia Foundation. MASAC guidelines for emergency department management of individuals with hemophilia. Document #175. https://www.hemophilia.org/sites/default/files/document/files/175.pdf. Accessed March 15, 2017.


MARK PRESENTS WITH INCREASED ANKLE PAIN• The pain in his ankle has made it very difficult for Mark to be active with

his grandchildren

• Because of the debilitating pain and lack of improvement, Mark and his doctors decide that ankle fusion surgery is appropriate

What would your treatment plan be if the EHL product Mark is currently using is not on formulary?

What would your treatment plan be if the EHL product Mark is currently using is on formulary?

What are your main concerns heading into surgery?

Hemophilia Facts• Arthrodesis of the ankle could provide pain relief and correction of deformity

with marked improvement in function1

• MASAC and WFH guidelines recommend adequate factor coverage in patients undergoing planned or unplanned surgeries1.2

• A hemophilia patient requiring surgery is best managed at or in consultation with a comprehensive hemophilia treatment center1

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1. Srivastava A et al. Haemophilia. 2013;19:e1-e47.


MARK’S SURGERY• Mark’s hematologist assesses his PK

– Mark’s FVIII half-life is 12-14 hours

• Before surgery – Mark was screened for the presence of inhibitors

– Mark was given an FVIII loading dose of 50 IU/kg immediately prior to surgery to ensure that his FVIII levels were adequate heading into surgery

– Twenty minutes after replacement treatment, his FVIII levels were rechecked

• During surgery – Mark was continuously assessed for bleeding

– FVIII replacement treatment was given at 50 IU/kg repeated 8 hours after transfusion

How frequently do you monitor FVIII levels during surgery?

How would you approach Mark’s postoperative care?

Hemophilia Facts• The recommended preoperative levels of FVIII for major and minor surgery are

80-100 IU/dL and 50-80 IU/dL, respectively1

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How would this process have differed for an unplanned surgery?


MARK’S SURGERY (CONT’D)• After Surgery

– After surgery, Mark’s FVIII level was 65% and he was given an infusion of 50 IU/kg

– Mark was then infused with 50 IU/kg every 8 hours for the first day, then every 12 hours the next day, before switching to daily infusions for 7 days

– Bandages were changed and sutures removed only when necessary, and only after administering factor treatment

• Follow-up

• Mark’s surgery was successful, and his pain has decreased during the weeks following his surgery

• He has returned to his EHL prophylaxis regimen and has physical therapy twice a week

KEY TAKEAWAYS• Surgery for patients with hemophilia will require more planning and interaction

with the health care team than what is required for other patients1

• Adequate laboratory support is required for reliable monitoring of clotting factor level and inhibitor testing during surgery1

PATIENT CASES: HEM

OPHILIA A-3


DANIEL, A HEMOPHILIA A PATIENT WITH A TAILORED TREATMENT REGIMEN

BASED ON HIS PHARMACOKINETIC PROFILEPATI

ENT

CASE

: HE

MOP

HILI

A A

DANI

EL

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1. Valentino LA. Haemophilia. 2014;20:607-615.

DANIEL, A HEMOPHILIA A PATIENT WITH A PHARMACOKINETIC-BASED TREATMENT REGIMENa

PATIENT HISTORY• Daniel, 28 years old, has been on an every-2-day prophylactic dosing regimen

with a standard rFVIII product for the last year

DANIEL RECENTLY EXPERIENCED BLEEDING EPISODES• Daniel just came in for his biannual visit, and recently had a few bleeds

• He wants to reduce the number of bleeding episodes

• He explains that he just took a job as a high school teacher, so he is on his feet for much of the day, and he has to keep up with his 2.5-year-old toddler

• Because of his new job and increasingly active toddler, Daniel will be more active all around

Sun Mon Tues Wed Thurs Fri Sat

25 IU/kg 25 IU/kg 40 IU/kg

What would you attribute Daniel’s recent bleeding episodes to?

What changes, if any, would you want to make to Daniel’s treatment? What factors would you consider in making that decision?

Hemophilia FactsThe following factors can contribute to a patient’s bleeding risk1

Image adapted from Valentino LA. Haemophilia. 2014;20:607-615.

