CME/MOC/CE/CPE Implementing Care With Extended Half-Life Factor VIII Therapy in Hemophilia A: An Interdisciplinary Conversation on Personalized Patient Management

Chair Doris Quon, MD, PhD Orthopaedic Hemophilia Treatment Center Los Angeles, California

Faculty Sean DeFrates, PharmD, BCOP Northwestern Memorial Hospital Chicago, Illinois

What’s Inside 4 A Closer Look at Hemophilia and Factor VIII Replacement Therapies for Hemophilia A 7 Extended Half-Life FVIII Regimens: Comparing the Options

10 Implications for Clinical Practice: Using a Collaborative Approach to Integrate EHL FVIII Regimens Into Practice

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Media: Enduring Material Continuing Pharmacy Education Accredited Activity Release Date: August 25, 2020 The Medical Learning Institute, Inc. is accredited by the Accreditation Accredited Activity Expiration Date: August 24, 2021 Council for Pharmacy Education as a provider of continuing pharmacy Time to Complete Activity: 30 minutes education. The Medical Learning Institute, Inc. (MLI) designates this continuing education Activity Description activity for 0.5 contact hours (0.05 CEUs) of the Accreditation Council for In this activity, experts in hemophilia discuss the use of extended half-life Pharmacy Education. replacement factor VIII products for the treatment of patients with hemophilia A. Universal Activity Number: 0468-9999-20-017-H01-P Type of Activity: Knowledge Target Audience This activity has been designed to meet the educational needs of hematologists, Faculty Disclosures nurse practitioners, physician assistants, clinical pharmacists, and other clinicians Chair involved in the management of patients with hemophilia A. Doris Quon, MD, PhD Medical Director Educational Objectives Orthopaedic Hemophilia Treatment Center Upon completion of this activity, participants will be able to: Los Angeles, California • Describe the benefits and limitations of conventional replacement factor VIII regimens for the management of hemophilia A Doris Quon, MD, PhD, has a financial interest/relationship or affiliation in the • Assess the latest clinical data regarding efficacy, safety, and tolerability of form of: extended half-life replacement factor VIII products for the treatment of Consultant and/or Advisor for Bayer Corporation; BioMarin; Genentech, Inc.; Novo hemophilia A Nordisk, Inc.; and Octapharma. • Incorporate extended half-life replacement FVIII regimens into the Speakers Bureau participant with BioMarin; Genentech, Inc.; Novo Nordisk, Inc.; management of patients with hemophilia A sanofi-aventis U.S. LLC; and Takeda Pharmaceuticals U.S.A., Inc. • Discuss the importance of a collaborative approach among physicians, pharmacists, and other clinicians in the management of patients with Faculty hemophilia A Sean DeFrates, PharmD, BCOP Pharmacy Practice Coordinator Providership, Credit, and Support Northwestern Memorial Hospital Chicago, Illinois This CME/MOC/CPE activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. Sean DeFrates, PharmD, BCOP, has no financial interests/relationships or affiliations in relation to this activity. This activity is supported by an educational grant from Bayer HealthCare Pharmaceuticals Inc. Planning Committee Disclosures Teresa Haile, RPh, MBA, Pharmacy Planner, MLI, has nothing to disclose. Physician Continuing Medical Education This activity has been planned and implemented in accordance with the The planners from Medical Learning Institute, Inc., the accredited provider, and accreditation requirements and policies of the Accreditation Council for PVI, PeerView Institute for Medical Education, joint provider, and the American Continuing Medical Education (ACCME) through the joint providership Academy of Physician Assistants reviewer do not have any financial relationships of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical with an ACCME-defined commercial interest related to the content of this Education. 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A Closer Look at Hemophilia and The genes that encode factor VIII and factor IX are located on the X chromosome, and because of this, there’s a sex-linked inheritance, Factor VIII Replacement Therapies so this disease almost exclusively affects males. The gene mutation for Hemophilia A for factor VIII or factor IX can result in either an abnormally low level of factor VIII or factor IX, or it can result in the total absence of Sean DeFrates, PharmD, BCOP factor VIII and factor IX. Northwestern Memorial Hospital Chicago, Illinois Bleeding Phenotype Dependent on Level of Clotting Factor Deficiency in Hemophilia1,2

Phenotype Factor Level Clinical Features • Bleed after severe injury or surgery Mild hemophilia >5% to 40% • Do not bleed often; some may never have bleeding problem

• May bleed for a long time after surgery, a bad Moderate hemophilia 1% to 5% injury, or dental work Dr. Quon: Hello, this is Doris Quon from Orthopedic Hemophilia • Experience spontaneous bleeding rarely

Treatment Center in Los Angeles. Welcome to this educational • Frequent and spontaneous bleeds into muscles Severe hemophilia <1% or joints (70% to 80% bleeds are hemarthrosis); activity on hemophilia, a program entitled: “Implementing up to 1 to 2 times/week without treatment

Care with Extended Half-Life Factor VIII Therapy in Hemophilia ~60% of hemophilia A ~44% of hemophilia B A: An Interdisciplinary Conversation on Personalized Patient cases are severe cases are severe Management.” Joining me in this discussion today is my pharmacy 1. https://www.wfh.org/en/page.aspx?pid=643. 2. Van Dijk K et al. Haemophilia. 2005;11:438-443. colleague Sean DeFrates from Northwestern Memorial Hospital in Chicago, where he is the Pharmacy Practice Coordinator. How this affects patients is categorized into three different categories. We bucket the severity into mild, moderate, and severe, Dr. DeFrates: Thank you, Dr. Quon. I’m glad to be here. We’ll and this is defined by the percent of factor level based on normal. start with this section going through some of the background of Patients with mild hemophilia are known to have factor levels hemophilia and begin to introduce our treatment options and between 5% and 40% of normal, moderate hemophilia between where we can improve moving forward. 1% and 5%, and severe is less than 1%.

