CME Recognizing and Managing Hemophilia in the …

Sarah Luisa Melendez, MDOrlando Health Arnold Palmer Hospital for Children Orlando, Florida

Doris Quon, MD, PhDOrthopaedic Hemophilia Treatment Center Los Angeles, California

Krystin Miller, MDThe Ohio State University Department of Emergency Medicine Columbus, Ohio

Co-Chair Co-Chair

Faculty

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CME

Recognizing and Managing Hemophilia in the Emergency Department in an Era of Expanding Therapeutic Options: A Progress-in-Practice MasterClass and Practicum

What’s Inside

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Introduction

Modern Hemophilia Management: A Closer Look at an Evolving Treatment Paradigm

What Can We Learn From Current Guidelines for the Treatment of Hemophilia in the Emergency Department?

The Role of Shared Decision-Making in the Management of Hemophilia in the Emergency Department

Audience Q&A

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Activity Information

Media: Enduring MaterialAccredited Activity Release Date: December 2, 2019Accredited Activity Expiration Date: December 1, 2020Time to Complete Activity: 90 minutes

Activity DescriptionIn this activity, experts in hemophilia discuss the latest advances in the treatment of hemophilia and the importance of shared decision-making in optimizing the management of patients with hemophilia who present to the ED.

Target AudienceThis activity has been designed to meet the educational needs of emergency medicine specialists and other healthcare professionals involved in the management of hemophilia.

Educational ObjectivesUpon completion of this activity, participants should be better able to:• Apply current data on the efficacy, safety, and tolerability of approved

therapeutic approaches when managing patients with hemophilia in the emergency department

• Cite available data on emerging treatment modalities for the management of hemophilia

• Employ current guidelines for the management of hemophilia in the emergency department

• Use shared decision-making when treating suspected bleeding episodes in patients who present to the emergency department

Providership, Credit, and SupportThis CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported by an educational grant from Genentech.

Physician Continuing Medical EducationThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

The Medical Learning Institute, Inc. designates this enduring material for a maximum of 1.5 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Faculty DisclosuresCo-ChairsSarah Luisa Melendez, MD Clinical Emergency Medicine Faculty Orlando Health Arnold Palmer Hospital for Children Orlando, Florida

Sarah Luisa Melendez, MD, has no financial interests/relationships or affiliations in relation to this activity.

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

Doris Quon, MD, PhD, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for Bayer Corporation; Bio Products Laboratory; BioMarin; Genentech, Inc.; Novo Nordisk A/S; Octapharma USA, Inc.; and uniQure Inc. Speakers Bureau participant with Bioverativ USA Inc./sanofi-aventis U.S. LLC; Genentech, Inc.; Novo Nordisk A/S; Shire; and Takeda Pharmaceuticals U.S.A., Inc.

FacultyKrystin Miller, MD Medical Education Fellow Clinical Instructor The Ohio State University Department of Emergency Medicine Columbus, Ohio

Krystin Miller, MD, has no financial interests/relationships or affiliations in relation to this activity.

Planning Committee DisclosuresThe planners from Medical Learning Institute, Inc., the accredited provider, and PeerView Institute for Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined commercial interest related to the content of this accredited activity during the past 12 months unless listed below.

Content /Peer Reviewer DisclosuresThe following Content/Peer Reviewer has nothing to disclose:

Kaushal Patel, MD

Disclosure of Unlabeled UseThis educational activity may contain discussions of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DisclaimerParticipants have an implied responsibility to use the newly acquired information to 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. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

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About This CME ActivityPVI, PeerView Institute for Medical Education, and Medical Learning Institute, Inc. are responsible for the selection of this activity’s topics, the preparation of editorial content, and the distribution of this activity. Our activities may contain references to unapproved products or uses of these products in certain jurisdictions. The preparation of PeerView activities is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and Medical Learning Institute, Inc.

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Sarah Luisa Melendez, MDOrlando Health Arnold Palmer Hospital for Children Orlando, Florida

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Dr. Melendez: Hi. Good morning, everyone. Thank you all for coming out. My name is Sarah Melendez.