EARLY TREATMENT

PHYSICAL ACTIVITYIN VIVO RECOVERY

AGE AT FIRST HEMARTHROSIS

AGE AT START OF PROPHYLAXIS

PRESENCE OF TARGET JOINTS

HALF-LIFE

ADHERENCE

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1. Valentino LA. Haemophilia. 2014;20:607-615; 2. Collins PW et al. J Thromb Haemost. 2010;8:269-275.


DANIEL’S HEMATOLOGIST CONDUCTS A PK ASSESSMENT• To help address Daniel’s desire to reduce the number of bleeds, his

hematologist assesses his PK profile

• Based on the results of his PK assessment, Daniel’s hematologist explains to him that he was not receiving enough coverage on his current dosing regimen – His FVIII peaks were low, and the time spent below his personalized FVIII

trough level was not ideal

How does PK analysis influence how you manage your patient?

Do you consider the accuracy of the PK analysis important in shaping your decision?

Hemophilia Facts• PK analysis, by providing quantitative data about FVIII half-life as well as peak and

trough levels, enables more precise tailoring of the prophylactic dose and dosing interval to minimize bleeding risk1

• FVIII half-life varies from patient to patient1,2

• Maintaining an adequate trough level and minimizing the time spent per week with FVIII concentrations below a certain level are key to successful prophylaxis treatment1

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1. ADVATE [prescribing information]. Lexington, MA: Shire US Inc; 2016; 2. Berntorp E and Andersson NG. Semin Thromb Hemost. 2016;42:1-8.

Would you consider another PK assessment on the new treatment?

What are your recommendations for Daniel’s new dose/frequency?

A diagram such as this one could help explain to Daniel how EHL treatments allow for less-frequent administration while still maintaining adequate protection against bleeds2

This chart is a visual representation only. It does not show actual patient data.


FOLLOW-UP• Daniel’s hematologist gives him 2 options: infuse more frequently or

switch to an EHL FVIII

• Daniel wants fewer infusions, so he opts for an EHL FVIII

Mon WedTues Thurs Fri Sat Sun

EHL rFVIII

Standard rFVIII1

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1. Valentino LA. Haemophilia. 2014;20:607-615.

This chart is a visual representation only. It does not show actual patient data. Activity shown may not be appropriate for all patients.


FOLLOW-UP (CONT’D)• Daniel is now on an EHL FVIII product at a dose of 50 IU/kg twice per

week to allow for coverage and reduction in the number of bleeds

KEY TAKEAWAYS• Many different considerations can impact patients’ needs and goals of

treatment; therefore, it is important to evaluate them thoroughly when developing a treatment plan1

• Determining the contributors to bleeding for the individual patient and tailoring the prophylactic regimen has the potential to improve clinical outcomes1

• Assessment of FVIII trough and peak levels may help fine-tune a patient’s prophylactic regimen and allow him or her to achieve predetermined goals1

PATIENT CASES: HEM

OPHILIA A-4

100

80 Playing With Son

Dosing Regimen

60

40

20

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INTRODUCTION:HEMOPHILIA A AND B

WITH INHIBITORS

INTR

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AND

B W

ITH

INHI

BITO

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HEMOPHILIA A WITH INHIBITORS CASE STUDIES

GEORGE, A HEMOPHILIA A PATIENT WHO HAS A NONRESPONSIVE BLEED

ROSS, A HEMOPHILIA A PATIENT WITH AN INHIBITOR AND AN ACTIVE LIFESTYLE

PATRICK, A 31-YEAR-OLD HEMOPHILIA A PATIENT WITH AN INHIBITOR UNDERGOING SURGERY

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AN INTRODUCTION TO HEMOPHILIA WITH INHIBITORS

HEMOPHILIA PATIENTS ARE AT RISK OF DEVELOPING AN INHIBITOR1,2

• The cumulative incidence (ie, lifetime risk) of inhibitor development in patients with severe hemophilia A is in the range of 20%-30%, and approximately 5%-10% in moderate or mild patients1

• The incidence of developing an inhibitor in hemophilia B patients is up to 6%2

• Inhibitors are antibodies that inactivate the infused factor treatment3

INHIBITORS ARE MORE FREQUENTLY ENCOUNTERED IN YOUNGER PATIENTS WITH SEVERE HEMOPHILIA1

• The risk of developing an inhibitor is greatest during the first 50 exposures to FVIII3

DIFFERENT PATIENT- AND TREATMENT-RELATED FACTORS MAY PLACE PATIENTS AT RISK OF DEVELOPING AN INHIBITOR3

MHC = major histocompatibility complex; IL = interleukin; TNF = tumor necrosis factor; CTLA-4 = cytotoxic T-lymphocyte–associated protein 4.

1. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 2. DiMichele D. In Schulman S, ed. Treatment of Hemophilia, 4th ed. Quebec, Canada; World Federation of Hemophilia. 2008:7;1-9; 3. Kempton CL and White GC. Blood. 2009;113:11-17.

Inhibitor Development in Hemophilia A

Lifetime Risk Median Age

Severe hemophilia 20%-30% ≤3 years

Moderate hemophilia 5%-10% ≈30 years

Patient-Related

Race

Family history

FVIII mutation

MHC class

Polymorphisms of immune-response genes (IL-10, TNF, CTLA-4)

Treatment-Related

Number of FVIII exposure days

Age at first exposure to FVIII concentrates

Concurrent infection/inflammatory state

Intensive exposure to FVIII concentrates

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HOW ARE INHIBITORS DETECTED?

• An inhibitor titer of ≥0.6 BU/mL is to be taken as clinically significant2

1. Kempton CL and White GC. Blood. 2009;113:11-17; 2. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 3. Duncan E et al. Methods Mol Biol. 2013;992:321-322.

CLINICAL INDICATION OF AN INHIBITOR1

• Poor recovery

• Shortened half-life

• Inadequate clinical response

Nijmegen-Modified Bethesda Assay2

Patient

Patient SampleFVIII-Deficient

Plasma

Incubate 2 hours

Measure factor activity

One Bethesda unit (BU) is defined as that amount of inhibitor that results in 50% residual FVIII coagulant activity3

Buffered Pooled Normal Plasma

Buffered Pooled Normal Plasma

Control

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1. MASAC National Hemophilia Foundation Web site. MASAC recommendation regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors. Document #167. https://www.hemophilia.org/sites/default/files/document/files/167.pdf. Accessed June 29, 2017; 2. Leissinger CA. Am J Hematol. 2004;77:187-193; 3. Ananyeva NM et al. Semin Thromb Hemost. 2009;35:735-751; 4. Shapiro AD and Hedner U. Ther Adv Drug Saf. 2011;2:213-225.

BYPASSING AGENTS

BYPASSING AGENTS ARE A RECOMMENDED TREATMENT FOR HEMOPHILIA PATIENTS WITH INHIBITORS1

• Bypassing agents circumvent the need for FVIII or FIX by supplementing other factors in the coagulation cascade2,3

BYPASSING AGENT ACTIVITY CAN SUPPLEMENT A COMBINATION OF ONE OR MORE OF THE FOLLOWING FACTOR(S)4

There are serious risks of thrombotic and thromboembolic events with the use of bypassing agents. Patients should be monitored for the development of signs and

symptoms of thrombosis.5

INTRINSIC PATHWAY

COMMON PATHWAY EXTRINSIC PATHWAY

These are the sites in the blood-clotting process where Bypassing Agents add Factors to compensate for missing FVIII or FIX

APC = Activated Protein CAT = AntithrombinCa++ = Calcium IonPL = PhospholipidsTF = Tissue FactorTFPI = Tissue Factor Pathway InhibitorTM = Thrombomodulin

Blood coagulation

(prothrombin) (thrombin)

FIX FIXa FX

FXa

CLOT

FII FIIa

FVIIa FVII

FXII FXIIa

FXI FXIa

FV FVa

FI FIa

FXIII FXIIIa

X XFVIII FVIIIaExample missing FactorsExample missing Factors

fibrin polymer

Ca++-PL

(fibrin)(fibrinogen)

TFPITFPI

AT

TMAPC

Protein S

TF

TF

Image adapted from Retzios AD. Bay Clinical R&D Services, LLC. Web site. http://adrclinresearch.com/Issues_in_Clinical_Research_links/The%20New%20Factor%20VIIas_18May2011.pdf. Accessed June 13, 2017.

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FDA = US Food and Drug Administration.