While those are the definitions, the clinical features are what really Congenital Hemophilia1-4 distinguish the three phenotypes. Mild hemophilia may not even have a significant bleeding problem that is apparent. Moderate Secondary hemostasis disorders • X-linked inherited hemophilia generally has excessive bleeding after significant • Clotting factor VIII (FVIII) or FIX is absent or surgery, after bad injuries, or even after dental work. However, present in low levels patients with moderate hemophilia tend not to have spontaneous Hemophilia A (FVIII deficiency) bleeding. Spontaneous bleeding is more of a finding in severe • Affects 1/5,000 to 1/7,000 males hemophilia. It can be a significant issue.

Hemophilia B (FIX deficiency) • Affects 1/25,000 to 1/30,000 males Hemarthrosis: A Long-Term Complication With Hemophilia1

1. Mannucci PM, Tuddenham EG. N Engl J Med. 2001;344:1773-1779. 2. Srivastava A et al. Haemophilia. 2013;19:e1-e47. 3. Roberts HR et al. In: Kaushansky K et al, eds. Williams Hematology. 8th ed. New York, NY: McGraw-Hill Companies, Inc; 2010:2009-2029. 4. Butler RB. Basic Concepts of Hemophilia: A Self-Study and Planning Workbook for Families With a New Diagnosis of Hemophilia. Atlanta, GA: CDC; 2007. Without treatment, bleeding events for patients with hemophilia may be life-threatening or result in chronic disability from recurrent Dr. DeFrates: Congenital hemophilia is primarily made up of hemarthrosis and intramuscular bleeding hemophilia A and hemophilia B. Hemophilia A is a deficiency in Target Joint the coagulation factor VIII, whereas hemophilia B is a deficiency in Repeated bleeding in the same joint; knees, elbows, and ankles most frequently affected coagulation factor IX. As you can see, hemophilia A is significantly more prevalent than hemophilia B. However, both are rare Hemophilic Arthropathy Persistent intra-articular blood results disorders. in progressive degeneration of the joint cartilage and bone

1. Images courtesy of Dr. Mauricio Silva.

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Hemarthrosis, which is the classic hallmark finding of hemophilia, Treatment Strategies1,2 presents as both an acute and a long-term complication. As you can see on the left, the picture of the joint that has had bleeding On-Demand Treatment into it can be an acute issue both from a pain standpoint but • The infusion of the deficient clotting factor at the time of bleeding even could be life-threatening. Over time, this can evolve after recurrent bleedings into a more chronic condition that results in Prophylactic Treatment degeneration of bone, degeneration of cartilage, and eventually • Regular IV infusions of the deficient clotting factor with the goal of preventing bleeding episodes chronic pain syndromes, immobility—certainly impaired quality • Considered the standard of care in severe hemophilia of life from that. When patients have repeated bleeding into these joints, we often refer to that as a target joint. The preventive nature that we’re going to discuss as we talk about treatment tries to target these specific joints to prevent their rebleeding episodes. 1. Manco-Johnson MJ et al. N Engl J Med. 2007;357:535-544. 2. Peyvandi F et al. Lancet. 2016;388:187-197.

The treatment strategies that we utilize in practice can be Evolution of Hemophilia Treatment bucketed into two different ways. One is on-demand treatment. On-demand treatment is the infusion of clotting factor at the FFP Plasma-derived First-gen Third-genb cryoprecipitate factor concentrates rFVIII rFVIII time of bleeding. When a patient presents with a bleeding

Whole F8 gene and Second-gena Fourth-genc event, you’re providing the deficient coagulation factor to try blood cloning rFVIII rFVIII and stop that bleeding and mitigate any adverse effects of the Prior to 1950 to Early 1950 early 1970 1970 1980s 1992 2000 2003 2015 bleed. Prophylactic treatment is the infusion of those clotting factors without bleeding. It is to prevent bleeding episodes from 1950s 1960s 1970s 1980s 1990s 2000s occurring.

a Cell culture media with human serum albumin and human plasma protein solution. b Cell culture media without human- or animal-derived solution. Factor Concentrates for Hemophilia Management c Human cell line, post-translational modification.