Coagulation is regulated through three distinct, sequential processes: 1. Vessel constriction 2. Primary hemostasis 3. Secondary hemostasis

Dependent upon the equilibrium between procoagulant and anticoagulant factors

Primary and secondary hemostasis are intimately intertwined yet function independently and have their own set of diseases and malfunctions

Hemostasis1,2

1. Colman RW et al. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. 2. Blanchette VS et al. SickKids Handbook of Pediatric Thrombosis and Hemostasis. Basel, Switzerland: Karger; 2013.

Okay, all right. So let’s get started. Before we can really talk about hemophilia and how we manage it, I just want to quickly go over how we have clotting and how we can actually activate coagulation.

In order to get hemostasis, or in order to clot, there are three pathways that are intrinsic and they’re intertwined. You first will have vascular injury, which will lead to vessel constriction or vascular spasm. Then, that is followed by primary hemostasis—which we will discuss in the next slide—and then secondary hemostasis. And depending on the balance between procoagulation factors and anticoagulation factors, you can have a variety of diseases. And even though these pathways are all intertwined, if there is a lack of one particular pathway, you can have different diseases.

Introduction

• Defined by platelet adhesion to exposed collagen within endothelium of vessel wall

• Mediated by GPlb and von Willebrand factor

• Results in initial clot formation; clot that forms is reversible and unstable

Primary Hemostasis1

1. Broos K et al. Blood Rev. 2011;25:155-167.

So with primary hemostasis, this is where you form a plug. So you have vascular injury and there’s exposed endothelium. With that exposed endothelium, platelets will adhere to collagen, which has been exposed in that injury area. These platelets are then sticking together, or adhering to one another, via the big one that we remember as von Willebrand factor. And, you’ll see in a slide or two, this is where von Willebrand disease comes in. The big thing about this is that, this is a temporary kind of clot. This is just a plug. It’s unstable and it’s reversible.

Secondary Hemostasis: The Coagulation Cascade1

Intrinsic pathway Extrinsic pathway

XII XI

IX VIII

Tissue factor

X

Common pathway VII

Thrombin Prothrombin (II)

Fibrinogen (I) Fibrin clot

(XIII)

V Ca+2 Lipids

1. Butler RB. Basic Concepts of Hemophilia: A Self-Study and Planning Workbook for Families With a New Diagnosis of Hemophilia. Atlanta, GA: CDC; 2007.

So we have to go down through secondary hemostasis, which is the coagulation cascade. So with hemophilia, this is the area that we are looking at: the intrinsic pathway. But with secondary hemostasis, you have your intrinsic pathway and your extrinsic pathway, which come together to form your fibrin clot. And that’s the glue. That’s the glue that will hold that initial plug together.



Primary vs Secondary Hemostasis Disorders1

Clinical Manifestation

Primary Hemostasis Disorders (Platelet Disorders)

Secondary Hemostasis Disorders (Coagulopathy)

Onset Immediate Delayed by hours or days

Site(s) Superficial: cutaneous, mucosal Deep: joints, muscle

Finding(s) Petechiae, ecchymosis Hematoma, hemarthrosis

Example von Willebrand disease Hemophilia (A, B)

1. Arrieta-Blanco JJ et al. Med Oral Patol Oral Circ Bucal. 2014;19:e280-e288.

When you have an issue with primary hemostasis versus secondary hemostasis, as you can see with something like hemophilia, usually your bleed is delayed by a couple of hours or days. You will have more deep bleeds—so, joints, deep muscles—and you’ll see hematomas or hemarthroses, things like that; versus with your primary hemostasis—more like von Willebrand disease—you’ll see more superficial bleeding, although, yes, you can have deeper bleeds. But you’ll see more cutaneous and mucosal bleeding, and that’s where you’ll see your petechiae and your ecchymotic areas.

Hemophilia1-4

Secondary hemostasis disorders • X-linked inherited • Clotting factor VIII (FVIII) or FIX is absent or present

in low levels

Hemophilia A (FVIII deficiency) • Affects 1/5,000 to 1/7,000 males

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; 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.

