CME/CNE Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making

Co-Chairs Brandon R. Allen, MD, FACEP University of Florida College of Medicine Gainesville, Florida

Anita Rajasekhar, MD, MS University of Florida Gainesville, Florida

Tung Wynn, MD University of Florida Gainesville, Florida

What’s Inside 3 Evolving Therapeutic Landscape for the Management of Hemophilia 12 Treating Hemophilia in the Emergency Department: What Do Current Guidelines Tell Us? 15 Best Practices From the Experts: Incorporating Shared Decision- Making Into the Management of Hemophilia

This CME activity is jointly provided by the University of Florida College of Medicine and PVI, PeerView Institute for Medical Education.

This CNE activity is jointly provided by the Medical Learning Institute, Inc. and Participate in interactive questions, download activity slides, PeerView Institute for Medical Education. and obtain your instant CME/CNE credit online. This accredited CE activity has been developed in collaboration with the Hemophilia Foundation of Greater Florida. PeerView.com​ /QUN900​ Activity Information

Activity Description and Educational Objectives In this activity, experts in hemophilia discuss available and emerging therapeutic The planners from Medical Learning Institute, Inc., the CNE accredited provider, PeerView approaches for the treatment of patients with hemophilia, as well as current guidelines Institute for Medical Education, the joint provider, do not have any financial relationships and treatment protocols for patients with hemophilia presenting to the emergency with an ACCME-defined commercial interest related to the content of this accredited department. activity during the past 12 months unless listed below.

Upon completion of this activity, participants will be able to: Content/Peer Reviewer Disclosures • Assess current data on available and emerging therapeutic approaches for the The following Content/Peer Reviewer has nothing to disclose: treatment of patients with hemophilia • Apply current guidelines for the management of patients with hemophilia in the Gina D. Cravey BSN, RN, CHRC, CCRC emergency department • Develop treatment protocols for suspected bleeding episodes in patients with Disclaimer hemophilia who present to the emergency department that incorporate shared Participants have an implied responsibility to use the newly acquired information to decision-making enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Target Audience Any procedures, medications, or other courses of diagnosis or treatment discussed or This activity has been designed to meet the educational needs of emergency department suggested in this activity should not be used by clinicians without evaluation of their physicians, nurses, and other clinicians involved in the care of patients with hemophilia. patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations Requirements for Successful Completion of other authorities. In order to receive credit, participants must view the activity and complete the post-test and evaluation form. A score of 80% or higher is needed to obtain CME credit and 70% or MLI is permitting the use of both brand drug names and generic drug names in this higher to obtain CNE credit. There are no prerequisites and there is no fee to participate enduring activity for ease of understanding of the information for patients and their in this activity or to receive CME/CNE credit. Statements of Credit are awarded upon families. No bias toward or promotion for any agent discussed in this program should be successful completion of the post-test and evaluation form. inferred.

Media: Enduring Material Providership, Credit, and Support Release and Expiration Dates: August 18, 2020 - August 17, 2021 Physicians Time to Complete: 60 minutes This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Faculty and Disclosure / Conflict of Interest Policy Continuing Medical Education (ACCME) through the joint providership of the In accordance with ACCME requirements, the University of Florida College of Medicine has University of Florida College of Medicine and PVI, PeerView Institute for Medical Education. a conflict of interest policy that requires faculty to disclose relevant financial relationships The University of Florida College of Medicine is accredited by the ACCME to provide related to the content of their presentations/materials. Any potential conflicts are resolved continuing medical education for physicians. so that presentations are evidence-based and scientifically balanced. No one else in a position to control content has any financial relationships to disclose. The University of Florida College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit Co-Chairs commensurate with the extent of their participation in the activity. Brandon R. Allen, MD, FACEP Clinical Assistant Professor Continuing Nursing Education University of Florida College of Medicine Medical Learning Institute, Inc. is accredited as a provider of continuing nursing Department of Emergency Medicine education by the American Nurses Credentialing Center's Commission on Medical Director, Adult Emergency Department Accreditation. Gainesville, Florida Successful completion of this continuing nursing education activity will be awarded 1.0 contact hour(s). Brandon R. Allen, MD, FACEP, has a financial interest/relationship or affiliation in the form of: Providership Consultant and/or Advisor for F. Hoffmann-La Roche Ltd. This CME activity is jointly provided by the University of Florida College of Medicine and Grant/Research Support from Beckman Coulter, Inc. and F. Hoffmann-La Roche Ltd. PVI, PeerView Institute for Medical Education.

Anita Rajasekhar, MD, MS This CNE activity is jointly provided by the Medical Learning Institute, Inc. and PeerView Associate Professor Institute for Medical Education. University of Florida Department of Medicine This accredited CE activity has been developed in collaboration with the Hemophilia Division of Hematology/Oncology Foundation of Greater Florida. Gainesville, Florida Support Anita Rajasekhar, MD, MS, has a financial interest/relationship or affiliation in the form of: This activity is supported by an educational grant from Genentech. Grant/Research Support from Alnylam Pharmaceuticals, Inc. (sanofi-aventis U.S. LLC/ Genzyme Corporation); BioMarin; Dimension Therapeutics, Inc.; F. Hoffmann-La Roche Ltd; Disclosure of Unlabeled Use Genentech, Inc.; Janssen Pharmaceuticals, Inc.; and Shire. The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to Tung Wynn, MD disclose to the audience any reference to an unlabeled or investigational use. Assistant Professor of Pediatrics Division of Pediatric Hematology and Oncology No endorsement of unapproved products or uses is made or implied by coverage of these University of Florida products or uses in our reports. No responsibility is taken for errors or omissions in reports. Gainesville, Florida For approved prescribing information, please consult the manufacturer’s product labeling.

Tung Wynn, MD, has a financial interest/relationship or affiliation in the form of: About This CME/CNE Activity Other Financial or Material Support from Novartis Pharmaceuticals Corporation (Wife). PVI, PeerView Institute for Medical Education, the University of Florida College of Medicine, and Medical Learning Institute, Inc. are responsible for the selection of this activity’s CME Reviewer topics, the preparation of editorial content, and the distribution of this activity. Our Michael Marchick, MD activities may contain references to unapproved products or uses of these products in Co-Clerkship Director certain jurisdictions. The preparation of PeerView activities is supported by educational Clinical Associate Professor grants subject to written agreements that clearly stipulate and enforce the editorial Department of Emergency Medicine independence of PVI, the University of Florida College of Medicine, and Medical Learning University of Florida College of Medicine Institute, Inc.

Michael Marchick, MD, has no financial interests/relationships or affiliations in relation to The materials presented here are used with the permission of the authors and/or other this activity. sources. These materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or supporters. Planning Comittee Disclosures Tracy L. Greene, MSN, RN, FNP-C, Nurse Planner, MLI, has nothing to disclose.

Go online to complete the post-test and evaluation for CME/CNE credit PeerView.com​ /QUN900​ 2 Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making

Evolving Therapeutic Landscape Congenital Hemophilia1-4 for the Management of Secondary hemostasis disorders Hemophilia • X-linked inherited • Clotting factor VIII (FVIII) or factor IX (FIX) is absent or present in low levels Brandon R. Allen, MD, FACEP Hemophilia A (FVIII deficiency) Anita Rajasekhar, MD, MS • Affects 1/5,000 to 1/7,000 males Tung Wynn, MD Hemophilia B (FIX deficiency) • Affects 1/25,000 to 1/30,000 males

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; This accredited CE activity has been developed in collaboration 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. with the Hemophilia Foundation of Greater Florida.

This activity is supported by an educational grant from Genentech. Dr. Rajasekhar: By way of background, congenital hemophilia is one of the most well-known and studied inherited bleeding disorders. Hemophilia affects secondary hemostasis since it Dr. Rajasekhar: Hello, and thank you for joining us on a discussion involves a deficiency of the clotting factors, namely factor VIII and that focuses on how to ensure the rapid recognition and optimal factor IX. It’s an X-linked inherited disorder, so it predominantly management of hemophilia in the emergency department, affects males, and mothers and daughters are obligate carriers with a special attention to the role of inclusive decision-making. of inherited hemophilia. You’ll see by these statistics on this slide This online educational activity is designed for an audience of that hemophilia A is more common than hemophilia B, and that’s emergency room physicians and nurses, and the activity will because factor VIII is larger and more susceptible to mutations than be divided into three segments. The first will focus on evolving factor IX. therapeutic landscapes in hemophilia, and then we’ll move on to how to best treat hemophilia in the emergency room, highlighting Dr. Allen: Yeah, Dr. Rajasekhar, this is certainly a rare event in what the current guidelines are. Then finally, we will end with a emergency medicine; however, it’s not a never event, and knowing case-based discussion from our expert panel to understand best the intricacies of this disease process and how to manage it are practices and how to incorporate shared decision-making into the going to be vitally important for morbidity and mortality of these management of hemophilia. patients.

My name is Dr. Anita Rajasekhar, and I’m an adult nonmalignant Bleeding Phenotype Dependent on Level hematologist at the University of Florida. Joining me today in of Clotting Factor Deficiency in Hemophilia1,2 this discussion are my colleagues at the University of Florida, Dr. Phenotype Factor Level Clinical Features Brandon Allen and Dr. Tung Wynn. • Bleed after severe injury or surgery Mild hemophilia >5%-40% • Do not bleed often; some may never have bleeding problem

Dr. Allen: Thank you for having me today. • May bleed for a long time after surgery, Moderate hemophilia 1%-5% a bad injury, or dental work • Experience spontaneous bleeding rarely

Dr. Wynn: Thank you for inviting me to participate in this talk. • Frequent and spontaneous bleeds into muscles Severe hemophilia <1% or joints (70%-80% bleeds are hemarthrosis); up to 1-2 times/week without treatment

Dr. Rajasekhar: Okay, excellent. Let’s begin by understanding what ~60% of hemophilia A ~44% of hemophilia B the current landscape is and what the recent advances have been cases are severe cases are severe 1. https://www.wfh.org/en/page.aspx?pid=643. 2. Van Dijk K et al. Haemophilia. 2005;11:438-443. in the management of hemophilia.