Treatment is a critical aspect of hemophilia given that the • Virally inactivated presentation can be acute, it can be life-threatening, it can be severe, and has long-term complications. It’s important that we • Plasma-derived have an adequate treatment, and that treatment continues to – Pooled from up to 30,000 plasma donations improve over time. • Recombinant – Produced in Chinese hamster ovary, baby hamster Going all the way back to the 1950s and before, we see that the kidney, or human cell lines treatment of patients with hemophilia was a transfusion of whole blood. As we go to the spectrum on the right and move through time, we see that the treatments become more precise. A major treatment advance came in the 1980s when we cloned the factor Factor concentrates themselves, as we mentioned, can be VIII. We can see that moving into the early 1990s, we were finally plasma derived or can be recombinant. One of the important able to manufacture a recombinant version of factor VIII. From improvements made in treatment with factor VIII was related to that point forward, we were able to improve on the way that those the inactivation of viruses and viruses being transmitted via these recombinant products were produced. That’s what you see in the products. The inherent risk with a plasma-derived product is still differences in the generations of the recombinant products— going to be significantly higher than with a recombinant product, going from first to second to third and eventually into the fourth and that is because you’re pooling plasma from thousands and generation. thousands of donors. Recombinant products require the use of a living cell line to produce them. There are a number of different cell lines, and as the generations increase, we become more able to use human-based cell lines.

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Standard Half-Life Factor Concentrates Inhibitors are generally measured in what’s called Bethesda units, or BU, and that’s often per milliliter. And the frequency of

• Options inhibitor development is somewhere around 20% to 30% in severe – Plasma-derived versus recombinant hemophilia A. It’s a bit less in the mild and moderates—3% to – First- versus second- versus third-generation recombinant 13%—but still prevalent. • Vary in protein structure (full-length, b-domain–deleted or truncated), cell line, or production techniques The development of inhibitors is a significant issue because • Similar PK profiles with a mean half-life of 12 hours (FVIII) you can no longer use your factor VIII products to treat your in adults hemophilia A patients in most scenarios. Because of that, you have • Typical prophylaxis with SHL to find bypassing agents or treatments that don’t use the factor – 25 to 40 units/kg three times weekly (FVIII) VIII.

The standard half-life of these factor concentrates is one limitation of their use. We find that from a pharmacokinetic standpoint, the half-life of these factor VIII products—whether it’s first, second, or third generation, whether it’s plasma or recombinant—tends to be somewhere around 12 hours or a bit less than 12 hours. You’re typically giving factor VIII infusions three times a week, or every other day based on the patient.

Major Hurdles to the Optimal Management of Hemophilia A

Standard Hemophilia Drugs Short in vivo half-life of standard replacement Plasma-derived or recombinant products factors; adherence can become a major issue • Short half-life due to the need for frequent infusions • Frequent injections Treatment with standard products rFVIII half-life: ~8-12 hour was suboptimal

Development of inhibitors (neutralizing antibodies) to replacement factors

• The most serious complication of hemophilia today • An IgG antibody that inhibits infused factor • Measured in Bethesda Units (BU) • Frequency: severe hemophilia A, 20% to 30%; mild and moderate hemophilia A, 3% to 13%

Prior to 2017, only two treatments were approved for patients with hemophilia and inhibitors 1. rFVIIa 2. Activated prothrombin complex concentrate

That leads us into some of the major hurdles and challenges for the optimal management of hemophilia A. Adherence can be a major issue. That is a challenging regimen to keep up with no matter who you are. If we could identify products that would help improve that pharmacokinetic profile, that could help improve adherence and ultimately, clinical outcomes.

However, there’s another important clinical manifestation within hemophilia, and that is the development of what’s called inhibitors. Inhibitors are an immune response to the exogenous factor that’s being administered. For example, a patient with hemophilia A who’s being given factor VIII infusions to either treat or prevent bleeding episodes can develop an immune response and, ultimately, an IgG antibody response that eliminates that factor product when it is infused.

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Extended Half-Life FVIII Regimens: There are a number of benefits of extended half-life products. In general, the half-life extension for the products range from Comparing the Options 1.5- to 1.6-fold compared to the standard half-life products. With this half-life extension, the number of infusions could be reduced Doris Quon, MD, PhD Orthopaedic Hemophilia Treatment Center on average by 30% to 35%, and even up to 50% if patients were Los Angeles, California previously on standard half-life prophylaxis every other day.

Another advantage of using extended half-life products is the ability to attain higher trough levels. Previously, the goals were to be more than 1%, but with the extended half-life products, trough levels in the clinical trials were higher—ranging from 1% to 3% as the targets. This resulted with a decrease in bleeding and reduction in the annualized bleed rate, the so-called ABR. With Recent and Potential Advances in Hemophilia A the use of the extended half-life products, the severe hemophilia Extended Half-Life Factors Therapies patients could be converted to a moderate phenotype with less Extended Half-Life Replacement Factor Products bleeding.

• Approved for Hemophilia A − Damoctocog alfa pegol − Efmoroctocog alfa Mechanisms of Half-Life Extension in Hemophilia1 − Rurioctocog alfa pegol − Turoctocog alfa pegol

Protein of interest Fc region Linker • Investigational Protein of interest Albumin

− BIVV001 PEG Protein of interest PEG

Hemophilia treatment paradigm has expanded considerably over the past five years. PEG Fc region Protein of interest Fc Fusion PEGylation Albumin Fusion • Fc portion of human • Creates “cloud” around • Albumin has a long IgG fused to factor attached proteins half-life (~3 weeks) Dr. Quon: Thank you, Sean. I will move into the discussion of • IgG has a long • Molecule too big to be newer extended half-life products that are available to treat half-life (~3 weeks) cleared by kidneys hemophilia A patients.

1. Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84-98. Shown here, there have been advances in technology that have allowed the development of factor VIII molecules with a longer There are several mechanisms of half-life extension. Two such or an extended half-life. The FDA has approved a number of approaches have been utilized for factor VIII. products: efmoroctocog alfa, rurioctocog alfa pegol, damoctocog alfa pegol, and turoctocog alfa pegol. I will discuss later the The first approach is the Fc fusion. Fc is a portion of the human mechanism of half-life extension for these molecules. Listed immunoglobulin IgG molecule that has been fused or attached also on this slide is the investigational product BIVV001, and it’s to the factor molecule with the goal of extending the half-life. currently in clinical trials. You can see that hemophilia treatment The IgG has a relatively long half-life of approximately 3 weeks. paradigm has changed and expanded considerably over the last The fusion protein, the factor VIII Fc, is rescued from intracellular several years. degradation pathways through interaction with the neonatal Fc receptor. The second mechanism is PEGylation, which involves the Beneficial Effects of EHL1 attachment of polyethylene glycol, or PEG, to the factor molecule. FVIII Extended Half-Life Products The PEG molecules are large and when attached to the factor molecule, they interfere with the ability of the kidney and the liver to clear the molecules attached to the PEG.

• Reduction in the number Trough of infusions levels: The last mechanism is fusion protein with albumin. This has been Reduction of 2-3 units/dL • Higher factor trough levels infusion number: • Decrease of bleeds with a used for factor IX to extend its half-life. 30% substantial reductions of Half-life: 1.3-1.7–fold 50% if previously the ABR increase on SHL Patients with severe hemophilia could be converted to a moderate phenotype.

1. Mannucci PM. Haematologica. 2020;105:545-553.

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EHL Products for Hemophilia A1-5 Clinical Data on EHL FVIII Products in Hemophilia A1-4

Damoctocog Alfa Pegol Efmoroctocog Alfa Rurioctocog Alfa Pegol Turoctocog Alfa Pegol Damoctocog Alfa Pegol • 96% reduction in ABR with weekly prophylaxis 2018 • 90.6% of bleeds were controlled with ≤2 infusions 2014 2015 2019 FDA Approval Adults and adolescents, (PROTECT VIII study) Adults and children Adults and children Adults and children • No inhibitors were detected during the study previously treated

rFVIII Design B-domain deleted B-domain deleted Full length B-domain truncated • 92% reduction in ABR with individualized prophylaxis Modification to Efmoroctocog Alfa • 76% reduction in ABR with weekly prophylaxis PEG (60 kDa) Fc fusion PEG (20 kDa) PEG (40 kDa) Extend Half-Life (A-LONG Study) • 97.8% of bleeding episodes resolved with ≤2 infusion Half-Life, h (adult) 19 19 14.3-16 19 • No subjects developed inhibitors during the study

30-40 units/kg 2x/week 50 units/kg every 4 days Adjust: 45-60 units/kg every 50 units/kg every 4 days • 90% reduction in ABR twice weekly prophylaxis Adjust: less or more Rurioctocog Alfa Pegol Dosing (adult) 5 days; may be further Adjust: 25-65 units/kg 40-50 units/kg 2x/week frequent dosing based on • 95.9% of bleeds were controlled with ≤2 infusions adjusted to less or more every 3-5 days bleeding episodes (PROLONG-ATE Study) frequent dosing • No subjects developed inhibitors during the study

• All highly effective when used as prophylaxis with ABRs that are similar to each other and similar to Efficacy non-EHL FVIII Turoctocog Alfa Pegol • 96% reduction in ABR with prophylaxis once every 4 days • Also effective for breakthrough bleeds and perioperative management • 95.5% of bleeds resolved with ≤2 infusions TM Safety • Generally well tolerated with no unexpected safety issues (Pathfinder 1 Study) • One patient developed inhibitors after 93 exposure days

1. Konkle BA et al. Blood. 2015;126:1078-1085. 2. Mahlangu J et al. Blood. 2014;123:317-325. 3. Coyle TE et al. J Thromb Haemost. 2014;12:488-496. 1. Mahlangu J et al. Blood. 2014;123:317-325. 2. Konkle BA et al. Blood. 2015;126:1078-1085. 3. Reding MT et al. J Thromb Haemost. 2017;15:411-419. 4. Tiede A et al. J Thromb Haemost. 2013;11:670-678. 5. Iorio A. Hematology Am Soc Hematol Educ Program. 2017;2017:595-604. 4. Giangrande P et al. Thromb Haemost. 2017;117:252-261.