So now let’s talk about hemophilia. Hemophilia is an X-linked, recessive, inherited disorder. So, basically, it’s mostly men that we’re going to see. And with the types of hemophilia that we’ll be discussing today— hemophilia A and B— you either have factor VIII or factor IX that is present in low levels or absent.

Hemophilia A is the most common one of the two, and it affects about 1 in 5,000 to 1 in 7,000 males. And hemophilia B, which is a factor IX deficiency, affects 1 in 25,000 to 1 in 30,000 males, so it’s much less common.

Bleeding Phenotype Dependent on Level of Clotting Factor Deficiency in Hemophilia1,2

1. https://www.wfh.org/en/page.aspx?pid=643. Accessed October 17, 2019. 2. Van Dijk K et al. Haemophilia. 2005;11:438-443.

Phenotype Factor Level Clinical Features

~60% of hemophilia A cases are severe

~44% of hemophilia B cases are severe

• Bleed after severe injury or surgery • Do not bleed often; some may never have

bleeding problem Mild hemophilia >5%-40%

Moderate hemophilia 1%-5% • May bleed for a long time after surgery, a bad

injury, or dental work • Experience spontaneous bleeding rarely

• Frequent and spontaneous bleeds into muscles or joints (70%-80% bleeds are hemarthrosis); up to 1-2 times/week without treatment

Severe hemophilia <1%

We labeled their bleeding phenotype based on how much factor they actually have present. In a normal person, generally, without hemophilia, you have anywhere between 50% to 100% of the factor present. With hemophilia, you’ll notice that they have less than 40%.

In mild hemophilia, they’ll have greater than 5% to 40% of factor present; and these patients may not even know they have hemophilia until they have a significant injury or a significant surgery, and they don’t tend to bleed as often. Then you have moderate hemophilia. And in moderate hemophilia, the factor level that they’ll have present is anywhere between 1% to 5%; so they may have prolonged bleeding after a significant injury, or prolonged bleeding after a surgery. They very rarely experience spontaneous bleeds.

And then, finally, severe hemophilia is the one that we are the most concerned about in the ER, where they’ll have less than 1% of factor present. And these patients will tend to have frequent, spontaneous bleeds. They will bleed into muscles and deep muscles—like retroperitoneal bleeds and iliopsoas bleeds. They’ll bleed into joints—actually, 70% to 80% of bleeds are in the joints—and they may bleed one to two times a week if they don’t have any treatment. About 60% of patients with hemophilia A have severe disease, whereas in hemophilia B, about 44% have severe disease.

Hemarthrosis: A Long-Term Complication With Hemophilia

Without treatment, bleed events for patients with hemophilia may be life-threatening or result in chronic disability from recurrent

hemarthroses and intramuscular bleeding

Target Joint Repeated bleeding in the same joint; knees, elbows, and ankles most frequently affected

Hemophilic Arthropathy Persistent intra-articular blood results

in progressive degeneration of the joint cartilage and bone

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So like I had mentioned before, hemarthrosis, or joint bleeds, is the most common type of bleed that we will see, and, without treatment, these bleeds can cause significant degeneration of the cartilage and of the bone, and can lead to significant disability. And they can also have, like I said, deep bleeds. The most common joints that are affected are the elbows, the knees, and the ankles. And, as you can see, if a patient has a particular joint that constantly gets bled into, that’s labeled their target joint. And as you can imagine, again, this can lead to significant disability, so they’ll get significant arthropathy.

Current Hemophilia Treatment Paradigm1

MASAC Recommendations

Concerning Prophylaxis

Individuals on prophylaxis should have regular follow-up visits to evaluate joint status; to document any complications, such as inhibitors; and to record any bleeding episodes that occur during prophylaxis

Prophylaxis is considered to be optimal therapy for individuals with severe hemophilia A or B

1. https://www.hemophilia.org/sites/default/files/document/files/241Prophylaxis.pdf. Accessed October 17, 2019.