1. Shapiro AD and Hedner U. Ther Adv Drug Saf. 2011;2:213-225; 2. Astermark J et al. Blood. 2007;109:546-551; 3. Peyvandi F et al. Lancet. 2016;388:187-197; 4. Berntorp E et al. Haemophilia. 2011;17e202-e210; 5. Santagostino E et al. Blood Rev. 2015;29(suppl 1):S9-S18; 5. Leissinger CA. Am J Hematol. 2004;77:187-193.

THERE ARE 2 BYPASSING AGENTS AVAILABLE FOR PEOPLE WITH INHIBITORS1

• pd-aPCC (plasma-derived activated protein complex concentrate)• rFVIIa (recombinant activated factor VIIa)

INDIVIDUAL RESPONSES TO BYPASSING AGENTS ARE HIGHLY VARIABLE2

• In the FENOC study, the hemostatic effect of each drug was evaluated in a crossover equivalence study design2

• One of the main findings was that substantial within-individual discordance with respect to the efficacy ratings between the 2 products was observed; there was no significant preference for either drug2

• 33%-40% of patients responded to one and not the other up to 12 hours post infusion; the variability in patient response reduced to 7.3% after 48 hours2

HAVING MULTIPLE BYPASSING AGENTS AVAILABLE FOR USE PROVIDES INDIVIDUALIZED OPTIONS FOR PATIENT TREATMENT3

• Bypassing agents have been prescribed in the following scenarios: prophylaxis, on-demand, and surgery3-5

• Combination sequential use of bypassing agents has been reported in cases of refractory bleeds3

– There are no FDA-approved bypassing agents indicated for combined-use sequential treatment3

What has your experience been with treating hemophilia patients with inhibitors?

There are serious risks of thrombotic and thromboembolic events with the use of bypassing agents. Patients should be monitored for the development of signs and

symptoms of thrombosis.1

HEMOPHILIA PATIENTS W

ITH INHIBITORS: CASE STUDIES

PATIENT CASES: HEMOPHILIA A WITH INHIBITORS

GEORGE, A HEMOPHILIA A PATIENT WITH AN INHIBITOR WHO HAS A NONRESPONSIVE BLEED

PATI

ENT

CASE

: HEM

OPHI

LIA

A W

ITH

INHI

BITO

RSGE

ORGE

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1. Berntorp E et al. Haemophilia. 2011;17:e202-e210.

GEORGE, A HEMOPHILIA A PATIENT WITH AN INHIBITOR WHO HAS A NONRESPONSIVE BLEEDa

PATIENT HISTORY• George was diagnosed with severe hemophilia A at birth

MEDICATION HISTORY• George has been on prophylaxis with standard FVIII treatment 3 times

per week at a dose of 30 IU/kg, 30 IU/kg, and 40 IU/kg

GEORGE HAS A NONRESPONSIVE BLEED• At 2 years of age, George finds himself in the hospital with a bleed in his

right ankle that is not responding to treatment – George’s parents have infused 3 times over the past 48 hours, but the bleed

has not resolved

Hemophilia Facts• Identification of a nonresponsive bleeding episode is based on the persistence

or worsening of pain, an increase or lack of change in swelling/tension, a decrease or lack of change in mobility relative to a bleed-specific baseline, patient perception of an active bleed, and laboratory parameters1

What would you check to assess why George’s bleeding has not stopped?

How often do you check for an inhibitor in your severe hemophilia A patients?

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67aBased on a hypothetical patient


DESPITE AN ADDITIONAL DOSE OF rFVIII, GEORGE’S BLEEDING EPISODE CONTINUES• George’s hematologist orders an x-ray to confirm that there are no

other potential causes of pain, swelling, or limited mobility that may be unrelated to the bleeding

• The hematologist also orders an assessment of George’s clotting factors and a Nijmegen-modified Bethesda assay to determine whether George may have an inhibitor

• George’s hematologist quickly prescribes treatment with a bypassing agent, which is able to control the bleeding

What do you do if a bleed does not resolve with the administered bypassing agent?

FVIII <1%

Inhibitor titer 22 BU

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1. National Hemophilia Foundation. MASAC recommendation regarding prophylaxis with bypassing agents in patients with hemophilia and high titer inhibitors. Document #220. https://www.hemophilia.org/sites/default/files/document/files/masac220.pdf. Accessed September 12, 2016; 2. National Hemophilia Foundation. MASAC recommendations on standardized testing and surveillance for inhibitors in patients with hemophilia A and B. Document #236. https://www.hemophilia.org/sites/default/files/document/ files/236.pdf. Accessed March 24, 2017; 3. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 4. Shapiro AD and Hedner U. Ther Adv Drug Saf. 2011;2:213-225; 5. Berntorp E et al. Haemophilia. 2011;17:e202-e210; 6. Peyvandi F et al. Lancet. 2016;388:187-197.