Shown here are the four approved extended half-life products And these are based on the clinical trials. For efmoroctocog, there currently available for hemophilia patients—their design, half-life, was the A-LONG study. For rurioctocog, it was the PROLONG- mechanism of half-life extension, dosing, and safety and efficacy. ATE study. For damoctocog, it was the PROTECT VIII study, and turoctocog, it was the Pathfinder study. Rurioctocog alpha is the only full-length factor VIII, and its half-life extension is through PEGylation. There are two molecules that are The annualized bleeding rates were reduced by 90% or more in B domain deleted: efmoroctocog, which is an Fc fusion protein, all of the studies—92% for efmoroctocog, 90% for rurioctocog, and damoctocog, which is a PEGylated protein. Turoctocog has a 96% for damoctocog and turoctocog. The efficacy in treatment modified truncated B domain delete, and it’s also PEGylated. Half- of bleeding was similar, with more than 90% of bleeds resolved life extension is from 1.4 to 1.6 times that of the standard factor with one or two infusions. It was 97.8% for efmoroctocog, 96% for products. The half-life range is from nearly 15 hours to almost 20 rurioctocog, 90.6% for damoctocog, and 95.5% for turoctocog. hours. All products were generally well tolerated, again, with no unexpected safety concerns, no inhibitors developed in the Approved EHL FVIII Replacement Strategies1-4 clinical trials for efmoroctocog, rurioctocog, and damoctocog.

rFVIII EHL rFVIII With turoctocog, one patient developed an inhibitor after 93 Half-life extension exposure days, but reportedly there was no change in efficacy, and Fc Fusion (fold change) Efmoroctocog alfa 12.4 h 19 h 1.5 the inhibitor eventually went away on its own without the use of PEGylation immune tolerance induction, or ITI. Rurioctocog alfa pegol 10.4 h 14.3-16 h 1.4-1.5

Damoctocog alfa pegol 13 h 19 h 1.5 EHL Products In Development Turoctocog alfa pegol 11.7 h 19 h 1.6

0 6 12 18 24 Half-Life, h FVIII Fc 1. Konkle BA et al. Blood. 2015;126:1078-1085. 2. Mahlangu J et al. Blood. 2014;123:317-325. 3. Coyle TE et al. J Thromb Haemost. 2014;12:488-496. 4. Tiede A et al. J Thromb Haemost. 2013;11:670-678. BIVV001 — rFVIIIFc-VWF-XTEN XTEN VWF D’D3 Looking at the extended half-life replacement products, you can see here is a comparison of the extension of half-life comparing Albumin Me++ standard half-life to the extended half-life products. You can see rD’D3 Albumin Fusion + rFVIII Single Chain A1 A2 A3 C1 C2 rFVIII Single Chain that the half-life of the EHLs compared to the standard half-life VWF D’D3 products, again, range from 1.4 to 1.6.

Here are two investigational extended half-life products that are currently in development. The first is BIVV001. The second is in preclinical trials.

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EHL FVIII Therapies: Is There a Difference?1 EHL FVIII Therapies: Is There a Difference?1 (Cont’d)

Study 1: Study 2: Damoctocog alfa pegol vs efmoroctocog alfa in an observed crossover study Efmoroctocog alfa versus rurioctocog alfa pegol in an observed crossover study

The PK profiles of damoctocog alfa pegol and efmoroctocog alfa were compared in a randomized, Comparative PK of two EHL FVIII concentrates (efmoroctocog alfa and rurioctocog alfa pegol) open-label, single-dose, crossover study with a washout period between in adolescent patients with hemophilia A

n = 9 Damoctocog Damoctocog • Previously treated 60 units/kg 60 units/kg ≥7-day male patients aged 18 Efmoroctocog alfa and When switching from one to another, washout to 65 years with 1:1 rurioctocog alfa pegol have almost no prophylaxis regimen change R followed by severe hemophilia A treatment identical PK parameters is needed with no history of FVIII crossover inhibitors Efmoroctocog Efmoroctocog n = 9 60 units/kg 60 units/kg

• Primary endpoint: AUC based on one-stage clotting assay (0-tlast)

1. Shah A et al. Ann Hematol. 2019;98:2035-2044. 1. Carcao MD et al. J Thromb Haemost. 2019;17:1085-1096.

Are there differences in extended half-life factor therapies? Well, The second study looked at the comparison of extended half- maybe. I will review two separate studies that try to answer life product efmoroctocog versus rurioctocog in an observed this. The first was a crossover study in previously treated adults crossover study. Comparative pharmacokinetics of two extended and adolescents—damoctocog versus efmoroctocog alfa. And half-life products, efmoroctocog versus rurioctocog factor the primary objective was to compare the pharmacokinetics of concentrates in adolescents with hemophilia A. What they found damoctocog and efmoroctocog. Patients were randomized 1:1 to was the efmoroctocog and the rurioctocog have almost identical receive a single infusion of 60 units/kg of damoctocog or 60 units/ pharmacokinetic parameters. When switching from one to another kg of efmoroctocog. This was followed by crossover to a single prophylaxis regimen, it appears that no change may be needed. infusion of the other treatment with a washout between the doses of 7 days or more.

