Managing Patients with Hemophilia: Coordinated Care for Optimal Clinical Outcomes

Surabhi Palkimas, PharmD Pharmacy Clinical Coordinator, Hematology University of Virginia Health System Presentation Objectives

• Discuss genetics and diagnosis of hemophilia • Describe clinical features of hemophilia • Discuss current and emerging treatment of hemophilia • Discuss treatment of congenital inhibitors Hemophilia: An Inherited Disorder

• X‐linked recessive bleeding disorder resulting in: Affected – Spontaneous bleeding Unaffected XY XX Carrier – Bleeding following trauma or surgery • Typically expressed in males XY XY XX XX –May also be expressed in females • Characterized by a deficiency of one or more clotting factors XY XX –Factor VIII (hemophilia A)

–Factor IX (hemophilia B) XY XY XX XX

Centers for Disease Control and Prevention. Hemophilia facts. http://www.cdc.gov/ncbddd/hemophilia/facts.html. Accessed October 2016. Detection and Diagnosis of Hemophilia

• Family history Laboratory Values – Positive family history Hemoglobin/Hematocrit Normal or low Platelet count Normal . Identify carriers Prothrombin time Normal . Pre‐conception counseling Activated partial • Significantly prolonged in . Cord blood testing of males thromboplastin time (aPTT) severe hemophilia • May be normal in mild and . Defer testing of females until moderate cases symptoms or considering Clotting factor tests Levels of Factor VIII/IX pregnancy • Normal • 50% to 100% • Mild • >5% to <50% –Negative family history • Moderate • 1% to 5% • Severe • <1% . Bleeding with birth trauma, circumcision, immunizations . Joint bleeds and hematomas appear when child begins to walk

Centers for Disease Control and Prevention. Hemophilia diagnosis. https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html. Accessed October 2016. Clinical Classification

Mild Moderate Severe Classification (30 to 40% of patients) (10% of patients) (30 to 40% of patients)

Factor VIII or factor IX activity 5% to <50% of normal 1% to 5% of normal <1% of normal

Pattern of bleeding episodes Uncommon ~4 to 6 per year ~2 to 4 per month

Cause of bleeding episodes Major trauma/surgery Minor trauma Spontaneous

More clotting factor Less clotting factor

Franchini M, et al. J Thromb Haemost. 2010;8:421‐432. Centers for Disease Control and Prevention. Hemophilia diagnosis. https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html. Accessed October 2016. Types of Bleeds

Joint Soft tissue (knee) (buttocks)

Deep muscle Intracranial (thigh) Hemophilia Care and Treatment

Goals Approach Strategies • Rapid and effective Comprehensive Hemophilia • Episodic or “on‐demand” replacement of missing Treatment Center (HTC) factor replacement factor: comprised of a • Prophylactic factor – Bleed prevention: multidisciplinary team of replacement experts who care for patients decrease frequency and • Continuous infusion for severity of bleeding with bleeding disorders including hematologists, long surgical procedures – Raise factor levels orthopedic surgeons, nurses, –Prevent the pharmacists, physical complications of bleeding therapists, social workers, and laboratory medicine

Centers for Disease Control. Hemophilia. http://www.cdc.gov/ncbddd/hemophilia/facts.html. Accessed October 2016. Evolution of Hemophilia Treatment

Low‐purity pd Intermediate‐ Manufacturing concentrates purity rFVIII changes for rFVIII concentrates available product

Mid Early Mid Late Early Late Early Late 1970s 1960s 1980s 1980s 1980s 1990s 1990s 2000s 2000s Today

Cryoprecipitate High‐purity Extended half‐life concentrates rFIX factor VIII and IX available

rFVIII=recombinant factor VIII rFIX=recombinant factor IX Hemophilia Treatment Options

Replacement of Desmopressin Adjunctive therapies missing clotting acetate • protein (DDVAP)/Stimate agents • Hemophilia A: • Synthetic vasopressin • Supportive measures Plasma‐derived and analog used in many including recombinant Factor patients with mild immobilization and VIII (FVIII) products hemophilia A for protection, rest, ice, • Hemophilia B: minor bleeding, and compression, Plasma‐derived and before and after elevation (PRICE) recombinant Factor IX surgery (FIX) products