Dr. Rajasekhar: It’s really important to understand the bleeding phenotype in these patients, and it varies across spectrums. The variability really depends on the factor level in an individual patient. You’ll see here on this slide that in mild hemophilia patients, which is defined as a factor level between 5% and 40%, they generally have very few bleeding problems unless they’re

Go online to complete the post-test and evaluation for CME/CNE credit PeerView.com​ /QUN900​ 3 Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making challenged with surgery or major trauma. Moderate hemophilia Current Hemophilia Treatment Paradigm1 patients, on the other hand, have lower factor levels, somewhere between 1% and 5%, and they tend to have moderate phenotype q Prophylaxis is considered to be optimal therapy for individuals of bleeding and do tend to bleed after a minor trauma. Then with severe hemophilia A or B you have our severe hemophilia patients, who have a baseline q Prophylaxis should be instituted early (prior to the onset of frequent bleeding), with the aim of keeping the trough FVIII MASAC or FIX level above 1% between doses factor level less than 1%. In these patients, they can have severe Recommendations Concerning Prophylaxis hemorrhage, most commonly into the joints and muscles, and they q Optimal dosing and frequency should be determined for each can present very early in childhood. Often, they have spontaneous individual by appropriate laboratory monitoring bleeding without any trauma. It’s really important to note also that q Individuals on prophylaxis should have regular follow-up visits to evaluate joint status; to document any complications, our mild and moderate hemophilia patients may not be diagnosed such as inhibitors; and to record any bleeding episodes that occur during prophylaxis until later in life, when they actually have a hemostatic challenge. 1. https://www.hemophilia.org/sites/default/files/document/files/241Prophylaxis.pdf.

Hemarthrosis: A Long-Term Complication With Hemophilia Dr. Rajasekhar: Absolutely. The National Hemophilia Foundation has the Medical and Scientific Advisory Council, or MASAC, Without treatment, bleed events for patients with hemophilia may be life-threatening or and they issue periodic recommendations and advisories on result in chronic disability from recurrent hemarthroses and intramuscular bleeding treatment, research, and other general health concerns for the hemophilia community. Factor prophylaxis is a regular infusion Target Joint Repeated bleeding in the same joint; knees, elbows, of factor concentrates in order to prevent bleeding. The idea and ankles most frequently affected of prophylaxis comes from the observation that people with Hemophilic Arthropathy Persistent intra-articular blood results moderate or mild hemophilia who have factor levels over 1% rarely in progressive degeneration of the joint experienced spontaneous bleeding. Based on that, MASAC has cartilage and bone issued recommendations on prophylaxis as the standard of care and optimal therapy for individuals who have severe hemophilia. Prophylaxis should be instituted early and ideally prior to the onset So while life-threatening bleeds can happen with hemophilia, of frequent bleeding. The goal is to keep the factor level above 1% especially severe hemophilia, the most common bleeds are in between doses to prevent bleeding. joints and muscles. When we see recurrent bleeding into the same joint, we term that joint a “target joint,” and eventually that Now, optimal dosing and frequency should be determined for each target joint can be affected by chronic synovitis and progressive individual, and that is an individual case-by-case decision based on degenerative changes of the cartilage and bone. Over time, this appropriate lab monitoring. The bottom line is that it’s not a one- can lead to end-stage joint damage with significant pain and size-fits-all in terms of the factor prophylaxis regimen. range-of-motion deficits, and eventually these patients may require surgical interventions, such as joint replacement or fusion. Then finally, MASAC recommends that individuals on prophylaxis should have regular follow-up visits to evaluate joint status; to Dr. Allen: Dr. Rajasekhar, in this case, certainly seeing the majority document any complications of factor infusions, like inhibitors, of cases being hemarthroses, and the significant disability that can which we’ll talk about; and to record any bleeding episodes that happen with the target joint, as you referenced. occur while on prophylaxis. So it’s clear that prophylaxis is not a static treatment and a patient’s regimen may change over time. Dr. Rajasekhar: Many of my patients in the adult clinic, I have to end up referring them to the orthopedic surgeons, and they Dr. Wynn, I found this guidance that MASAC gives us particularly discuss what options exist in terms of replacement and fusions, helpful when I’m talking to patients. I’m curious, do you use these so it’s certainly a significant morbidity for these patients who are recommendations in your day-to-day discussions in clinic with your having recurrent bleeds in their joints. patients?

Dr. Allen: It’s definitely a high-risk surgery as well, and it can be Dr. Wynn: Yeah, I would add that beyond the MASAC quite complicated perioperatively. guidelines, there are well-established studies that show that early and aggressive use of prophylaxis can delay and, in many circumstances, prevent the development of the joint complications that you’re discussing. These MASAC guidelines, as well as the numerous studies that exist, I use to discuss with my patients about when and how and what form that may take.

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Potential Barriers to the Optimal Management they’ve done in the past that’s worked for them to get out of one of of Hemophilia in the Emergency Department these potential emergent situations.

Although bleeding episodes in patients with hemophilia are frequently and routinely managed at home and/or at specialized hemophilia treatment Prophylaxis: The Standard of Care for Hemophilia centers, they do present to local EDs in emergency situations. Potential challenges to optimal management include:

The benefits of prophylaxis in patients with severe hemophilia q Disease rarity: How frequently is hemophilia encountered in the ED? are well established q Need for a consult: Is there a hematologist on call?

q Expanding number of available treatments: Does the hospital stock the • Joint Outcomes Study1 Hemophilia A medicine an individual patient needs? • ESPRIT trial2

Evidence • Multicenter, open-label study comparing on-demand Hemophilia B treatment with prophylaxis3

Dr. Allen: We’re going to transition into the potential barriers to the 1. Manco-Johnson MJ et al. N Engl J Med. 2007;357:535-544. 2. Gringeri A et al. J Thromb Haemostat. 2011;9:700-710. 3. Valentino LA et al. Haemophilia. 2014;20:398-406. optimal management of hemophilia in the emergency department. This is something, as we mentioned, that is a rare disease and you may want to ask yourselves, in your current emergency department Dr. Rajasekhar: Let’s move on to what the evidence is for routine setting, what is the number of these that you potentially encounter, prophylaxis. Dr. Wynn, you alluded to these studies. There have and also what kind of resources you have at your disposal when been a few studies that have looked at the benefits of routine you need something with these patients. The great thing though prophylaxis. The one that many are familiar with is the Joint is that hemophilia patients are very knowledgeable about their Outcomes Study, and that was the first study to really show us disease state and they can routinely be managed at home with that prophylaxis with regular scheduled factor infusions reduced specialized treatment centers as a consultant prior to heading to joint bleeds and joint damage on imaging studies and really led the emergency department. the way for this strategy to become the standard of care in severe hemophilia patients. This study was then confirmed by the ESPRIT However, they do present in emergent situations, and expanding study, which found that prophylaxis was particularly beneficial in the number of available treatments is also something that has to preventing joint damage when started early. Then finally, a similar be a consideration where, does your hospital stock the medicine or study documented the benefits of prophylaxis in hemophilia B is the expectation that the patient should have it? Sometimes you patients as well. have to go kind of off formulary, but we’re going to discuss that a little bit more in future slides, in regards to the approach to this, to So Dr. Wynn, I know in my adult hemophilia patients, despite this keep the patient in the best scenario of wellness. evidence that shows a benefit to regular prophylaxis, I still see a lot of hesitation on the part of infusing themselves several times Dr. Rajasekhar: Brandon, I agree. I think this is mostly an a week. Understandably, it’s burdensome, it’s expensive to give outpatient disease, thankfully, which is probably why many ER two- to three-times-a-week infusions. Do you find resistance in this providers don’t have a lot of experience with it. I think it’s really approach in your pediatric patient population? important for ER providers to remember that patients really know a lot about their disease, for the most part, and know what works Dr. Wynn: In the pediatric population, especially the youngest for them, and so when they come in and give you a history and population of toddlers and newborns, the most difficult challenge tell you, “This drug has worked for me, this has not worked for me is IV access for these patients. The resistance comes in how can we in the past, this is the dose that works for me usually”—I think it’s establish the most accessible IV access for them. Generally, patients important to believe that they know that and to really trust the are very, very compliant in pediatrics because the administration patient from that standpoint. of the factor is provided to them at an early age either by a home health nurse or by the parents themselves. But oftentimes as we Sometimes patients, as you mentioned, bring their own transition to self-infusion, in which the patient learns and provides medications. Other times, especially in our mild and moderate the factor for themselves, the challenge becomes maintaining that hemophilia patients, because they don’t either know how to self- compliance to the prophylactic recommendation. The adolescent infuse or don’t need to self-infuse much because they don’t bleed and teenage population in our practice does face challenges often, they don’t have drug with them, so we end up having to similar to the ones that you’re describing in adults. use whatever is on the hospital formulary. It is important to know what’s on your hospital formulary and how to dose that. Dr. Rajasekhar: That’s why it’s really important, again, to involve the patient in the decision process and really practice shared Dr. Allen: Great points, Dr. Rajasekhar. I couldn’t agree more that decision-making because it’s really not helpful if we prescribe one of the first things I do in an encounter with a hemophilia something and ultimately on the patient side, they’re not going patient is to ask them about what they do at home and what to take it. We have to have buy-in from them for this prophylaxis

Go online to complete the post-test and evaluation for CME/CNE credit PeerView.com​ /QUN900​ 5 Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making regimen. who might be high risk, and these are outlined here. These include patient-specific factors on the left-hand side and treatment-related factors on the right-hand side. There’s a lot of work being done Major Hurdles to the Optimal Management of Hemophilia in this area to try and predict and minimize the risk of inhibitor

Short in vivo half-life of standard replacement factors; adherence can become a major issue because formation, but ultimately it’s a complex interaction of many of the need for frequent infusions variables that leads to inhibitor development in any individual t rFVIII: ~8-12 h ½ patient. t½ rFIX: ~18-24 h 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) Standard Half-Life Factor Concentrates • Frequency: severe hemophilia A = 20%-30%, mild and moderate hemophilia A = 3%-13%, and severe hemophilia B = 5% Prior to 2017, only two treatments were approved for patients with hemophilia and inhibitors • Options 1. rFVIIa 2. Activated prothrombin complex concentrate – Plasma-derived vs recombinant – First-gen vs second-gen vs third-gen recombinant • Vary in protein structure (full-length, B-domain–deleted or –truncated), cell line, or production techniques

• Similar PK profiles with a mean t½ of 12 h (FVIII) or 25 h (FIX) in adults What are the other hurdles of prophylaxis and optimal • Typical prophylaxis with SHL management of hemophilia? Unfortunately, replacement of the – 25-40 units/kg three times weekly (FVIII) missing factor with factor concentrates is short-lived with the – 25-40 units/kg twice weekly (FIX) traditional standard half-life therapies. Factor VIII’s half-life is about 8 to 12 hours, and factor IX’s half-life is about 18 to 24 hours. This really translates into a burdensome regimen of twice- to three- times-per-week factor infusions for prophylaxis to keep a patient Let’s discuss what options exist for hemophilia treatment currently. above that over 1% and prevent bleeding. Another challenge To remind everyone, there’s been an evolution of products over in the treatment of hemophilia is the dreaded consequence of the years. Initially, we had plasma-derived factor concentrates inhibitor formation. Inhibitors are these neutralizing antibodies that were introduced in 1969, and they’ve really come a long against exogenous factor that is infused, rendering standard factor way in terms of safety, with modern methods of purification. replacement ineffective. Then came along recombinant or genetically engineered factor concentrates, and these were really developed as a response to Dr. Wynn: Dr. Rajasekhar, I would also add that the vast majority of the HIV and hepatitis epidemic in our hemophilia patients in the inhibitors, when they develop, develop in young children—infants 1980s. The third- and fourth-generation recombinant products and toddlers—and usually those patients are within the first 50 have no human or animal protein in the final preparation of doses, the first 50 exposure doses in their lifetime. the product. Then there are differences in protein structures, including B-domain–deleted and truncated versions of the product Dr. Rajasekhar: That’s right. By the time they come to me in my compared with full-length factor molecules. Among the standard adult clinic, often they’ve already developed inhibitor, often they’re half-life products, half-lives do not really vary significantly, with already on a very good regimen that works for them, so it really is the mean half-life of about 12 hours for factor VIII products and 24 the pediatric hematologists who have the burden of diagnosing hours for factor IX products. So again, this really translates to rather and treating these diseases early on. frequent infusions for our patients based on these half-lives.