EHL FVIII Therapies: Is There a Difference?1 (Cont’d)

Study 1: Damoctocog alfa pegol vs efmoroctocog alfa in an observed crossover study

Geometric Mean, %CV (95% CI) Geometric Least Parameter P Damoctocog Alfa Pegol Efmoroctocog Alfa Square Mean Ratio AUC, units h/dL 3,010 (38.3) 2,400 (32.2) 1.26 .0001 CL, dL/h/kg 0.0200 (38.3) 0.0250 (32.2) 0.80 .0001 Cmax, units/dL 150 (26.0) 194 (64.1) 0.76 < .05 Half-life, h 16.3 (34.1) 15.2 (33.1) 1.07 < .05 For 18 patients, including the PK outlier patient, damoctocog alfa pegol demonstrated noninferiority to efmoroctocog alfa for AUC(0-t ) last

• Damoctocog alfa pegol demonstrated an improved PK profile compared with efmoroctocog alfa • Real-world data may provide an insight into whether these PK advantages provide additional bleeding protection

1. Shah A et al. Ann Hematol. 2019;98:2035-2044.

The results are shown here. Damoctocog demonstrated to have an improved pharmacokinetic profile with regards to the area under the curve, or the AUC, as well as the mean clearance, mean terminal half-life, and median time to targeted factor VIII level compared to efmoroctocog. Real-world data may provide an insight into whether these pharmacokinetic advantages provide additional bleed protection.

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Implications for Clinical Practice: perspective, but within the agent you do select. Looking at what type of dose they should get, what scheduled infusion Using a Collaborative Approach they should have, is there data to support one frequency to Integrate EHL FVIII Regimens over another for annualized bleeding rate? What is the patient’s level of activity? That is going to be important in Into Practice this case given that this individual is involved in sports. It is probably important to know what type of sport and what Sean DeFrates, PharmD, BCOP level of contact is involved. Northwestern Memorial Hospital Chicago, Illinois One of the major points that we want to discuss today is the idea of shared decision-making. The decision on how to move forward for this patient should not only be with the provider, but with the provider, other members of the care team, and collaboratively with the patient involved.

Goals of Shared Decision-Making1 Patient Scenarios: Case 1

 Inform the patient to improve their knowledge about A 28-year-old athletic man their own illness  Currently approved EHL with moderate hemophilia A treatment options on prophylaxis with  Personalize therapy Activate the patient to increase the role they assume standard half-life factor, based on dose, schedule  of infusions, ABR, level in illness management presents with a recurrent of activity, etc breakthrough bleeding  Shared decision-making and critical role of each Promote interaction between patient and healthcare member of the  Should you use an healthcare team and how professional ? EHL therapy? they work collaboratively

1. Cramm JM, Nieboer AP. BMJ Open. 2014;4:e005914.

The goals of this shared decision-making process are to Dr. DeFrates: Thank you, Dr. Quon, for that excellent A. inform the patient to improve their knowledge about summary on extended half-life factors and the available their illness. You’re encouraging, and you’re providing that data, as well as the movement forward to improve on that education to the patient by providing resources, so they group of agents that you mentioned. This is going to be can educate themselves, become involved, and better a case-based discussion, and we’re going to start with understand their own illness. this first patient scenario and talk through some of the considerations that Dr. Quon and I recommend that you B. You’re activating the patient to increase the role that have as you’re looking into similar patients out in practice. they assume in the management of their illness. You’re not only giving them the information, but you’re empowering Case 1 is a 28-year-old male athlete with moderate them and encouraging them to take action, so they can be hemophilia A, who is on prophylaxis with standard half-life involved in these types of decisions. factor. He presents with a recurrent breakthrough bleed. The question is: should you use an extended half-life factor C. Not only provide that education and encourage their product or a nonfactor replacement therapy? engagement but promote the interaction between the patient and their healthcare professional. Having those As you’re evaluating this case, I’m sure many of you would types of conversations—whether it’s in the office, virtually, like more information to make the case a little better- or through some other type of innovative mechanism— rounded. However, the major things that you should be they can have interaction with various members of the thinking through are: what are our options at this point? healthcare team, and they can work together to solve some Looking at the different extended half-life factor options, of these treatment considerations. and does any one of them stand out to you?

It’s important to consider personalization of therapy, and with the number of options that are out there, it should hopefully allow us to do that—not only from an agent

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Essential Steps of Shared Decision-Making1 Dr. DeFrates: It’s also extremely important to get the perspectives of various members of the healthcare team. The SHARE Approach Including those like clinical pharmacists, nurses, and nurse Treatment recommendations for S Seek patient’s participation our patient practitioners and ensuring that all their perspectives are  He prefers factor replacement therapies Help patient explore and  EHL is recommended for this patient taken into account as you make treatment decisions. H compare treatment options Sometimes not only to be able to provide things like Assess patient’s values and A Benefits to Healthcare Professionals preferences • Improved quality of care delivered education but be able to provide a different perspective • Increased patient satisfaction on what may be helpful for a patient, whether it’s a specific each a decision with patient R R Benefits to Patients • Improved patient experience of care type of administration frequency or maybe whether it’s • Improved patient adherence to treatment E Evaluate patient’s decision recommendations a specific challenge that the nurse has noted. It is really important to bring that whole healthcare professional team 1. https://www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/tool-1/index.html. together when making these types of important decisions for patients. The essential steps of the shared decision-making model can be summarized through of the SHARE approach. SHARE Dr. Quon: Absolutely. I agree with you, bringing the whole is the mnemonic that guides you through the five steps to team together is extremely important in making these the approach. decisions for our patients. Thank you for that.