National Hemophilia Foundation. http://www.hemophilia.org/Bleeding‐Disorders/Types‐of‐Bleeding‐Disorders. Accessed October 2016. Control of Acute Bleeding

Factor Level Frequency of Usual Duration Bleeding Episode Required Administration of Treatment (% of normal) Minor Every 12‐24 hours ± • Early hemarthrosis 30‐50 7 to 10 days • Minor muscle or oral bleed antifibrinolytic Moderate • Bleeding into muscles or oral Every 12‐24 hours 50‐80 7 to 10 days cavity until resolved • Definite hemarthrosis

Major • GI, intracranial, intra‐ Every 12‐24 hours 80‐100 7 to 10 days abdominal, intrathoracic, CNS, until resolved or retroperitoneal bleeding

World Federation of Hemophilia. http://www1.wfh.org/publications/files/pdf‐1494.pdf. Accessed October 2016. Dosing of FVIII and FIX Products

FVIII Products FIX Products

20 to 50 units / kg 40 to 100 units / kg Dose* body weight body weight

Half‐life 8to 12 hours 18 to 24 hours Average change in plasma factor activity +2% +1% with each unit/kg infused *Dosing of FVIII: • (Patient weight in kg) x 50 units/kg = 100% correction *Dosing of FIX: • (Patient weight in kg) x 100 units/kg = 100% correction

National Hemophilia Foundation. http://www.hemophilia.org/Bleeding‐Disorders/Types‐of‐Bleeding‐Disorders. Accessed October 2016. National Hemophilia Foundation. https://www.hemophilia.org/sites/default/files/document/files/Nurses‐Guide‐Chapter‐6‐Treatment‐of‐ Hemophilia‐A‐B.pdf. Accessed October 2016. Prophylactic Hemophilia Treatment

Prophylaxis: • Standard of care for children • Can be continued into adulthood when started in childhood Benefits Challenges • Reduces joint bleeds • Requires frequent factor • Reduces joint damage (as assessed administration by MRI) • Adherence • Disability prevention • Invasive, may require port access • Reimbursement

Oldenburg J. Blood. 2015;26;125:2038‐2044. Kempton CL, Meeks SL. Blood. 2014;124:3365‐3372. Manco‐Johnson MJ, et al. N Engl J Med. 2007;357:535‐544. Walsh CE, Valentino LA. Haemophilia. 2009;15:1014‐1021. Ragni MV, et al. Haemophilia. 2012;18:63‐68. Hemophilia Management Challenges

Prophylaxis/Treatment of Acute Bleeding • <50% of adults treat prophylactically • Identification of optimal trough levels •Peri‐surgical considerations Inhibitor Formation •Genetic predisposition • Associated with high morbidity

Fischer K, et al. Blood. 2013;122:1129‐1136. Manco‐Johnson MJ, et al. Haemophilia. 2013;19:727‐735. Gringeri A, et al. Haemophilia. 2012;18:722‐728. Simpson ML, Valentino LA. Expert Rev Hematol. 2012;5:459‐468. Sørensen B, et al. Haemophilia. 2012;18:598‐606. Konkle BA. Am J Hematol. 2012;87(Suppl 1):S27‐32. Shapiro A. Hematology Am Soc Hematol Educ Program. 2013;2013:37‐43. New and Emerging Therapeutics

• Extended half‐life (EHL) products allow for fewer infusions, longer protection • Several EHL FVIII and FIX factor replacement products have been recently approved and several more expected in the next few years –Safe, well tolerated –Improved half‐life (t½), recovery; delayed clearance –Efficacy and safety comparable to rFVIII and rFIX products

rFVIII=recombinant factor VIII; rFIX=recombinant factor IX Mahlangu J, et al. Blood. 2014;123:317‐325. Konkle BA, et al. Blood. 2015;126:1078‐1085. Powell JS, et al. N Engl J Med. 2013;369:2313‐2323. Collins PW, et al. Blood. 2014;124:3880‐3886. Sustained Factor Levels >1% Can Be Achieved with EHL Products

• Treatment with a rFVIIIFc for prophylaxis was associated with continued protection against bleeds