Factors Influencing Inhibitor Development1 Extended Half-Life Factors and Nonfactor Replacement Therapies

Recent and Potential Advances in Hemophilia A and B

Patient Variables Treatment Variables Extended Half-Life Nonfactor Replacement Strategies Replacement Factor Products • Disease severity • Number and pattern of • Approved for hemophilia A with and • FVIII gene defect • Approved for hemophilia A without inhibitors FVIII exposures – Efmoroctocog alfa (Eloctate) – Emicizumab-kxwh • Ethnicity Inhibitor • Type of FVIII product – Rurioctocog alfa pegol (Adynovate) • Approved for hemophilia A or B • FH of inhibitors – Damoctocog alfa pegol (JIVI) • Concurrent immune – Turoctocog alfa pegol (Espercot) with inhibitors • HLA type system challenges • Approved for hemophilia B – Coagulation factor VIIa (recombinant)-jncw • Individual immune • Frequency of monitoring – Eftrenonacog alfa (Alprolix) • Investigational response traits – Albutrepenonacog alfa (Idelvion) – Fitusiran – Nonacog beta pegol (Rebinyn) – Concizumab • Investigational – Gene-replacement therapy strategies A complex interaction of many variables leads – BIVV001 for hemophilia A and B to inhibitor development in a particular individual Hemophilia treatment paradigm has expanded considerably over the past 5 years

1. Gouw SC. Semin Thromb Hemost. 2009;35:723-734.

What are the factors that influence inhibitor development? There In the past 5 years, there’s been really an explosion of new are a variety of them, and while we can’t predict who will ultimately therapies available in the pipeline for hemophilia treatment, and develop an inhibitor, there are risk factors that help us understand

Go online to complete the post-test and evaluation for CME/CNE credit PeerView.com​ /QUN900​ 6 Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making to address the burden of factor VIII and factor IX prophylactic thereby reducing the clearance and increasing the half-life of the infusions, these extended half-life products were developed. Here product. Essentially, PEG creates a cloud around the factor, making you’ll see a list on the left of those that are approved for hemophilia it too big for the kidney to clear. A and B, and we’ve listed here both the generic and brand names since most of our patients and providers in the ED will be familiar The third method of extending half-life of a factor product is with those brand names. through albumin fusion. Here, the half-life extension builds on the long half-life of albumin itself, which is attributed to its high The last product here is a new-generation factor VIII that circulates molecular weight, and also to the Ph-dependent interaction independently of von Willebrand factor, and so it breaks that von with the neonatal Fc receptor, which then in turn prevents the Willebrand factor–imposed half-life barrier. Phase 1 results with this intracellular degradation. These are all methods of extending the product have been really encouraging, and the half-life has been half-life of products, and we’ve had quite good success with these on the order of 40 hours with weekly or every-10-day dosing. newer products.

On the right side, we have a list of all the newly approved products 1-5 and investigational products that Dr. Wynn will be reviewing Approved EHL FVIII Replacement Strategies shortly in the next section of this presentation. rFVIII EHL rFVIII t½ extension (fold change) Fc Fusion Dr. Allen: Dr. Rajasekhar, these are certainly names that I think Efmoroctocog alfa (Eloctate) 12.4 h 19 h 1.5-1.7 every emergency physician would struggle to pronounce, and PEGylation I want to underscore the fact that you may not know the exact Rurioctocog alfa pegol (Adynovate) 10.4 h 14.3-16 h 1.4-1.5 name of these or what it’s for, but knowing where to gather that Damoctocog alfa pegol (JIVI) 13 h 19 h 1.5 information and whom to discuss with from a specialist standpoint Turoctocog alfa pegol (Espercot) 11.7 h 19 h 1.6 is probably of the utmost importance for the emergency physician. 0 6 12 18 24 t½, h 1. Powell JS et al. Blood. 2012;119:3031-3037. 2. Konkle BA et al. Blood. 2015;126:1078-1085. 3. Mahlangu J et al; A-LONG Investigators. Blood. 2014;123:317-325. 4. Coyle TE et al. J Thromb Haemost. 2014;12:488-496. 5. Tiede A et al. J Thromb Haemost. 2013;11:670-678. Dr. Rajasekhar: Absolutely. Thanks, Dr. Allen.

Here you’ll see that there’s a list of various extended half-life factor 1 Mechanisms of Half-Life Extension in Hemophilia VIII products on the market. What you’ll notice here is that with the

Linker current methods of extension, it really has not been a homerun; Protein of interest Fc region Protein of interest Albumin

PEG we’ve been able to extend the factor VIII half-life of the product Protein of interest PEG by at most 1.7-fold. This is largely because like native factor VIII,

o H H o n the half-life of extended half-life products is regulated largely by PEG Protein of Fc region interest the interaction with von Willebrand factor, so consequently, the Fc Fusion PEGylation Albumin Fusion half-life of von Willebrand factor, which is about 15 hours, has been • Fc portion of human • Creates “cloud” around • Albumin has a long IgG fused to factor attached proteins half-life (~3 weeks) the limiting factor to factor VIII products being extended in their • IgG has a long • Molecule too big to be half-life. What I think is important to know is that these products half-life (~3 weeks) cleared by kidneys are available, that patients are asking about them, and patients 1. Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84-98. are presenting to the ER on these new products, so I think it’s important for ER physicians and nurses to be familiar that these Now let’s talk about the mechanisms by which we can extend the exist. standard half-life products’ half-life to an extended half-life product. There are three main mechanisms by which we can extend the half- Dr. Wynn: Dr. Rajasekhar, I think it is also important to note that life of factor concentrates. the half-life extension is very variable between patients. So some patients may have 19 hours, but some patients may have a large The first is Fc fusion, and this was the first extended half-life variance from that, and a large portion of patients may have much, technology on the market. Here what we have is a fusion of the Fc much shorter half-lives, and some may actually have slightly longer portion of IgG to the factor molecule, and this promotes half-life half-lives. extension by altering the normal clearance of the factor. So what you have is the factor VIII molecule linked to the Fc IgG, and that Dr. Rajasekhar: That’s particularly true for your pediatric patients complex then is recycled back into circulation rather than being in whom clearance often with these products is much quicker than directed to lysosomal degradation within a cell. our adult patients.

The second method of extension of half-life is PEGylation, and what we’re doing here is they attach a covalent PEG product to the factor molecule itself, and that protects against proteolytic degradation,

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You know, the factor VIII uptake has been a lot slower because the Clinical Data on EHL FVIII Products in Hemophilia A1-4 increase in half-life has been more incremental in its nature.

• 92% reduction in ABR with individualized prophylaxis Efmoroctocog Alfa • 76% reduction in ABR with weekly prophylaxis (Eloctate) • 87.3% of bleeding episodes resolved with 1 injection • No subjects developed inhibitors during the study Clinical Efficacy on EHL rFIX Products in Hemophilia B • 95% reduction in ABR twice-weekly prophylaxis Rurioctocog Alfa Pegol • 95.9% of bleeding episodes treated with 1-2 infusions (Adynovate) • No subjects developed inhibitors during the study Eftrenonacog Alfa (Alprolix)1

• 92% reduction in ABR with prophylaxis once every 5 d • 83% reduction in ABR with weekly prophylaxis Damoctocog Alfa Pegol • 90.6% of bleeds were controlled with ≤2 infusions • 87% reduction in ABR with interadjusted prophylaxis (JIVI) • No inhibitors were detected during the study • 90.4% of bleeding episodes resolved after 1 injection • No subjects developed inhibitors during study

• 96% reduction in ABR with prophylaxis once every 4 d 2 Turoctocog Alfa Pegol Nonacog Beta Pegol (Rebinyn) • 83.6 % of bleeds resolved with 1 injection (Espercot) • One patient developed inhibitors after 93 exposure days • 93% reduction in ABR with weekly prophylaxis • 99% of bleeding episodes resolved after 1 injection 1. Mahlangu J et al; A-LONG Investigators. Blood. 2014;123:317-325. 2. Konkle BA et al. Blood. 2015;126:1078-1085. • No subjects developed inhibitors during study 3. Reding MT et al. J Thromb Haemost. 2017;15:411-419. 4. Giangrande P et al; Pathfinder™2 Investigators. Thromb Haemost. 2017;117:252-261. Albutrepenonacog Alfa (Idelvion)3

• 100% reduction in ABR with prophylaxis once every 2 weeks • 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection • No patients developed antibodies or inhibitors

In general, the pivotal data that led to the FDA approval of these 1. Powell JS et al. N Engl J Med. 2013;369:2313-2323. 2. Collins PW et al. Blood. 2014;124:3880-3886. 3. Santagostino E et al. Blood. 2016;127:1761-1769. extended half-life products are based on studies that compared the product using regular prophylaxis with the extended half- life product and comparing it with on-demand standard half-life Right. You know, with the improvement in convenience with these products. Most of these studies found that with regular prophylaxis extended half-life products, it’s really important to make sure that with these newer products, we had a reduction in annual bleed they’re still efficacious. So you’ll see here that there have been rate, or ABR. You’ll see that the prophylaxis with these agents is several pivotal trials leading to the FDA approval of these factor IX much less frequent. It also had good success, and in those who extended half-life products that have shown not only a reduction in developed a bleed and had to take more factor, typically they annual bleed rates with regular prophylaxis, but also for those who only required one or two doses of the extended half-life product have a bleed, they typically again only require one to two doses to to resolve the bleed. Finally, from a safety standpoint, which we control the bleed. In terms of safety, there were no inhibitors that obviously need to consider, is the inhibitor formation. From these developed in these studies. studies, you’ll see that there was either no inhibitor formation or very rare incidence of inhibitor formation. The Use of Bypassing Agents for Preventing Bleeding in Patients With Hemophilia With Inhibitors1

Intrinsic pathway Extrinsic pathway 1-3 Bypassing Agents Approved EHL rFIX Replacement Strategies Tissue factor