'S' stands for seek patient’s participation. This is the Patient Scenarios: Case 2 process of including the patient in the education as well as the decision-making process. 'H' is help the patient explore and compare treatment options. Again, you are A 17-year old boy with severe  EHL treatment options hemophilia A going off to going back to that data—that evidence—that is available  Validated and recommended college. He was on standard laboratory tests with approved EHL to weigh risks and benefits. You’re helping the patient half-life product and wants to therapies to understand and go through that. 'A' is assess patient’s switch to a newer product with  Collaboration with laboratory professionals to ensure proper values and preferences. That’s talking about having a clear extended half-life reagent selection for clotting assays conversation with a patient about what their goals are,  Patient education on EHL therapy What should you consider  Locating an HTC near college  Regular follow ups what’s important to them, what are their values, and what ? during transitioning?  Compliance are their preferences? 'R' is reach a decision with the patient. That is using all the available data, having a conversation where you come together with the patient to make a decision on how you’re going to move forward. In this case, Now we’re going to move to our second case, and this is a are you going to use an extended half-life factor and which 17-year-old with severe hemophilia, and he’s planning to go one? Finally, 'E' is evaluate the patient’s decision. Being able to college. He’s currently on a standard factor VIII half-life to recap and summarize why we made the decision that we product. He wants a change, and he wants to switch to a did—then things to watch for as you move forward. Monitor newer product with an extended half-life. the decision that was made so that the plan can be adjusted if necessary. What are some of the things you would consider during this transitioning? Of course, you want to discuss with him the I would like to seek Dr. Quon’s input on what she things extended half-life options that he has. We need to look at would be a treatment recommendation for this case 1 the importance of using the validated and recommended patient. laboratory tests with each of the approved extended half- life therapies. I’ll go into some of the reasons of why in the Dr. Quon: With regards to this specific case and treatment next slide. recommendation for our patient, in talking to him, he prefers using the treatment of extended half-life, and he The importance of collaborating with the laboratory wants to use factor. professionals to ensure proper reagent selection for monitoring the plasma levels of the factor levels by either a There are a number of benefits for using the shared validated chromogenic substrate assay or validated one- decision-making model. There are benefits to the healthcare stage clotting assay. professionals. You have improved quality of care delivered, and there’s increased patient satisfaction. I think the patients want to participate in their own care, and if they feel like you’re listening to them, I think they have better satisfaction.

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There are two assays that are available to monitor plasma In selecting or tailoring a treatment regimen, there are factor VIII levels. One is a one-stage clotting assay, which a number of factors to consider. One important factor currently is most often used in the United States, and the is age. The age influences other factors, such as his other is a chromogenic substrate assay, which some say is pharmacokinetics, the half-life, the recovery, the clearance, more accurate in terms of detecting the levels. peaks, and troughs. Venous access needs to be taken into account. Other variables to consider are a person’s The last thing is when you’re switching somebody, is to adherence as well as his activities. Individualization of educate him on the extended half-life therapies. Since he hemophilia care is highly recommended, and this certainly is moving, he’s going to need a new HTC that is closer to underscores the need for shared decision-making. his college. The patient needs to be encouraged to have regular follow-ups. The importance of prophylaxis as well as Rationale for Using PK to Individualize compliance needs to be reviewed with him in detail. Hemophilia Treatment1

Variability in PK … Importance of Using Validated Laboratory Tests

… among different concentrates Perform recommended and validated chromogenic substrate or … to monitor FVIII activity for one-stage clotting assays … EHL therapies

Monitor for development of FVIII inhibitors and perform … if expected FVIII plasma levels are not attained or if bleeding is … among different individual patients a Bethesda inhibitor assay … not controlled

Collaborate with laboratory professionals to ensure proper reagent … by either a validated chromogenic substrate assay or … in the same individual over time selection for monitoring plasma FVIII levels … one-stage clotting assay and across different concentrates

• Select silica-based one-stage assays may underestimate the 1. Iorio A. Hematology Am Soc Hematol Educ Program. 2017;2017:595-604. Laboratories intending to measure the FVIII activity should check FVIII activity for damoctocog alfa pegol their procedures for both accuracy and reagent selection • Some kaolin-based activators may overestimate FVIII activity for damoctocog alfa pegol Sean, would you like to talk about some of the other factors or rationales for pharmacokinetics to individualize this type of treatment? Looking at the validated laboratory tests, we need to perform recommended and validated chromogenic or one- Dr. DeFrates: Absolutely. The whole rationale for using stage clotting assays to monitor factor VIII activity for the pharmacokinetics to make a patient-specific treatment extended half-life products. Monitor for the development regimen is based on the significant variability that exists, of factor VIII inhibitors and perform a Bethesda assay if and that’s variability in the pharmacokinetics among the the expected factor VIII plasma levels are not obtained. different products that are out there. Laboratories intending to measure factor VIII activity should check their procedures for accuracy and reagent selection. There’s also variability in pharmacokinetics among different For example, with damoctocog, if you select a silica-based patients. There can also be variabilities in pharmacokinetics one-stage assay, this may underestimate the factor VIII within an individual as time progresses or as you transition activity. However, if you use a kaolin-based activator, this different factor concentrates. may overestimate the factor VIII activity. Going into the lab and trying to find out which reagent they use as an Advantages of Personalizing Therapy1,2 activator is very important because you don’t want to either underestimate or overestimate the factor VIII activities. Reduction of factor administration