FVIII Activity >1%: FVIII Activity >1%: Standard Half‐Life Product Extended Half‐Life Product

rFVIII=recombinant FVIII (Advate) rFVIIIFc=recombinant FVIII Fc fusion protein (Eloctate) Mahlangu J, et al. Blood. 2014;123:317‐325. New and Emerging Treatment Options

Agent Manufacturer Description Status Recombinant Factor VIII Products (rFVIII) AFSTYLA (rVIII‐SingleChain) CSL Behring rFVIII Approved May 2016 KOVALTRY Bayer rFVIII Approved March 2016 NUWIQ Octapharma rFVIII Approved September 2015 NovoEight (turoctocog alfa) Novo Nordisk rFVIII Approved October 2013 ADYNOVATE Shire rVIII, long‐acting Approved November 2015 ELOCTATE Biogen rVIII, long‐acting Approved June 2014 N8‐GP (turoctocog alfa pegol) Novo Nordisk rVIII, long‐acting Phase 3 Recombinant Factor IX Products (rFIX) Emergent IXINITY (trenonacog alfa) rFIX Approved June 2015 Biosolutions RIXUBIS Shire rFIX Approved June 2013 IDELVION CSL Behring rFIX, long‐acting Approved March 2016 ALPROLIX Biogen rFIX, long‐acting Approved March 2014 N9‐GP (nonacog beta pegol) Novo Nordisk rFIX, long‐acting BLA submitted Inhibitors: Definition and Prevalence

• Polyclonal allo‐antibodies to the infused replacement factor Definition • Neutralize the procoagulant effect of the infused factor as well as naturally produced factor protein

• Develop in ~15‐20% of patients; greater prevalence in Prevalence hemophilia A (~30%) vs hemophilia B (2‐5%)

Age of • Typically develop early in life (median age 1.7–3.3 years) Onset

• Associated with high health care resource utilization (factor use, Burden hospitalization, etc) and increased morbidity and mortality

DiMichele D. World Hemophilia Federation. Inhibitors in Hemophilia: A Primer. Available at: http://www1.wfh.org/publication/files/pdf‐ 1122.pdf. Accessed October 2016. Soucie JM, et al. Haemophilia. 2001;7:198‐206. Risk Factors for Inhibitor Development

• Genetic –Factor deficiency –Disease severity Genetic – Hemophilia gene defect Mutation – Family history of inhibitor – Race/ethnicity individuals of African or Hispanic descent have 2x greater risk Inhibitor – Immune response and modifying genes • Treatment‐related Product Immune – Frequency and intensity of exposure to Exposure Response factor products –Type and structure of product used (SIPPET trial) –Greatest risk for inhibitor development occurs within first 50 exposures to infused product

Ragni MV, et al. Haemophilia. 2009;15:1074–1082. Peyvandi F, et al. N Engl J Med. 2016;374:2054‐2064. Diagnosis of Inhibitors

• A poor clinical response to factor products of lower FVIII/FIX level after factor product administration suggests the presence of inhibitors • A Bethesda inhibitor assay confirms their existence –Amount of antibody is reported as a number of Bethesda units (BU), or a Bethesda titer . High titer: >5 BU . Low titer: <5 BU –Higher the titer the more inhibitor is present

Collins PW, et al. Br J Haematol. 2013;160:153‐170. Currently Treatment Options for Inhibitors

Inhibitor Characteristics Treatment • Patients with low inhibitor titer (<5BU) • Immune Tolerance Induction • Treat with higher amounts of factor (ITI) concentrate to overcome the inhibitor • FVIII products and still form a clot • Patients with high inhibitor titer • Activated prothrombin complex • Instead of replacing the missing factor, concentrates (FEIBA VH; Baxter) treatment involves going around (or +/‐ Recombinant factor VIIa bypassing) the factors blocked by the (NovoSeven®RT; Novo Nordisk) inhibitor