CURRENT SITUATION• Moving forward, George’s parents plan to use the bypassing agent for

his prophylactic treatment1

KEY TAKEAWAYS• Screening for and identification of an inhibitor is critical2

• Bypassing agents are recommended for treating hemophilia patients with inhibitors3

• There are 2 bypassing agents available for people with inhibitors4 – pd-aPCC4

– rFVIIa4

• Individual responses to bypassing agents are highly variable4

• Having multiple bypassing agents available for use provides individualized options for patient treatment5 – Combination sequential use of bypassing agents has been reported in cases of

refractory bleeds6

– There are no FDA-approved bypassing agents indicated for combined use or sequential treatment6

PATIENT CASES: HEM

OPHILIA A WITH

INHIBITORS


WITH INHIBITORSROSS, A HEMOPHILIA A PATIENT WITH AN

INHIBITOR AND AN ACTIVE LIFESTYLE

PATI

ENT

CASE

: HEM

OPHI

LIA

A W

ITH

INHI

BITO

RSRO

SS

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1. National Hemophilia Foundation Web site. MASAC recommendation regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors. Document #167. https://www.hemophilia.org/sites/default/files/document/files/masac167.pdf. Accessed June 14, 2017; 2. Colowick AB et al. Blood. 2000;96:1698-1702.

ROSS, A HEMOPHILIA A PATIENT WITH AN INHIBITOR AND AN ACTIVE LIFESTYLEa

PATIENT HISTORY• 35-year-old diagnosed with severe hemophilia A at birth

• Developed a high-titer inhibitor after treating a joint bleed with FVIII as a child (peak titer, 80 BU)

• Has 2 target joints: his right elbow and right knee

• Manages his bleeds on-demand

MEDICATION HISTORY• Treats bleeds (usually 1-2 per month) with a bypassing agent

ROSS’S BLEEDING EPISODES HAVE INCREASED• Ross recently took a job at a warehouse and has been using his arms a lot more

• He has also developed recurrent bleeds in his right knee

• He has had to treat 6 bleeds with his bypassing agent in the last 2 months

• He comes to his hematologist concerned about the increased frequency of his bleeds

What are some of your biggest concerns for managing Ross?

What would you want to know to determine the next steps for Ross?

Hemophilia Facts• Bypassing agents are a recommended treatment for hemophilia A patients with inhibitors1

• Patients with inhibitors have a higher likelihood of complications compared with patients without inhibitors2

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1. duTreil S. J Blood Med. 2014;5:115-122.


ROSS CONSULTS HIS HTC CARE TEAM• The HTC care team helps Ross determine an appropriate course of

action, with the goal of reducing the number of bleeding episodes

• They discuss Ross’s treatment history, inhibitor titer, current bleed rate, and lifestyle

What are some potential treatment approaches to minimize Ross’s risk of bleeds?

Hemophilia Facts• Treatment plans should involve the entire comprehensive team and encompass both

physical and psychosocial evaluations and intervention strategies1

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1. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 2. Poon MC and Lee A. Thromb J. 2016;14(suppl 1):32.

What goals would you set with Ross?

How would you assess if the new treatment plan is working?


ROSS’S NEW TREATMENT PLAN• After reviewing his medical history, Ross’s hematologist and care team

decide to recommend that Ross begin a prophylactic regimen with his bypassing agent

• Ross’s hematologist proposes this plan to Ross during his consultation

KEY TAKEAWAYS• For management of bleeding in patients with inhibitors, consultation

with a center experienced in their management is recommended1

• A patient’s lifestyle and activities they engage in are factors to consider when determining an appropriate prophylaxis regimen2

PATIENT CASES: HEMOPHILIA

A WITH INHIBITORS


WITH INHIBITORSPATRICK, A 31-YEAR-OLD HEMOPHILIA A PATIENT

WITH AN INHIBITOR UNDERGOING SURGERY

PATI

ENT

CASE

: HEM

OPHI

LIA

A W

ITH

INHI

BITO

RSPA

TRIC

K

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a Based on a hypothetical patient ER = emergency room.