XII

XI • Recombinant activated FVII and activated Common rFIX EHL rFIX VII pathway prothrombin complex concentrate t½ extension IX (fold change) VIII Fc Fusion X • Activated FVII (FVIIa) can directly activate FX, by passing the need for FVIII and FIX Ca+2 Eftrenonacog alfa (Alprolix) 33.8 h 82.1 h 2.4 Lipids V • Bypassing agents are indicated for the PEGylation treatment and control of bleeding episodes Prothrombin (II) Thrombin occurring in adults and adolescents with ~5 Nonacog beta pegol (Rebinyn) 19 h 93 h hemophilia A or B with inhibitors

Albumin Fusion Fibrinogen (I) Fibrin clot (XIII) Albutrepenonacog alfa (Idelvion) 23.7 h 102 h 4.3 1. https://www.fda.gov/news-events/press-announcements/fda-approves-additional-treatment-adults-and-adolescents-hemophilia- or-b-and-inhibitors. 0 24 48 72 96

t½, h 1. Powell JS et al. N Engl J Med. 2013;369:2313-2323. 2. Negrier C et al. Blood. 2011;118:2695-2701. 3. Santagostino E et al. Blood. 2016;127:1761-1769. We’ve spent a lot of time talking about patients without inhibitors and the multiple drugs that are available—standard half-life Unlike extended half-life factor VIII products, we’ve had much more products, extended half-life products—for these patients. But success with extending factor IX half-life drugs. What you’ll see here for patients with inhibitors, infusion of factor concentrates is is that there are a few factor IX extended half-life products in which generally not effective. Limited options exist for these patients, their half-lives have been extended up to five times the standard and they include bypassing agents. The purpose of a bypassing half-life product. Now Dr. Wynn, in your experience, because of this agent is to provide essentially a detour to bypass the factors in significant prolongation in half-life with the factor IX products, has the coagulation cascade that are blocked by the inhibitor to help there been more enthusiasm in the hemophilia community about generate a fibrin clot. The two available bypassing agents that we switching patients from standard half-life factor IX products to use mostly in inhibitor patients are recombinant activated factor these extended half-life factor IX products? VIIa and prothrombin complex concentrates. Dr. Wynn will be discussing advances and treatment options that are particularly Dr. Wynn: Yes, for all the reasons that you stated, our pediatric exciting for patients with inhibitors in whom we’ve had very few patients have been very enthusiastic in switching from a standard options over the years. half-life factor IX product to an extended half-life factor IX product.

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Dr. Allen: This is something that really could be problematic for the Interactions of Emicizumab-kxwh With FIXa and FX1 emergency physician, when you provide the factor replacement as thought would work and then you’re still running into a potential FVIIIa

HC A2 HC emergent condition that could require an intervention. Making A1 FIXa FX A3 decisions with these medicines, which are quite expensive and LC LC Gla C1 C2 Gla not benign themselves, is definitely going to take some shared Phospholipid membrane decision-making with a specialist. Emicizumab

Dr. Rajasekhar: And it’s important to note that the presentation FIXa FX of an inhibitor may be for the first time in the ED, so it may be that Gla Gla Phospholipid membrane the patient doesn’t know they have an inhibitor. They’ve just been 1. Kitazawa T et al. Thromb Haemost. 2017;117:1348-1357. noticing over time that their factor is not working as it previously had or they’re having more bleeds, and they finally come into the ED and there has to be a high clinical suspicion to look for these First of all, emicizumab, like I mentioned, is a bridging agent, inhibitors. so it acts in replacement of factor VIII by bringing factor IX in close proximity with factor X. Because of the proximity on the Okay, so now I’d like to turn over the presentation to Dr. Wynn. Dr. phospholipid membrane, they will go ahead and interact and lead Wynn, I’m very excited to hear about some of the novel therapies to further activation of factor proteins to eventually develop the that are coming down the pipeline in the hemophilia space. fibrin clot.

Novel Nonfactor Therapies for the Management HAVEN 1 and HAVEN 2 Studies1-3 of Hemophilia With and Without Inhibitors1

All bleeding events Bleeding events treated with bypassing agents Approved Investigational Treated events of spontaneous bleeding Treated events of joint bleeding Treated events of target-joint bleeding HAVEN 1 Inhibitors: Emicizumab 87% difference in annualized rate of treated bleeding events Prophylaxis vs No Prophylaxis (risk ratio = 0.13; P < .001) 87% reduction ABR Prior BPA prophylaxis → emicizumab prophylaxis: 79% fewer bleeds 30 28.3 (17.0-47.3) Zero 63% vs 6% 25 23.3 (12.3-43.9) bleeds, % ISR = 15% 20 AE 5 thrombosis/TMA Emicizumab-kxwh Fitusiran Concizumab Gene Therapy 16.8 (9.9-28.3) 15

Bispecific Small inhibitory Monoclonal Replacing the (95% CI) monoclonal RNA-targeting antibody: TFPI gene needed for 10 HAVEN 2 study showed emiciziumab-kxwh 6.7 (2.0-22.4) 6.5 (3.4-12.4) antibody: bridges 5.5 (3.6-8.6) 5.1 (2.3-11.2) is effective and well-tolerated in pediatric antithrombin inhibition of production of 5 FIXa and FX to 2.9 (1.7-5.0) 3.0 (1.0-9.1) 3.1 (1.2-8.0) 2,3 FXa/TF/FVIIa endogenous 1.3 (0.7-2.2) patients with hemophilia A and inhibitors 0.8 (0.3-2.2) 0.6 (0.2-1.5)0.3 (0.1-1.0) restore function of 0.1 (0.0-0.6) factor protein Annualized Rate of Bleeding Events 0 missing FVIIIa Group A Group B Group C Emicizumab Prophylaxis No Prophylaxis Emicizumab Prophylaxis (n = 35) (n = 18) (n = 49) 1. Oldenburg J et al. N Engl J Med. 2017;377:809-818. 2. Young J et al. International Society on Thrombosis and Haemostasis 2017 1. Hartmann J, Croteau SE. Am J Hematol. 2016;91:1252-1260. Congress (ISTH 2017). Abstract OC 24.1. 3. Young G et al. Blood. 2018;132:632.

Dr. Wynn: Thank you, Dr. Rajasekhar. It’s my pleasure to talk The studies that support the use of emicizumab are the HAVEN about these new products. As you mentioned at the beginning series of studies, the 1 through 4. Starting with HAVEN 1, HAVEN 1 of your lecture, these are very, very exciting times in the world looked at patients who have inhibitors and how effective they were of hemophilia and the introduction of new products, and these in the control of bleeding. The results from HAVEN 1 show that products, which are what we consider novel products, are coming unlike bypass therapies that these patients were on, emicizumab very, very quickly. It becomes important to have expertise to keep can reduce annual bleeding rates by more than 90%. HAVEN 2 was up with all of these introductions. a follow-up study for those patients, and this was a pediatric study looking at its use in the same population. HAVEN 2 showed similar The first in the currently approved novel agent class is a product results compared with the reduction in annual bleeding rates that called emicizumab. Emicizumab is a bispecific monoclonal were provided to adults. antibody that acts as a bridge between factor IX and factor X to replace the factor VIII product. Very, very shortly, we will begin 1 using additional agents. Fitusiran is in late development, as well HAVEN 3 and HAVEN 4 Studies as a product called concizumab. And very, very exciting, all of us HAVEN 3 Study HAVEN 4 Study are expecting gene therapy to be on the horizon and will be a HAVEN 3 Noninhibitors Emicizumab Prophylaxis vs ABR, all 4.5 therapeutic product that patients will be utilizing. No Prophylaxis ABR, treated 0.6 ABR 96% reduction spontaneous bleeds Zero ABR, treated joint bleeds 1.7 56% vs 0% bleeds, % ABR, treated target 1 AE ISR = 25% joint bleeds No thrombosis/TMA 0 1 2 3 4 5

No thrombotic events or development of de novo antidrug antibodies with neutralizing potential or FVIII inhibitors were observed

1. Pipe SW et al. Lancet Haematol. 2019;6:e295-e305.

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The HAVEN 3 study looks at the use of emicizumab in the prevention Dr. Wynn: Moving on from emicizumab and to other nonfactor of bleeding for patients who do not have inhibitors. Similarly to the products that are in development and hopefully soon to be HAVEN 1 and HAVEN 2 studies, the results do show also a reduction approved, another exciting one is a product called fitusiran. in annualized bleeding rates to greater than 90%. Then finally, Fitusiran is a product that uses interference RNA, a short snippet HAVEN 4 looks at alternative dosing regimens for emicizumab. The of RNA sequence that will block the production of antithrombin dosing regimens previously approved were to be given once a week, 3 by preventing its translation into a protein. It represents a type and HAVEN 4 establishes the use of emicizumab dosing once every of therapy that rebalances the hemostatic system rather than 2 weeks or once every 4 weeks, and alternative regimens are equally directly replacing the factor that is missing. It will reduce the effective to reduce bleeding rates for adults and pediatric patients. counterbalance to coagulation and put clotting and bleeding into a more even balance. Dr. Rajasekhar: Dr. Allen, I think what’s important for ER providers here to know is that this is becoming widely used in our hemophilia Targeting Antithrombin in Patients population, that you will be seeing patients on this new medication With Hemophilia A or B With Fitusiran and that it’s used for prophylaxis, not to treat a bleeding episode. Phase 1 dose-escalation study showed once-monthly subQ administration of fitusiran was well-tolerated and resulted in dose-dependent lowering of the antithrombin and increased So if a patient on emicizumab comes to the ER and has an acute thrombin generation in participants with hemophilia A or B who did not have inhibitors1 bleed, you would revert back to using a factor VIII product if they’re Interim analysis of phase 2 open-label extension study, which included patients with hemophilia A or B with or without inhibitors who completed the phase 1 study, has indicated a noninhibitor patient or a bypassing agent if they’re an inhibitor fitusiran prophylaxis provides sustained AT lowering, results in low ABR over an extended 2 patient. period of time, and is generally well tolerated Ongoing phase 3 prophylaxis trials • ATLAS-INH: fitusiran vs FVIIa or aPCC in patients with hemophilia A or B and inhibitors3 • ATLAS-A/B: fitusiran vs FVIII or FIX in patients with hemophilia A or B without inhibitors4 Dr. Allen: These are great points, Dr. Rajasekhar and Dr. Wynn. • ATLAS-PEDS: fitusiran in patients 1 to <12 years of age with hemophilia A or B5 • ATLAS-PPX: fitursiran in patients with hemophilia A or B previously receiving Knowing about these is probably going to be half the battle with bypassing agents6

1. Pasi K et al. N Engl J Med. 2017;377:819-828. 2. Pasi K et al. ISTH 2019. Abstract OC 11.3. recognition, as you mentioned, and into your treatment strategy 3. https://clinicaltrials.gov/ct2/show/NCT03417102. 4. https://clinicaltrials.gov/ct2/show/NCT03417245. 5. https://clinicaltrials.gov/ct2/show/NCT03974113. 6. https://clinicaltrials.gov/ct2/show/NCT03549871. where that shared decision-making that we’re going to discuss quite a bit in the near future is going to be paramount to their success in improving morbidity and mortality. Dr. Wynn: The development of fitusiran has been years in the making, and currently the process of development has fitusiran Dr. Wynn: The other major advantage of emicizumab is that it is in phase 3 trials. The trials are showing good results with good administered in a subQ fashion, subcutaneous fashion, rather than bleeding control, and the most exciting thing is that fitusiran is a an intravenous fashion, so it is much, much easier for our patients therapy that will be not limited to just factor VIII patients, but also to learn and perform the infusions. can be used to manage the bleeding of factor IX patients as well.