Kempton CL, Meeks SL. Blood. 2014;124:3365‐3372. Immune Tolerance Induction

• Regular infusions of factor VIII or IX administered for a period Initiate immediately regardless of BU level; time to remission is of weeks to years in an effort decreased if started when inhibitors are to increase tolerance of the <10 BU/mL (ideally immune system <5 BU/mL) • Limitations include Patients whose peak –Variable efficacy (70‐85% for inhibitor levels have Initiating ITI within never reached 5 years of inhibitor FVIII and ~30% for FIX) >200 BU/mL and have diagnosis ideally stayed –Time‐consuming and <50 BU/mL expensive

DiMichele D. World Hemophilia Federation. Inhibitors in Hemophilia: A Primer. Available at: http://www1.wfh.org/publication/files/pdf‐ 1122.pdf. Accessed October 2016. Pro‐FEIBA: Study Results

• In comparison to aPCC on‐demand treatment, aPCC prophylaxis given at 85 U/kg ± 15% on 3 nonconsecutive days per week

Reduced all Reduced Reduced target bleeding by joint bleeding by joint bleeding by 62% 61% (P<0.001) (P<0.001) 72% (P<0.001)

aPCC=activated prothrombin complex concentrate (FEIBA)

Leissinger C, et al. N Engl J Med. 2011;365:1684‐1692. PROOF Study Results

• In comparison to aPCC on‐demand treatment, aPCC prophylaxis given at 85 U/kg ± 15% every other day

Reduced median ABR for all Reduced median bleeds by ABR for joint Reduced median bleeds by ABR in new target 72.5% joints* by (P=0.0003) 73.8% (P=0.0006) 100% (P=0.0271)

*Ankles, knees, elbows and/or hips with ≥4 bleeds over 6 months aPCC=activated prothrombin complex concentrate (FEIBA) ABR=annual bleed rate

Antunes S, et al. Haemophilia. 2014;20:65‐72. Recombinant Factor VIIa (rFVIIa)

• Complexed with tissue factor can activate coagulation and factor IX • Minimizes risk of systemic coagulation seen with FEIBA • Dose –90 mcg/kg every 2 hours until hemostasis is achieved

NovoSeven RT (coagulation factor VIIa [recombinant] Prescribing information. Novo Nordisk. October 2015. FEIBA and NovoSeven Appear to Exhibit a Similar Effect on Joint Bleeds

• FENOC Study – Prospective, open‐label randomized, 90% CI: ‐11.41‐15.67 100 crossover equivalency trial to test the P=0.59

equivalence of FEIBA and NovoSeven 80.9% 78.7% Hours

80 6

in the treatment of ankle, knee, and at elbow joint bleeding 60 Efficacy

• Parameter of interest: percentage of patients reporting efficacy in response 40

to FEIBA vs NovoSeven Reporting

–A difference of ≤ 15% determined to be a 20 Patients indicative of equivalence of the 2 products of

• Primary endpoint: Bleeding episodes 6 % 0 hours after treatment FEIBA NovoSeven

FENOC=FEIBA NovoSeven Comparative (FENOC) Study FEIBA (factor VIII inhibitor bypassing activity)=an activated prothrombin complex concentrate (aPCC) NovoSeven=recombinant factor VIIa (rFVIIa)

Astermark J, et al. Blood. 2007;109:546‐551. Dilemmas Encountered in Treating Inhibitors

• Treating and preventing bleeds –No universally effective agent . aPCC work in some, not all . rFVIIa works in some, not all –No laboratory test that accurately predicts or confirms hemostasis – rFVIIa has short half‐life, needs frequent infusions Emerging Agents for the Management of Inhibitors

Agent Description Status LR769 rFVIIa Phase 3 CSL689 rFVIIa‐FP Phase 2/3 ACE910 FVIIIa‐mimetic bispecific antibody Phase 2/3* ALN‐AT3 siRNA knockdown of antithrombin Phase 2/3 Factor VIIa‐CTP rVIIa‐CTP, long‐acting Phase 2

*breakthrough therapy designation Summary

• Hemophilia treatment goals include rapid and effective replacement of missing coagulation factor to prevent and/or decrease the severity of bleeding and prevent bleeding‐related complications –Emerging therapeutics in the form of EHL agents and therapies with novel mechanisms of action present promising options for the advancement of prophylaxis and management of hemophilia • Inhibitors and prophylaxis considerations represent two of the greatest clinical challenges in the treatment of hemophilia – Aggressive and vigilant therapeutic intervention is crucial to success and minimization of morbidity/mortality Jointly provided by This activity is supported by independent A Midday Symposium conducted at the educational grants from Alnylam Pharmaceuticals, 51st ASHP Midyear Clinical Meeting and Novo Nordisk, Inc., and Shire. Exhibition. Optimizing the Pre‐Certification and Prior Authorization Process