PATRICK, A 31-YEAR-OLD HEMOPHILIA A PATIENT WITH AN INHIBITOR UNDERGOING SURGERYa

PATIENT HISTORY• Diagnosed with severe hemophilia A as a child

• He developed a high-titer inhibitor as a child (180 BU), which was discovered after a bleed in his left ankle that sent him to the ER

MEDICATION HISTORY• Has managed bleeds with prophylactic bypassing agent treatment and has a

current annual bleed rate of 6

PATRICK BREAKS HIS ARM AND REQUIRES SURGERY• He experiences a severe fall and breaks his arm, requiring surgery for the fracture

• He is rushed to the ER of a local hospital

• He has a medical alert bracelet for his condition, and the ER staff calls the HTC for guidance ahead of the surgery

What information would you need to know prior to surgery?

Hemophilia Facts• Surgery for patients with hemophilia will require more planning and interaction with the

health care team than what is required for other patients1

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1. Srivastava A et al. Haemophilia. 2013;19:e1-e47; 2. Kulkarni R. Haemophilia. 2013;19:2-10; 3. Teitel JM et al. Haemophilia. 2009;15:227-239.


PATRICK’S SURGERY• Before surgery

– Patrick’s inhibitor level was measured prior to beginning surgery (45 BU)

– The surgical team, hematologist, and anesthesiologist collaborated ahead of the procedure to develop a surgical plan

– He has no personal or family history of thrombosis

– He receives a one-time infusion of his current bypassing agent prior to surgery

• During surgery – The surgeon restores Patrick’s broken bone to its correct position

– The surgeon uses an ultrasonic scalpel to maintain hemostasis during the surgery

– Throughout the surgery, Patrick’s factor levels are monitored

How would you determine dosing before, during, and postsurgery?

What signs would you look for to assess thrombotic risk during surgery?

How would you change your perioperative treatment approach for major surgery? Major surgery is defined as a surgical procedure requiring hemostatic support for periods exceeding 5 consecutive days.1

Hemophilia Facts• A hemophilia patient requiring surgery is best managed at or in consultation with a

comprehensive HTC1

• Preoperative planning that includes a strategy for monitoring hemostasis during surgery is recommended2

• Ultrasonic scalpels may be safer than cautery in people with hemophilia, as cautery may lead to late bleeding in hemophilia patients; however, dissection with them is very slow, and slow surgery further increases risk of infection3

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1. Kulkami R. Haemophilia. 2013;19:2-10; 2. National Hemophilia Foundation Web site. MASAC recommendation regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors. Document #167. https://www.hemophilia.org/sites/default/files/document/files/masac167.pdf. Accessed June 14, 2017.

How would you monitor Patrick during his recovery?


PATRICK’S SURGERY (CONT’D)• After surgery

– Patrick remained in the hospital for 3 days before being discharged home

– His recovery was managed by the HTC

• Follow-up – Patrick resumes his prophylactic regimen after he recovers from surgery and is

discharged from the hospital

– He has physical treatment at the HTC twice per week, scheduled to coincide with his infusion dates

KEY TAKEAWAYS• Comprehensive care and advances in hemostatic treatments have

made it possible to safely perform a wide array of surgical procedures, specifically in patients with inhibitors1

• Bypassing agents can be used in patients with hemophilia A with inhibitors before, during, and after surgery2

SUMM

ARY

SUMMARY

SUM

MAR

Y

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1. Lenting PJ et al. Blood. 1998;92:3983-3996; 2. Johari V and Loke C. Dis Mon. 2012;58:421-423; 3. Berg JM et al. In: Biochemistry. 5th ed. New York, NY: WH Freeman; 2002; 4. Canadian Hemophilia Society. Factor replacement therapy. http://www.hemophilia.ca/en/bleeding-disorders/hemophilia-a-and-b/the-treatment-of-hemophilia/factor-replacement-therapy/. Accessed July 12, 2017; 5. Valentino LA. Haemophilia. 2014;20:607-615; 6. Peyvandi F et al. Lancet. 2016;388:187-197; 7. World Federation of Hemophilia. Guidelines for the Management of Hemophilia. 2nd ed. Montreal, Quebec: World Federation of Hemophilia; 2012; 8. National Institutes of Health Clinical Trials Registry Web site. Ongoing and complete clinical trials using factor in patients with hemophilia. https://clinicaltrials.gov/ct2/results/details?term=Factor+VIII&recr=Closed&fund=2. Accessed April 28, 2017; 9. US Food and Drug Administration Web site. User fee billable biologic products and potencies approved under Section 351 of the PHS Act. http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CBER/ucm122936.htm. Accessed May 1, 2017.