Dr. Allen: And Dr. Wynn, I imagine that probably improves their 1-4 quality of life as well. Concizumab: Monoclonal Antibody Directed Against TFPI

Concizumab Dr. Wynn: It improves their quality of life, both because of the • Humanized IgG4 antibody • High affinity for Kunitz-2 domain of TFPI route of administration and the frequency of administration, and • Complete neutralization of TFPI inhibition of FXa/TF/FVIIa it has actually increased the compliance of our patients who have Concizumab switched to it because of those factors, that ease of use. TFPI K1 K2 K3

Dr. Rajasekhar: Then finally, from a safety standpoint, we are really VIIa X Xa happy to see that this medication is not associated with inhibitor TF development. 1. Hilden I et al. Blood. 2012;119:5871-5878. 2. Shibata S et al. Proc Natl Acad Sci USA. 2013;110:7838-7843. 3. Shapiro AD et al. ASH 2019. Abstract 1973. 4. Eichler H et al. ASH 2019. Abstract 2417.

1 Targeting Antithrombin in Hemophilia With RNAi: Fitusiran The next agent that we wanted to discuss is concizumab. Fitusiran Concizumab is similar to fitusiran in that it hopes to rebalance ASGPR RNA interference (RNAi) Clathrin- (pH >5) coated pit the coagulation system rather than just simply increase a missing Lowers antithrombin production AT Recycling Clathrin-coated vesicle ASGPR factor. The mechanism of action of concizumab is to block a Promotes thrombin generation RISO Endosome mRNA molecule called tissue factor pathway inhibitor, and thereby allow Nucleus Hemophilia A FVIIa FVII Restores hemostasis FX FVIII FVIIIa the production of factor X into production of a fibrin clot. Hemophilia B FIX FIXa Investigational RNAi therapy that specifically FXa AT targets antithrombin mRNA (encoded by FVa FV

SERPINC1) to suppress the production and thereby Prothrombin Thrombin rebalance coagulation system and promote hemostasis in hemophilia Fibrinogen Fibrin Blood clot

1. Sehgal A et al. Nat Med. 2015;21:492-497.

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Phase 2 Results of SubQ Concizumab Daily in Hemophilia A Selected Investigational Gene Therapy for Hemophilia1,2 and Hemophilia A/B With Inhibitors1

Gene Therapy for Hemophilia A Serotype Transgene Mean Factor Activity Post-Infusion Key Safety Findings Key Safety Findings Valoctocogene roxaparvovec rAAV5 BDD-FVIII 52% • No AE-related withdrawals • ABR (after 24 weeks): 3.0-7.0 (BMN 270) • All patients chose to continue Spark SPK-8011 200/LK03 BDD-FVIII 30% at 12 wk • No safety concerns with to extension phase in both trials breakthrough-bleed treatment TAK 754 • Concizumab exposure, free rAAV8 BDD-FVIII To be determined (BAX 888, SHP 654) TFPI reduction, and TG potential were similar across all groups Gene Therapy for Hemophilia B Serotype Transgene Mean Factor Activity Post-Infusion Fidanacogene elaparvove • Concizumab exposure was associated AAV8 FIX-Padua 33.7 ± 18.5 (SPK-9001) with normalized TG potential Etranacogene dezaparvovec (AMT-061) rAAV5 FIX-Padua 41% Three concizumab studies—phase 2 Explorer 5, global phase 3 Explorer 7, rAAV6 Zinc finger-FIX To be determined and Explorer 8—are on hold because of thrombotic events SB-FIX

1. Astermark J et al. ISTH 2019. Abstract LB 01.1. 1. Miesbach W et al. Haemophilia. 2019;25:545-557. 2. Doshi BS, Arruda VR. Ther Adv Hematol. 2018;9:273-293.

Concizumab also is in development. It is currently in phase 2 trials, The gene therapy products that are in development are ongoing. and so far, it has shown good results. There are concerns currently The factor production for these patients has been effective. It has of related thrombotic events that have the most recent studies reduced bleeding rates in men who have received the product and on hold, but those patients hopefully will be starting up real soon has produced stable rates, anywhere from the 20% to 40% range. once the events have been clarified. Some of the studies are still ongoing and the products are still being developed. The BMN agent will probably be the first of many agents to come to be introduced. Gene Therapy: Restoring Normal Factor Production1

AAV-Mediated, Liver-Directed Gene Therapy for Hemophilia Gene therapy also has its limitations. The AAV vector has a limited AAV Genome Modifications ITR Rep Cap ITR lifetime, so the production of factor is expected to decrease over • Codon optimization rAAV Vector Genome • CpG content ITR Promoter Intron Transgene polyA ITR time as the cells live their own lifespans. We also know that gene FVIII/FIX inhibitors Pediatric patients Modifications therapy is a single-dose treatment at the current time. Because Liver disease Therapeutic Options • Serotype • Empty capsids • Antiviral therapy it is a virus vector, the immune system will develop an immune • Production system • Skeletal muscle gene therapy

Pre-existing neutralizing CD8+ Capsid-triggered response against the virus, and the reintroduction of the virus will antibodies to AAV serotype T Cell cellular immune response Therapeutic Options Therapeutic Options • Lower vector dose cause a destruction of the carrier molecule without any uptake into • Plasmapheresis • Immunosuppression • Empty capsids • Immunosuppression the producer cells. Hopefully, with those obstacles, we’ll be able to • Novel serotype • Regional delivery Protein production address them and overcome those with the introduction of even 1. Doshi BS, Arruda VR. Ther Adv Hematol. 2018;9:273-293. newer agents.

Then moving on to the most exciting new therapy that providers Dr. Rajasekhar: Dr. Wynn, it strikes me as important as you’re as well as patients have been hearing for decades about is gene talking about these new pipeline drugs and gene therapy, that if therapy. Gene therapy, unlike any of the other factors, looks to a patient on one of these clinical trials presents to the ER, whether restore normal factor production in our patients. The current it has to do with bleeding or something else, that it’s important generation of gene replacement therapy uses a virus vector called for ER providers to then contact the institution—the principal AAV, which has the inability to reproduce itself and is able to be investigator or the study coordinator—to let them know that a modified to carry a gene to be the template for production of the clinical trial patient is in the ER, and so that we can investigate factor. whether this adverse event is related to a product.

The virus will be injected into the body and carry the gene to a Dr. Wynn: That is right, Dr. Rajasekhar. producer cell, which is typically a cell in the liver. The DNA will be uptaken and will exist in the nucleus, and the new DNA will use Dr. Allen: This is very interesting Dr. Wynn and Dr. Rajasekhar. the nuclear mechanisms to translate itself and produce the factor I think the awareness of the emergency physician, as you VIII within the patient’s own body. The cells, being living cells, will mentioned, and speaking with the study coordinator or PI would continue to produce the factor over an extended period of time. be incredibly important because there also may be some other mitigating factors to severity of illness based off of the study, outside of just the recognition and documentation of a potential event. I think calling a hematologist in these situations is of the utmost importance to start therapy, if anything could be different that’s more in their specialty.

Dr. Wynn: Next, I would like to go ahead and have Dr. Allen present the approach in the emergency department for our patients.

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Treating Hemophilia in the MASAC Guidelines for ED Management: Assessment1 Emergency Department: What Do • Treatment for a suspected bleeding disorder is based on clinical history • Physical findings may be NORMAL in the early phases of most hemophilic bleeds Current Guidelines Tell Us? • Spontaneous bleeding is common in individuals with severe disease (<1% factor level)

Brandon R. Allen, MD, FACEP When in doubt, administer clotting factor replacement immediately; DO NOT DELAY for imaging studies, lab results, or consultations Anita Rajasekhar, MD, MS • Treatment decisions should be based on the SUSPICION of a bleeding-related problem

Tung Wynn, MD • If the patient or parent of a patient suspects that occult bleeding is occurring, administer clotting factor replacement • Patients often are instructed to carry with them appropriate factor replacement dosing with the Hemophilia Foundation of Greater Florida. guidelines as advised by their treating hematologist 1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019.

This activity is supported by an educational grant from Genentech. That leads us into the assessment of the patient, and we’re going to

MASAC Guidelines for ED Management of Individuals do a great clinical history. As mentioned before by Dr. Rajasekhar, With Hemophilia and Other Bleeding Disorders: Triage1 it’s really important with this that the patient is incredibly knowledgeable with this disease state. With that comes a lot of help to the emergency physician in regards to what they tried at q Individuals with known Delays in administering factor home, what they know about their factor replacement, do they bleeding disorders concentrate can significantly should be triaged impact morbidity and mortality have any with them, things like that. urgently q Consultation with the patient’s hematologist It’s also important to point out that in your physical exam, it could or a regional HTC This should not delay giving professional is strongly clotting factor concentrate be normal in the early phases of someone’s potential emergency advised when possible replacement to the patient and that in severe disease states, as we’re going to talk about in a couple slides on a really nice table, spontaneous bleeding can 1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019. occur without trauma. I think one thing that’s a little bit of a pitfall for emergency physicians is to think that a hemophilia patient may Dr. Allen: Thank you, Dr. Wynn. We’re going to talk about what the require trauma to have a potential injury and that’s potentially not current guidelines tell us for the treatment of hemophilia in the the case in these severe disease states. This goes back to the big emergency department. This should be right in our wheelhouse piece of this slide, which is when in doubt, administer replacement in regards to the approach, evaluation, and management of these and do not delay for imaging studies, labs, or consultations. I think patients. this is the best way for us to have better outcomes for our patients.