Amber Federizo, APRN, FNP‐BC Nurse Practitioner Hemophilia Treatment Center of Nevada Learning Objective

• Describe current and evolving strategies for health‐ system pharmacists to facilitate high quality care for patients with hemophilia What is Prior Authorization (PA)?

• Approval of a health care service before it is delivered • Proactive process to verify medical necessity and appropriateness of services • Often used as a cost‐ containment tool • Criteria are based on clinical guidelines and medical literature, and can vary by payer

Academy of Managed Care Pharmacy. April 2012. http://www.amcp.org/prior_authorization/. Accessed October 2016. What is Pre‐Certification?

• An administrative procedure that confirms patient eligibility for coverage prior to the delivery of care • Often required before hospital admissions, inpatient or outpatient surgeries, and elective procedures • Emergencies are usually exempt

American Medical Association. Standardization of prior authorization process for medical services white paper. June 2011. Role of the Pharmacist in PA and Pre‐Certification

• Possible roles for the pharmacist include – Collecting patient information – Verifying patients’ health insurance benefits – Submitting the required forms – Conducting regular status checks on the approval process – Filing an appeal if coverage is denied PA Submission Process

Collect Verify Submit Follow Appeals Information Benefits Request Up PA Submission Process: Collect Information

• Patient information including signed Collect consent/release form Information • Plan type • Insurance number • Contact information

• Diagnosis code(s) • Office notes • History and physical exam

• Statement of medical necessity PA Submission Process: Verify Benefits

• Contact payer to verify benefits and patient out‐of‐pocket expenses (eg, co‐pay, Verify deductible, out‐of‐pocket maximum) Benefits • Verify eligibility and medical policy requirements

• Verify physician and facility contract network status with payer

• Verify payer requirements for prior authorization PA Submission Process: Submit Request

• Contact payer to see if they have a required Submit payer submission form Request • Complete the required forms

• Attach requested clinical documentation alert

• Submit request and create a follow‐up alert PA Submission Process: Follow Up

• Routinely follow up with payers Follow Up • Document calls and interactions with payer (date, time, name of contact person, etc)

• Obtain reference numbers for all communication with payer

• Prior authorization approval can generally take between 3 and 30 days depending on the payer

• If approved, document approval number PA Submission Process: Appeals Process

• Make sure the physician and patient want to appeal the pre‐appeal denial Appeals • If an appeal is required, contact payer to determine their appeals process

• Attach requested documentation to appeal form and submit

• Follow up with payer for final prior authorization decision Optimizing the Approval Process Approval Processes Can Be Lengthy and Cumbersome

Day 1 Day 1Day 1‐14 Day ?

Physician Pharmacist Provider and After waiting Patient is sends a informs payer days or notified the prescription patient the exchange possibly prescription to the medication multiple calls, weeks, payer is available pharmacy requires a PA faxes, and grants PA for and initiates PA forms request pick up

AMCP Electronic Prior Authorization Work Group. J Manag Care Spec Pharm. 2015;21:545‐550. Streamlining Approval is a Top Priority for Payers

Current Gaps • Prescriber often not aware that prescribed drug requires PA • PA criteria not visible to the prescriber • Implementation of one off “work‐ arounds” to bypass or expedite PA process • Paper forms require manual entry and potential for error • Routes to obtain PA are not standardized and vary depending on the health plan, drug, pharmacy, and patient situation Optimizing the Approval Process: Best Practices

• Be familiar with the rules and appropriate procedures of each payer • Document events as they occur • Communicate clearly, precisely, and in a timely manner • Utilize electronic submission when available Current Methods of Communication Between Prescribers and Payers

Paper‐based • Pre‐printed paper forms faxed

Telephone‐based • Person‐to‐person/voice mail

Electronic • Digital systems integrated into the EMR and/or other online systems Streamlining the Process: Electronic PA