1-4 Every Patient Represents a Unique Challenge Financial impact to health system

Is an EHL factor product the right choice for this patient? Variables that affect decision-making A single, severity-based, FVIII levels are based on peaks and troughs, not on in vivo recovery therapeutic model does not Adherence Age represent the optimal treatment strategy for all patients with Bleeding Venous phenotype access hemophilia Maximize efficacy Peak/trough Half-life • Individualization of hemophilia care is recommended 1. Iorio A. Hematology Am Soc Hematol Educ Program. 2017;2017:595-604. 2. Hazendonk HCAM et al; OPTI-CLOT study group. Blood Rev. 2018;32:265-271. Joint status Activity type and pattern Pharmacokinetics • Underscores need for shared decision-making Personalized dosing can help reduce the amount of factor that you’re going to administer to the patient. You may 1. Sorenson B et al. Blood Coagul Fibrinolysis. 2003;14:469-477. 2. Collins PW. Haemophilia. 2012;18(suppl 4):131-135. 3. Oldenburg J. Blood. 2015;125:2038-2044. 4. Valentino LA. Haemophilia. 2014;20:607-615. find that a patient’s half-life is a little longer than what the

Go online to complete the post-test and evaluation for CME/MOC/CE/CPE credit PeerView.com/CEV900 12 Implementing Care With Extended Half-Life Factor VIII Therapy in Hemophilia A: An Interdisciplinary Conversation on Personalized Patient Management average would suggest. You may find that instead of dosing needs to be encouraged to follow up. And the importance every 3 or 4 days, you’re able to maintain the same target of prophylaxis must be reviewed with him as well as the trough but dose every 5 days—or maybe you can dose once importance of complying. a week depending on the patient scenario and what their pharmacokinetics are. Not only is this being a good steward Dr. DeFrates: Great. I would also add that the patient of resources, but it also can help the financial impact for education component is another realm where incorporating patients and for the health system. Additionally, the factor various members of the healthcare team is important. VIII and factor IX levels—whether this is hemophilia A or B— Certainly the provider, the patient’s physician, is well adept are based on peaks and troughs. at doing this type of patient education. The pharmacists and nurses can hone in on the importance of the dosing In the preventive setting, you’re focused a lot on troughs and what to do in different scenarios, and any changes from and ensuring that you stay above a certain level that you the original product— from an infusion and administration know is protective for that patient. In the treatment of standpoint—are all important things the patient should get bleeding, you’re looking at those peaks and ensuring before they leave. that you get to the level that you need be to mitigate the bleeding episode. Dr. Quon: Listed here are organizations aimed at patient education for hemophilia. Importance of Patient Education Dr. DeFrates: That’s great. Those resources are really

HTCs Treatment recommendations important not only for providers, but also for the patients as for our patient  He prefers factor replacement you mentioned. Local hemophilia chapters therapies with extended prophylaxis intervals National Hemophilia  EHL is recommended for Foundation (NHF) this patient Clinical Take-Homes  Patient education on EHL Hemophilia Foundation of therapy, dosing, and frequency America (HFA) of infusion  Patient education on locating a World Federation of new HTC near college, regular • Advances in biotechnology have permitted the development of EHL Hemophilia (WFH) follow-ups, and the importance replacement clotting factors for prophylaxis of compliance Other organizations • Morbidity and mortality can be reduced significantly through SDM by involving hemophilia patients and family members, as they are often very well educated in the disease and its management

In terms of making a treatment recommendation for this • SDM can increase the use of the treatment option that is most clearly patient by using the shared medical decision-making model associated with health benefits that we covered previously, it’s really important to take into account that this patient prefers factor replacement therapy, and specifically with an extended prophylaxis interval. Here are some of the clinical takeaways for this. The Dr. Quon, would you agree, or would you take a different treatment of hemophilia A has certainly evolved approach for this patient? considerably over the last 10 years—and for the better. The advances in the technology have allowed the development Dr. Quon: No. Using the shared decision-making, he has a of extended half-life replacement products for prophylaxis clear preference for using factor replacement. He wants a and the treatment in patients with hemophilia A, with more change. He’s going off to college, but he doesn’t want too treatment options than ever for these patients. Patients many changes happening at once, preferring the factor with hemophilia and family members are usually very replacement, but essentially not wanting to do as many well educated in their disease state and its management. infusions thus extending his prophylaxis intervals. This And this can significantly reduce both the morbidity and makes the extended half-life a good recommendation for mortality and underscores their role in shared decision- this patient. making. Finally, shared decision-making has been shown to increase the use of the treatment option that is most clearly We need to educate the patient on the extended half- associated with health benefits. Shared decision-making life therapy because it is new for him. We need to review is very important to the patient as well as the healthcare the dosing and the frequency of infusions. He is moving, providers. Thank you. so he needs to find a new provider and probably a new hemophilia treatment center that is near his college. He Narrator: This activity has been jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

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This CME/MOC/CPE activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported by an educational grant from Bayer HealthCare Pharmaceuticals Inc.

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