SUMMARY – FACTOR TREATMENT

• Factor plays an important role in a complex balancing act1-3

– Factor treatment replaces what’s missing in the coagulation cascade for people with hemophilia4

– Factor activity is regulated by the natural hemostatic processes of activation and inactivation—processes that are controlled1,3

• Factor treatment offers an individualized approach – A one-size-fits-all treatment approach does not meet the unique needs of all

patients5

– Factor treatment allows for individualized dosing5

– Dose and frequency of infusions can be adjusted based on the patient’s PK response and lifestyle needs5

• Factor treatment provides a comprehensive treatment approach6

– Factor treatment can be used in the following scenarios: prophylaxis, on-demand, and surgery6,7

• Factor treatment has also been studied in more than 170 clinical trials and used for over 50 years, and has demonstrated bleed reduction when given prophylactically5,8,9

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TF = tissue factor.

1. Leissinger CA. Am J Hematol. 2004;77:187-193; 2. Meeks SL and Batsuli G. Hematology Am Soc Hematol Educ Program. 2016;2016:657-662; 3. Shapiro AD and Hedner U. Ther Adv Drug Saf. 2011;2:213-225; 4. Hoffman M and Monroe DM. Thromb Haemost. 2001;85:958-965; 5. Retzios AD. Bay Clinical R&D Services, LLC Web site. http://adrclinresearch.com/Issues_in_Clinical_Research_links/The%20New%20 Factor%20VIIas_18May2011.pdf. Accessed June 13, 2017; 6. Astermark J et al. Blood. 2007;109:546-551; 7. Peyvandi F et al. Lancet. 2016;388:187-197; 8. National Hemophilia Foundation Web site. MASAC recommendation regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors. Document #167. https://www.hemophilia.org/sites/default/files/document/files/masac167.pdf. Accessed June 14, 2017; 9. National Institutes of Health Clinical Trials Registry Web site. Ongoing and complete clinical trials using bypassing agents in hemophilia patients with inhibitors. https://clinicaltrials.gov/ct2/results/details?term= hemophilia+a+with+inhibitors%2C+hemophilia+b+with+inhibitors&recr=Closed&cond=hemophilia+a+with+ inhibitors%2C+hemophilia+b+with+inhibitors. Accessed May 17, 2017; 10. Mehta R et al. Haemophilia. 2006;12(suppl 6):54-61.

SUMMARY – BYPASSING AGENTS

• Bypassing agents bypass the need for FVIII or FIX replacement therapy, not the coagulation process – They circumvent the need for FVIII or FIX by supplementing other factors in the coagulation

cascade1,2

– They help generate thrombin by supplementing factors that are naturally part of the coagulation cascade1,3

• Bypassing agents help maintain the delicate balance of hemostasis – During a bleed, bypassing agent activity is localized as procoagulant proteins localize to

TF-bearing cells and/or activated platelets3

– Since bypassing agents supplement factors that exist in the coagulation cascade, they are regulated by the already-coordinated activity of naturally occurring pro- and anticoagulants during a bleed4,5

• There are 2 bypassing agents available for people with inhibitors

– pd-aPCC (plasma-derived activated protein complex concentrate)2

– rFVIIa (recombinant activated factor VII)2

• Clinical responses to the bypassing agents are variable; in one study, 33%-40% of patients responded to one bypassing agent and not the other up to 12 hours post infusion, which reduced to 7.3% after 48 hours6

• Bypassing agents provide options for individualized treatment – Bypassing agents can be used in the following scenarios: prophylaxis, on-demand, and

surgery7,8

• Bypassing agents are also backed with extensive clinical experience and up to 40 years of use9,10

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Documents

A Case Study Discussion · • Hemophilia is caused by the absence or defect of crucial constituents of the coagulation cascade • Hemophilia A is the most common type of hemophilia