First, we’re going to start out with the National Hemophilia Dr. Rajasekhar: Dr. Allen, if I can just interject here, I think we Foundation MASAC guidelines. If there are any two take-home talked a little bit about when a patient brings clotting factor points I want you guys to know from this is (1) when in doubt, give concentrate with them, it’s generally best to allow them to use factor, and (2) treat first, image or diagnose second—these are two that concentrate if at all possible. This recommendation really things that have really been the standards and the major highlights acknowledges that many emergency rooms, especially at smaller of these guidelines. hospitals, do not have the majority of clotting factor options and may not have any clotting factor, for that matter, on their formulary. First, you start out with triage, of course. If someone’s to arrive to the emergency department, either by ambulance or into your Then the other piece is you mentioned that you should infuse lobby, they should be urgently triaged if they have a history of factor before imaging and labs, but if a patient is being transported hemophilia. Delays in administering factor can significantly impact to your ED or transported from your ED to another facility for a their outcomes with morbidity and mortality. step up in care, again, it’s really important to infuse before that transport. The other big take-home point on this little checklist that we have here is urgent and early consultation with the hematologist or a Dr. Allen: Those are such great points, Dr. Rajasekhar. One of the regional center or professional is strongly advised. But that doesn’t realities of this, too, is that these factor replacements are expensive, take away the responsibility of the emergency physician to perform and pharmacies at your local hospitals or in your emergency an appropriate medical screening examination and get therapy departments may not carry the exact one that the patient may started quickly. have, but they may have one. And if not, then a referral and transport is of the utmost importance to get them what they need.

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MASAC Guidelines for ED Management: MASAC Guidelines for ED Management: Diagnostic Studies1 Indications for Factor Replacement Therapy1

1. Suspected bleeding into a joint or muscle Clotting factor should be given before any diagnostic studies are performed, 2. Any significant injury to the head, neck, mouth, or eyes, or evidence of bleeding especially in cases of head trauma, abdominal trauma, or suspected ICH in these areas 3. Any new or unusual headache, particularly one following trauma 4. Severe pain or swelling at any site • Routine joint bleeds DO NOT require imaging 5. All open wounds requiring surgical closure, wound adhesive, or wound closure strips • For the established patient, routine surveillance labs (PT, PTT, factor levels) 6. History of an accident or trauma that might result in internal bleeding ARE NOT indicated unless requested by the patient’s hematologist 7. Any invasive procedure or surgery • If an invasive procedure is required (ie, lumbar puncture, ABG, lung/joint tap) 8. Heavy or persistent bleeding from any site or if surgery is indicated, clotting factor to raise the patient’s level to 100% must be administered in the ED prior to the procedure 9. Gastrointestinal bleeding 10. Acute fractures, dislocations, and sprains

1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019. 1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019.

Moving on into diagnostic studies, and there are some “do nots” on This is a nice summary of the MASAC guidelines for ED here that I think are incredibly important for resource utilization. management, and I think a lot of these indications for factor One thing that we talked about earlier was a target joint and replacement are self-explanatory and just go ahead and peruse hemarthroses and routine bleeding in those joints do not require yourself through this list and we’ll move on to the actual imaging. I think that that actually is tough to manage in an management and treating of the patients. emergency department setting, especially if they have decreased range of motion and things like that, but that’s a part of those MASAC Guidelines for ED Management: Treating Patients With MASAC guidelines and I think they’re important to point out. Hemophilia A or B Without Inhibitors1-3,a

Target Percent Dose of FVIIIb, Dose of FIXb, Bleeding Type Correction units/dL units/dL Back to what we were talking about earlier, clotting factor Minor 25% 12.5 25 Moderate 50% 25 50 replacement should always supersede any diagnostic studies, Severe 100% 50 100-120 especially in the cases of trauma. There are frequent cases of • Minor • Moderate • Severe – Early hemarthrosis – Definite hemarthrosis – CNS minor trauma that can result in intracranial hemorrhage and – Mild soft tissue – Moderate muscular – Retroperitoneum – Mild muscular – Hematuria – Retropharynx abdominal trauma that can result in intra-abdominal injuries and – Dental – Surgery – Epistaxis (rare) – GI hemoperitoneum. Remember: Treat first, diagnose later

a Calculations based on factor dosing recommendations. Refer to package insert for full dosing information. b Recombinant clotting factor or patient’s product of choice is preferred; plasma-derived concentrate is a suitable alternative in emergency situations when recombinant factors are not available. Dr. Rajasekhar: Dr. Allen, it seems like what you’re saying here is 1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019. 2. Factor VIII Dosing Calculator. https://mprcalc2.usbmis. com/24535.html. 3. Factor IX Dosage Calculator. https://www.empr.com/medical-calculators/factor-ix-dosage-calculator/article/170191. that treatment decisions really should be based on the suspicion of a bleeding-related problem, not documentation necessarily of one. That kind of goes into what you were saying about labs and I think one thing that’s outside of the remembering of the imaging not being required. Frankly, labs are not expected to guide “treat first, diagnose later” is about minor, moderate, and severe management and factor levels are not often available in real time, indications for factor replacement, and then the target percentage so it’s not really feasible to check some of the specialized labs to of correction. As it states here, these are really nice criteria in which guide your treatment decisions. you get into the severe, the moderate, and the minor.

Dr. Allen: I couldn’t agree more. You know, another thing that For the severe, I think we should focus on things in regard to the we haven’t really touched on is invasive procedures that are very central nervous system, areas where you can have expansion of common in the emergency department. There are some examples blood in a space like the retroperitoneum; the retropharynx, which like a lumbar puncture, arterial blood gas or an arterial line, lung could be quite scary for an airway; any type of surgery; or GI, as we or thoracentesis or even arthrocentesis, or a joint tap, or if major mentioned on the last slide. Then in the moderate, you get into surgery or an emergent surgery is indicated, it’s paramount that the hemarthrosis, potentially the target joint; dental; and anything you replace and raise that patient’s level to 100% in the ED prior to do with hematuria or muscular. Then the minor is obviously the to the procedure, or the risk of complications and hemorrhage more mild cases of such. I don’t expect emergency physicians to increases substantially. memorize these things, but having to know where to reference this is going to be important for you to be able to manage first and do that “treat first” strategy.

Dr. Rajasekhar: Dr. Allen, there are online calculators that can help calculate what dose to give.

Dr. Allen: We love online calculators. That’s great.

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Dr. Wynn: Dr. Allen, one thing to remind everybody is that these on emicizumab comes into the ED with a bleed, we should be patients are oftentimes on prophylactic regimens, as well as they treating them with factor concentrate, in the case of noninhibitor have the ability to self-infuse and sometimes they have levels that patients, or a bypassing agent, in the case of an inhibitor are freestanding. Another rule of thumb to keep in mind is that if patient. The one caveat to that is that recombinant factor VIIa is these patients have ongoing treatment, if you don’t know what the recommended over one of the prothrombin complex concentrates, level is, go ahead and treat to the full intended level that you want and that’s because in clinical trials, prothrombin complex and assume that the patient is at 0%. concentrates were noted to have a higher incidence of thrombosis or thrombotic microangiopathy when used in combination with Dr. Allen: Thank you, Dr. Wynn. That’s a great rule of thumb. When emicizumab prophylaxis. in doubt, assume that they’re at 0%. I think we’ll be able to really standardize that. Warnings and Precautions for Patients With Hemophilia A on Emicizumab-kxwh Prophylaxis1

MASAC Guidelines for ED Management: Thrombotic Microangiopathy Laboratory Coagulation Treating Patients With Hemophilia and Inhibitors1 and Thromboembolism Test Interference • Cases of thrombotic microangiopathy • Emiciziumab-kxwh interferes with ACT, and thrombotic events were reported aPTT, and coagulation laboratory tests • Treatment decisions may be more complicated when, on average, a cumulative amount based on aPTT, including one-stage • The care of inhibitor patients should be urgently discussed with the patient's hematologist of >100 units/kg/24 h of aPCC was aPTT-based single-factor assays, administered for ≥24 hours to patients APC-R, and Bethesda assays • If an individual with an inhibitor presents in a life- or limb-threatening scenario, the safest receiving emicizumab-kxwh prophylaxis (clotting-based) FVIII inhibitor titers immediate action is to prescribe: • Monitor for the development of thrombotic • Intrinsic pathway clotting-based microangiopathy and thrombotic events laboratory tests should not be used if aPCC is administered • Discontinue aPCC and suspend dosing of emicizumab-kxwh if symptoms occur rFVIIa OR aPCC 90 mcg/kg 75-100 units/kg 1. Hemlibra (emicizumab-kxwh) Prescribing Information. https://www.gene.com/download/pdf/hemlibra_prescribing.pdf.

1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019. Dr. Wynn: While the thrombotic complications of factor choice with emicizumab are well noted, there have been thrombotic Moving forward, there’s this challenge with hemophilia and events that have been reported when providing acute inhibitors that’s worthy of discussion with the ED management. management for patients on emicizumab. The incidence of This brings in another complication, and we discussed this a thrombosis has been defined as when patients have received little bit earlier, but this is the patient who may be refractory to an activated prothrombin complex concentrate at high doses, your initial factor replacement. This is where a hematologist and generally greater than 100 units/kg in a 24-hour period of time, discussing with a specialist is paramount to the patient’s success. and with repeated dosing of those high doses—multiple doses for If someone presents with an inhibitor or presumed an inhibitor more than 24 hours. As a result, it is our general recommendation and has a life- or limb-threatening scenario, the two options that to consider the use of factor VII first for patients on emicizumab. we have at this point in time are factor VII or prothrombin complex concentrates. This would certainly be shared decision-making, in In addition to the caution of the choice of bypass therapy for my opinion, with the specialist to talk about the risks and benefits an inhibitor patient on emicizumab, we also know that the of both of these, and also the capability of your institution to be measurement of factor levels while a patient is on emicizumab able to provide one of these hopefully. If not, you certainly need to can be problematic. The emicizumab causes falsely high levels of transfer the patient to a higher level of care. the aPTT assay, as well as the one-stage clotting-based factor VIII assays. It’s recommended if you are looking to try to determine a

Managing Patients With Hemophilia A factor level, you should use a chromogenic assay. on Emicizumab-kxwh Prophylaxis1 Dr. Rajasekhar: Dr. Wynn, for those emergency departments

NOT used alone in patients with that don’t have recombinant factor VIIa, we would want them to breakthrough bleeding episodes use prothrombin complex concentrates in an inhibitor patient on • Depending on individual’s inhibitor status, patients should be treated with emicizumab prophylaxis if they come in with a bleed, the point – FVIII replacement product being that you would try to use the lowest possible dose to control or the bleed. – Bypassing agents such as rFVIIa or aPCC (with caution) Dr. Wynn: Now we’re going to move into our case discussions regarding how to manage these patients in the emergency room. 1. Hemlibra (emicizumab-kxwh) Prescribing Information. https://www.gene.com/download/pdf/hemlibra_prescribing.pdf. Dr. Allen is going to introduce the first case and discuss it with us.

Dr. Rajasekhar: Emicizumab is solely used for prophylaxis or prevention of bleeds, and we touched on the fact that if a patient

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Best Practices From the Experts: home, but mother does not have it with her. Your pharmacy only Incorporating Shared Decision- carries a different one. Is it okay to switch them?