Benefit & formulary data referenced ELIGIBILITY REQUEST / RESPONSE

PA INITIATION REQUEST / RESPONSE

PHYSICIAN Pre‐approved PBM Notified if e‐prescription selected drug needs prior authorization

Academy of Managed Care Pharmacy/National Council for Prescription Drug Programs. http://www.amcp.org/ePA/. Accessed October 2016. Advantages of Electronic PA

• Leverages eligibility and formulary data to notify providers of PA requirements before prescribing • PA questions are sent to the EHR, based on patient, plan, and medication • Pre‐population of required patient information adds efficiency and accuracy to administrative tasks • Real‐time communications with payer (eg, PBM) to complete PA review before sending prescription to the pharmacy • Preapproved prescriptions routed to pharmacy • Minimizes delays in medication delivery to the patient

Academy of Managed Care Pharmacy/National Council for Prescription Drug Programs. http://www.amcp.org/ePA/. Accessed October 2016. Caveat: Electronic PA Implementation Varies Across Prescriber and Payer Settings

Prescriber Payer Fully‐ Capability Portal Portal Integrated • Integrated into physician EHR workflow  • Prospective workflow capabilities  • Retrospective workflow capability  • Integrated into the e‐prescribing workflow  • Automatically pull patient medical history from EHR into PA question set  • Broad connections to several PBMs/payers  • Bi‐directional network of PBM/payers and providers/EHRs 

Academy of Managed Care Pharmacy/National Council for Prescription Drug Programs. http://www.amcp.org/ePA/. Accessed October 2016. Summary

• PA is used to verify medical necessity and appropriateness of services, including prescription drugs • Pre‐certification is an administrative procedure that confirms patient eligibility for coverage prior to delivery of care • Best practices for optimizing the approval process include –Increased familiarity with the procedures of each payer –Real‐time documentation of events –Clear and timely communication between involved parties –Use of electronic submission where available Jointly provided by This activity is supported by independent A Midday Symposium conducted at the educational grants from Alnylam Pharmaceuticals, 51st ASHP Midyear Clinical Meeting and Novo Nordisk, Inc., and Shire. Exhibition. Emergency Department Patient Case Study: HTC and Health‐System Pharmacy Collaboration: Steps for Success

Amber Federizo, APRN, FNP‐BC Surabhi Palkimas, PharmD Nurse Practitioner Pharmacy Clinical Coordinator, Hematology Hemophilia Treatment Center of Nevada University of Virginia Health System Learning Objectives

• Explain hemophilia‐related complications associated with emergency department (ED) visits and its significant clinical and economic consequences • Identify processes for health‐system pharmacists to improve communications and collaborations with hemophilia treatment centers (HTCs) Patient Introduction

• 30‐year old, 14 weeks gravid female; G3P2A0 with mild Factor VIII deficiency (27%) • Examined in the Emergency Department for vaginal bleeding –Examination reveals gravid uterus and continuous vaginal bleeding • Husband reports they told ED staff at her bedside she has VWD and Hemophilia A –ED staff indicated they would contact the HTC – Attending on the case states that women do not have hemophilia and therefore the bleeding is only related to threatened miscarriage –Orders monitoring only Diagnosis and Initial Treatment

• PTT: 38 seconds • H and H fell precipitously within 4 hours – Required replacement with 10 units PRBCs • OB was finally contacted –Patient underwent an emergency D and C • Patient discharged at Day 3 with what was reported as spotting Follow Up

• Patient was seen in follow‐up at the HTC and provided with daily infusions for 3 days to stop the bleeding • She was subsequently referred to counseling secondary to severe grief Critical Issues

• Coordination of care between the ED, ICU, and HTC –Lack of adequate training –Lack of factor replacement product • Discharge and ongoing follow‐up care and monitoring Best Practice

• Contact HTC provider for any patient presenting with a suspected bleeding disorder • On call provider at the HTC sent to hospital to consult care or consult with ER and GYN • Pharmacy should stock factor on consignment • ER staff is trained to recognize, assess, and treat bleeding disorders • Patient receives replacement as soon as possible • Patient is scheduled with follow‐up visit at HTC clinic upon discharge