Making Into the Management of Every Patient Represents a Unique Challenge

Hemophilia A single severity-based therapeutic model does not represent the optimal treatment strategy for all patients with hemophilia1 Individualization of hemophilia care is recommended Brandon R. Allen, MD, FACEP

1-4 Anita Rajasekhar, MD, MS Factors to consider for individualized treatment

Condition of the patient’s Level and timing Patient’s bleeding pattern Individual PK profile Tung Wynn, MD musculoskeletal system of physical activity

Patient likelihood Central venous access Presence of target joint Psychosocial factors of good adherence with the Hemophilia Foundation of Greater Florida. Underscores need for shared decision-making 1. Sorenson B et al. Blood Coagul Fibrinolysis. 2003;14:469-477. 2. Collins PW. Haemophilia. 2012;18:131-135. 3. Oldenburg J. Blood. 2015;125:2038-2044. 4. Valentino LA. Haemophilia. 2014;20:607-615. This activity is supported by an educational grant from Genentech.

Thankfully, we’ve talked about a lot of these with the MASAC Case 1: Head Trauma guidelines and I think that it’s really important to talk about how every patient represents a unique challenge. A lot of these are A boy 7 years of age with a history of severe hemophilia A going to require shared decision-making, and this is something Key PE Findings Receives FVIII prophylaxis 2x/wk that I’m a real advocate of. I try to do this with almost every patient q Boy is alert, interactive, and appears well who I have a discussion with in the emergency department when it q Presents to ED after tripping over a rock Vitals are normal comes to care options and potentially a safe discharge plan. In this while running and striking his head q Does not appear to be in any distress case with hemophilia in this patient, the individualization of care is Boy’s mother states q No scalp hematoma • He has been complaining of a q Neurologic exam is recommended and encouraged. Here are some factors to consider mild headache normal for age for individualized treatment. With all these factors that you can • His last FVIII infusion was 2 days ago see down here, it really underscores the need for shared decision- making.

Dr. Allen: Okay, thank you Dr. Wynn. This is a head trauma case, 1 a pediatric case, actually, who just rolls into your emergency Goals of Shared Decision-Making department. A seven-year-old boy, and he has a known history of severe hemophilia A. He receives factor VIII prophylaxis twice a week, and he tripped over a rock while running and he struck his Inform the patient to improve their knowledge about their own illness head. Mother states he’s been complaining of a mild headache, and his last infusion was about 2 days ago. Pertinent findings on exam: Activate the patient to increase the role they assume in illness management he’s alert, interactive. He appears well. Vitals are normal on your first set of vital signs, and he’s not in any distress. You don’t even see a Promote interaction between patient and healthcare professional scalp hematoma, and his neurological exam is normal for age.

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

Key Questions What are the goals of shared decision-making? I think it’s to impart • Is head imaging warranted? knowledge and inform the patient; to activate the patient to • Does he need FVIII infusion? – If so, when should it be administered and how much? increase the role they assume, which means that they have to be • The patient uses rurioctocog alfa pegol at home, but mother does not have it with her in the action phase for their own wellness; and to and to promote – Your pharmacy only carries efmoroctocog alfa interaction between the patient and their health care professionals. Ø Is it okay to switch them? That may be you in the emergency department, but it also may

How can we incorporate shared decision-making be for their follow-up care with their specialist or if they require and individualize hemophilia care? admission.

Let’s talk about some key questions. Is head imaging warranted? Does he need a factor VIII infusion? He uses a factor replacement at

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NQP Playbook for Shared Decision-Making1 Case 1: Management

Recently, the National Quality Forum developed the National Quality Partners Playbook™: Shared Decision Making in Healthcare with input from a team of experts and recognized leaders committed After brief discussion with boy’s mother, efmoroctocog alfa to making SDM a standard of care for all patients 1 administered at 50 units/kg to bring his factor level to 100%

NQP Playbook Requirements for SDM

Clear, accurate, and unbiased medical evidence Head CT scan obtained after efmoroctocog alfa was 1 about reasonable alternatives (including no medical 2 administered shows a small subdural hematoma without intervention) and the risks/benefits of each overlying skull fracture

Clinician expertise in communicating and 2 tailoring that evidence for individual patients 3 Boy admitted to the PICU for serial neurologic exams; consult hematology for his treatment while in the ICU Patients’ values, goals, informed preferences, 3 and concerns, which may include treatment burdens

1. NQP Playbook™: Shared Decision Making in Healthcare. 2018 National Quality Forum.

The National Quality Forum created a playbook for this. It’s called Now back to that case that we talked about earlier, and we’re the National Quality Partners Playbook. To get through it and for going to talk a little bit about the management. As you know, some basic fundamental requirements for shared decision-making, we’ve talked about before, when in doubt, treat prior to seeking you want to think about clear and accurate and unbiased medical a diagnosis. After shared decision-making with the mother of the evidence, so you’re sharing knowledge, and then the clinician patient, we’re going to administer factor to get them up to 100% expertise in communicating and tailoring that evidence for your because of their history of severe hemophilia, and we’re going to patient. talk about imaging because of the concern with the mechanism of injury, when he fell and hit his head on a rock. After you understand and are able to impart the knowledge of that evidence, you need to be able to communicate that effectively to And guess what? That CT shows a small subdural hematoma your patient, who may have different levels of healthcare literacy. without a skull fracture, which makes sense with the physical exam Furthermore, the patient’s values, goals, and preferences have to findings of no hematoma externally. The boy is admitted to the be considered in these situations. I think we frequently encounter pediatric ICU and serial exams and consults hematology while in in the emergency department times where patients may not want the ICU. This is a great strategy, and higher level of care is certainly to follow your exact treatment plan, but your respect of their values encouraged in these patients getting factor and who have a known and their goals in someone who has capacity should always be injury, which you can then de-escalate as necessary after the considered and encouraged. necessary consultants are present.

Essential Steps of Shared Decision-Making1 Case 1: Clinical Pearls1

The SHARE Approach: • When treating patients with hemophilia, factor replacement takes priority over imaging Seek patient’s participation S and other diagnostic tests • Remember: If you are ever in doubt about how much factor a patient will need—and there H Help patient explore and compare treatment options is not enough time to touch base with the patient’s hematologist—correct the factor level up to 100% A Assess patient’s values and preferences • If you don't know severity of patient's hemophilia or baseline factor activity, assume patient is <1% and calculate dose based on that using the American Society of Hematology dosing calculator1 R Reach a decision with patient • Shared decision-making: Always consult with the patient’s hematologist to coordinate disposition of discharge home vs admission for observation and continued factor infusion E Evaluate patient’s decision

1. AHRQ. The Share Approach – Essential Steps of Shared Decision Making. https://www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/tool-1/index.html. 1. http://ashpocketguides.hematology.org/#/app/tools.

What the playbook really encourages, as well as the AHRQ, is the This leads us to our clinical pearls, and I want to bring in Dr. Wynn SHARE approach. Seek their participation, help them explore and and Dr. Rajasekhar to really underscore these pieces of that last compare options, and assess their values and preferences. The case and about shared decision-making together. social history is a big component of this. Reach a decision with the patient, evaluate the patient’s decision. I would add a D to this— Dr. Wynn: This is a great case, Dr. Allen. You know, it’s an document. Document this discussion in your shared decision- unfortunate situation that our families can find themselves in making, and this goes a long way to great charting, but also for sometimes, but I think, as you’re highlighting, good decision- continuity of care with that specialist in follow-up. making can prevent further complications and worsening of the situation. I would highlight especially the decision to provide factor replacement for this patient early when they arrive in the

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Dr. Rajasekhar: Dr. Allen, I would add that with regards to shared • What is the suspected source of the pain? • What studies should be done to determine the source of the bleeding? decision-making, it often goes a long way for the ER provider to • What is the initial care provided in the ED? contact either the patient’s hematologist, if that’s possible, or the • To hospitalize or not to hospitalize? hematologist on call at that institution, and for the ER physician • What does the continued treatment look like? to then say, “We’ve discussed this with a specialist.” I think a lot of • What are the significant complications if the treatment is delayed? • What does return to activity look like as he receives treatment? patients really appreciate that extra level of communication.

Dr. Allen: Those are both really great points, Dr. Wynn and Dr. Rajasekhar. You know, Dr. Wynn, this bullet number two really underscores what you said earlier about when in doubt, correct to the appropriate level and assume that they’re at 0%. And Dr. What are some key questions you should be asking yourself in Rajasekhar, you and I have done this frequently together—have the ER? Well, what is the suspected source of pain, obviously? these discussions. The peace of mind, back to the patient and/ What studies should be done, if any, to determine the source of or their family member, is really large and significant when we do bleeding? What is the initial care provided in the ED? What should have those discussions. I can say, just like what you said, “I talked that look like? Should this patient be hospitalized or not? What to Dr. Rajasekhar, your hematologist, and we’re both on the same does continued treatment after the initial treatment in the ER look page with your treatment plan. How does that sound to you?” like? What are the significant complications if we don’t treat this patient in a timely manner? Then finally, most adults want to know when they can get back to normal and go back to work or school. Case 2: Iliopsoas Bleed

Case 2: Management

• Man aged 28 years with severe hemophilia A • On prophylaxis with octocog-alfa, but missed his • Suspected source of the pain: hip joint bleed, thigh muscle bleeding, iliopsoas bleed, morning dose hernia, testicular torsion, epididymitis • Experienced left upper thigh pain after returning from a bike ride • The inability to extend the hip joint is highly suggestive of iliopsoas hemorrhage • Administered the prophylactic dose of his factor, but – Ultrasound and CT s/o similar findings the pain continued to get worse • CBC, FVIII activity, FVIII inhibitor, urinalysis • Came to the ED with his home factor when he was • Initial care: administer the patient’s factor no longer able to walk on his leg because it was too painful for him to fully straighten it • Labs and imaging are done after infusion has been given • Consider PRBC because a large amount of blood can be lost in this type of hemorrhage • Corticosteroids for paresthesia and pain relief

Dr. Rajasekhar: Absolutely. Well, let’s move on to case two, and letting the cat out of the bag here, it’s titled iliopsoas bleed, but let’s walk through this as if you didn’t know that. So we have a In this case, the suspected source of pain could be anything and 28-year-old man with severe hemophilia A on prophylaxis with while bleeding is certainly high on the differential, we have to think octocog-alfa, but he missed his morning dose. He experienced left of other things. In the case of a young man with pain in this area, upper thigh pain after returning from a bike ride and administered we should be thinking of a hip joint bleed; a thigh muscle bleed; his prophylactic dose of factor. But then the pain continued to an iliopsoas bleed, which is a very specific type of bleed; as well worsen, and so he came into the ER with his home factor when as other nonhemophilia-related disorders, like hernias, testicular he was no longer able to walk on his leg because it was just too torsion, or epididymitis. The inability of this patient to extend his painful for him to fully straighten the leg. hip joint is highly suggestive of an iliopsoas bleed, and while you can, again, confirm this with imaging studies, remember treating is paramount early on. Same thing with labs, those should not delay treatment.

Importantly, if a patient is an inhibitor patient, you would use bypassing agents, and if they were a noninhibitor patient, you would use factor. As we’ve talked about before, if they bring those with them to the ED, you should use the patient’s if at all possible. Then one thing to remember about these specific bleeds in the iliopsoas muscle is that these are deep muscles and they can hold a lot of blood in terms of amount, and it sometimes is not noticeable

Go online to complete the post-test and evaluation for CME/CNE credit PeerView.com​ /QUN900​ 17 Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making until the patient clinically deteriorates. Often, you’ll have to use in the beginning to prevent from some diagnostic anchoring, too, corticosteroids for paresthesias and pain relief. In this case, again, while still keeping that mindset of treat first, find a diagnosis later. having that iliopsoas bleed on the differential and just thinking about it is really critical. Dr. Wynn: Yeah, I think the greatest point that this case highlights is to keep a high index of suspicion for the bleed, and knowing what the key physical findings are for how an iliopsoas bleed Case 2: Management presents can be very, very important for an emergency room physician. Rurioctocog alfa pegol administered at 50 units/kg to bring his factor 1 level to 100% for 48 hours, then 60% for remainder of 1 week Dr. Rajasekhar: Importantly, sometimes when you give factor, it CT scan obtained after rurioctocog alfa pegol was administered 2 shows an iliopsoas bleed can be both therapeutic and diagnostic. So if it helps the patient after you give them factor, that’s a clue that this really was a bleed 3 Maintain 60% levels for longer during physical therapy and not something else that was not hemophilia related.

4 Begin prophylaxis regimen thereafter Case 3: Patient With Inhibitor and Bleeding

• Boy 15 months of age with severe hemophilia A This patient received a factor replacement at 50 units/kg to bring presents with right knee bleeding his factor up to 100% for about 48 hours, and then he was kept on • You remember him when he presented to the ED as an infant with hemorrhage for a circumcision done factor replacement to a target goal of 60% for the remainder of the before he was known to have hemophilia. He was treated for 7 days in the hospital at that time and the week. A CT scan was eventually obtained after factor replacement family thanked you when he was discharged • He had a port placed last week and began 2x/week and again confirmed what you suspected as an iliopsoas bleed. prophylaxis with moroctocog alfa and had received During periods of physical therapy, which this patient will likely his second dose this morning require, it’s important to maintain factor levels so as not to exacerbate bleeding and take two steps backwards. In general, we like to keep factor levels around 60% during aggressive physical therapy, and once physical therapy is complete, the patient can Dr. Wynn: Okay, I will go ahead and start the third case. Our third then go back to their normal prophylaxis dosing. case presents, interestingly, with a 15-month-old boy who is known to have severe hemophilia A, and he is experiencing a right knee bleed. You, as the emergency physician, know the family Case 2: Clinical Pearls because you can remember when he comes to you that he came as an infant, and at that time, he had a hemorrhage following a • Common symptoms of iliopsoas bleed: pain (abdominal, back, groin, hip, or thigh) • Signs: flexion contracture, distal paresthesia circumcision. It was eventually determined that he had hemophilia • Hospitalization and he was admitted to the hospital. Your memory of him is jogged – Mild bleeds: manage at home, bedrest, and pain control by the fact that the family actually walked down to the emergency – Moderate to severe bleeds: hospitalized room and thanked you for helping them when he was discharged • Complications of untreated iliopsoas bleed: rebleeding with too rapid of return to activity, femoral nerve compression, or nerve palsy previously. • Amount of activity while on treatment – Strict bedrest for the first 48 hours – Gradual return to activity over 2-3 weeks Since that time, he has had a port placed, and last week they – Physical therapy is often needed to rehab began prophylaxis. The prophylaxis is with rurioctocog alfa, and the patient has been receiving that twice a week. He received his second dose of prophylaxis this morning and then developed the It’s important that these patients also have strict bedrest initially, bleed. and ambulation should really be discouraged initially, even if it’s with crutches, because any form of ambulation requires contraction of that iliopsoas muscle.

So Dr. Wynn, Dr. Allen, I know you’ve seen these types of bleeds before. Any thoughts that you have on these patients presenting to the ER with symptoms specific to an iliopsoas bleed?

Dr. Allen: Yeah, these are definitely sinister and can be certainly occult, but I really liked how we kept a broad differential diagnosis

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Key Questions Case 3: Clinical Pearls

• Reasons for bleeding despite prophylaxis – Underdosed: more rapid clearance in children than adults • What are the reasons that he is bleeding despite prophylaxis? – Injury: breakthrough bleeding on prophylaxis • What are risk factors for inhibitor? – Training: family or provider not properly trained

• What are the laboratory tests that demonstrate the presence of an inhibitor? – Storage: factor will lose efficacy if not stored properly – Inhibitors: antibody-neutralizing factors • How would you treat the child’s bleeding? • Laboratory tests that demonstrate inhibitors • How would the family manage an inhibitor long-term? – Lower-than-expected FVIII activity – Lack of aPTT correction to normal – Mixing study that does not correct – Nijmegen Bethesda assay for inhibitor quantification

In this case, questions that we want to be asking are, what are the Dr. Rajasekhar: I think it was really important and critical that the reasons why he is bleeding despite starting on prophylaxis? What ER physician, recognizing that this was not a straightforward case, are the risk factors that might cause an inhibitor to develop? To involved the hematologist, and I think that’s how we got to the determine the inhibitor, what laboratory tests are important? How diagnosis of inhibitor early on. It’s important also to know that not would this affect your treatment choice for the child’s bleeding? many institutions will have inhibitor assays available in real time. And lastly, what does the family need to know in order to manage So, one thing that can be done is look at the PTT and if it does the inhibitor for his early childhood and long term? not correct, you would expect in that case that this patient has indeed developed an inhibitor, as opposed to a patient without an inhibitor, in which case the PTT should correct on mixing. Case 3: Management Dr. Allen: Really great points, Dr. Rajasekhar. I think it’s safe to Given the complexity of this patient’s case, you decide to 1 consult with the patient’s hematologist say that any emergency physician would be anxious and a little nervous with this patient arriving to their ED. I think that the 2 High-titer inhibitors (>5 BU/mL) to rFVIIIa first bullet point with some reasons [for bleeding] and factor replacement—maybe it’s been underdosed at home, maybe there’s 3 After a discussion with parents of the patient and his hematologist, a shared decision is made to administer FVII an issue there.

The patient is observed in the ED for 2 hours and parents report 4 significant improvement in his swelling and pain; he is discharged home with close follow-up and strict return precautions Case 3: Clinical Pearls (Cont’d)

• Treatment for bleeding – Bypass therapy The outcome of this case, given the complexity of the presentation, – Recombinant FVIIa – aPCC you decide to go ahead and consult with the patient’s pediatric – Supertherapeutic dose of FVIII hematologist. It’s determined and suspected that he has an – Porcine factor • Long-term management of inhibitors inhibitor, and in discussing the treatment options for bypass – Low titer therapy, it was decided to go ahead and provide this patient with – Supertherapeutic factor with spontaneous resolution activated factor VII. The patient was observed in the emergency – High titer: emicizumab, prophylaxis only, needs bypass therapy for bleeding; caution with aPCC >100 units/kg for >24 hours room for 2 hours and the parents note that he has improved. – Immune tolerance: to eradicate the inhibitors He was eventually discharged home with consultation by the hematologist to have a very, very close follow-up and precautions on when to return for further treatment. So Dr. Rajasekhar and But having that awareness that an inhibitor could be the etiology Dr. Allen, how do you think the management for this patient is why I think this is a big part of this educational activity that we’re proceeded? having today, too, is to build that awareness around some of these things, and the whole mindset of “treat early and consult early” when you start to get into a potential predicament in which it’s going to impact their outcome.

Dr. Wynn: Yes, and I think the fact that the emergency room physician consulted and brought in the involvement of the hematologist early on in the evaluation in this case is a very, very important point to highlight.

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This ends our discussion for today. Thank you, Dr. Rajasekhar and Summary Dr. Allen, for your insights during our discussion. We hope that you found this activity informative and useful to your practice and we • The treatment of hemophilia has evolved considerably over the past several years • Advances in biotechnology have permitted the development of EHL replacement clotting also highly encourage you to earn extra credit by participating in factors for prophylaxis in patients with hemophilia A or hemophilia B PeerView’s “Optimal Management of Hemophilia in the Emergency • Novel rebalancing therapies are being evaluated in hemophilia A and hemophilia B • MASAC guidelines for ED management of hemophilia recommend that suspected bleeds Department Quality Improvement” module. Assess your practice, be treated first and diagnosed second set your goals, and improve the level of your care for your • In this regard, patients with hemophilia and family members are often very well educated in the disease and its management, which can significantly reduce morbidity and mortality hemophilia patients. and underscores their role in SDM • SDM has been shown to increase the use of the treatment option that is most clearly associated with health benefits Dr. Allen: Thanks, everybody.

Dr. Rajasekhar: Thank you.

To summarize our discussion today, the treatment of hemophilia Narrator: This activity has been jointly provided by University of has evolved, and it’s evolved very, very rapidly and considerably Florida College of Medicine and PVI, PeerView Institute for Medical over the past several years. The advancement in what we know has Education; the activity is also co-provided by Medical Learning permitted the development of extended half-life factors, as well Institute, Inc. as its use in prophylaxis for hemophilia A and B. Newer therapies that look at rebalancing therapies for our patients also now exist. MASAC guidelines for treatment of hemophilia in the emergency room do recommend that you treat these patients based upon the suspicion of bleeding, and diagnostic testing and imaging remain secondary in treatment. In regards to family members, remember that a shared decision-making approach is very, very important because our patients are very, very well-educated in their disease, as well as managing the bleeds that may develop. By listening to the family, you can arrive at a treatment much more quickly, and it will reduce the morbidity and mortality that could complicate the situation. Shared decision-making will also increase the amount of treatment options that patients may know to be available to them, and it may actually be associated with increased health benefits.

The Hemophilia Foundation of Greater Florida

Education

Research Improving Information quality of life for patients with hemophilia and their families

Referral Advocacy services hemophiliaflorida.org 800-293-6527

We wanted to take a minute to acknowledge the Hemophilia Foundation of Greater Florida. The Hemophilia Foundation supports patients and families who have hemophilia and all bleeding disorders in the greater Florida area. They provide all manner of support to these patients. To find out more about what the Hemophilia Foundation does, you can visit their website or you could call their 1-800 number.

Go online to complete the post-test and evaluation for CME/CNE credit PeerView.com​ /QUN900​ 20 CME/CNE Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making

This CME activity is jointly provided by the University of Florida College of Medicine and PVI, PeerView Institute for Medical Education.

This CNE activity is jointly provided by the Medical Learning Institute, Inc. and PeerView Institute for Medical Education.

This accredited CE activity has been developed in collaboration with the Hemophilia Foundation of Greater Florida.

This activity is supported by an educational grant from Genentech.

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