Prophylaxis should be instituted early (prior to the onset of frequent bleeding), with the aim of keeping the trough FVIII or FIX level above 1% between doses

Optimal dosing and frequency should be determined for each individual by appropriate laboratory monitoring

The Medical and Scientific Advisory Council actually recommends prophylaxis; and this is where the patient is really working with their hematologist and coming up with a plan that works for them. So if they have severe disease, they should be on prophylaxis, and the type of prophylaxis that they get, the dosing, the frequency, is all an intricate balance that they will have with their hematologist. The aim of the prophylaxis is to keep that factor level greater than 1% between doses of their prophylactic factor infusion. And they should have regular follow-up visits to document if there are any bleeds that happen in between dosing of prophylaxis. They should have regular visits to see if they’re developing inhibitors. Any complications that have developed are to be documented by the patient and the hematologist, and, ideally, they should come in with a nice plan on a card if they’re really good at following up.

Factor Concentrates for Hemophilia Management

• Virally inactivated

• Plasma-derived – Pooled from up to 30,000 plasma donations

• Recombinant – Produced in Chinese hamster ovary, baby hamster

kidney, or human cell lines

So just quickly—and we’re going to go a little bit more into this in a little bit—factor concentrates and how they’re made for hemophilia. There’s virally inactivated factor concentrate; there’s the plasma-derived one that we’re more familiar with, which is from pooled human plasma; and then there’s recombinant factor. And the key thing with recombinant factor is it’s mostly mammalian cells. There are some human cell lines, but the majority of the recombinant factor is actually from nonhuman cells.

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

Potential Barriers to the Optimal Management of Hemophilia in the Emergency Department

Disease rarity: How frequently is hemophilia encountered in the ED?

Need for a consult: Is there a hematologist on call?

Expanding number of available treatments: Does the hospital stock the medicine an individual patient needs?

So, what are some of the barriers? Because this is the big thing that we’re worried about in the emergency room. There are hemophilia treatment centers, and a lot of times patients will manage bleeds at home, and they will go to a hemophilia treatment center, but they will present to the ED. And the question we have is, what do we do when they come to the ED? So some of the barriers are that it’s just rare for us to see it very often in the ED, so it’s not something that we necessarily are familiar with to deal with every day.

The other question is, is there a hematologist on call? Does the patient have a hematologist that they are following up with? Do you, at your center, have a hematologist that’s on call that you can call at 3 AM? That may be one of your barriers.

And then, just the number of treatments that are available. What does your hospital carry? What is the patient on? Those are all things that we have to think of and things that we’ll address.

Evolution of Hemophilia Treatment

1900 1950s 1960s 1970s 1980s 1990s 2010s

Whole- blood

Plasma

Cryoprecipitate

PD-IP concentrates

PD-HP concentrates

Recombinant factors

First nonfactor therapy

approved in 2017

First EHL factors approved in

2014

Hemophilia treatment paradigm has

expanded considerably over the past 5 years



And just briefly, hemophilia treatment has actually evolved pretty significantly over the past 5 years. But if you recall, early on in the 1900s, patients with hemophilia were given whole-blood infusions, and that’s how they were treated. And then, several years later, they started getting things like plasma and cryoprecipitate, and that was the treatment then. And then, eventually, we started having factor concentrates that were made in the 70s and 80s—plasma-derived concentrates.

And then, in the 90s, is when we had our recombinant factors. And we were using that up until a couple of years ago, when we started having some development of extended half-life factors, which we will actually talk about, and nonfactor therapy, which was just developed in 2017. So over the past 5 years, a pretty significant change has been made in the treatment of hemophilia.

Agenda

• First, we’ll discuss available data on extended half-life replacement factor products and nonfactor replacement strategies for hemophilia management

• Then, we’ll turn our attention to the current guidelines for the management of hemophilia in the emergency department

• Finally, we’ll share some patient cases to highlight the role of shared decision-making with hemophilia patients who present to the ED

All right, so now, moving on to today and this agenda. We’ll start by discussing those extended half-life replacement factor products and the nonfactor replacement strategies for hemophilia. We’ll then talk about the current guidelines and how we manage it in the ED. And, then, we actually have some cases to highlight how we will deal with pretty common complaints, and how we use our shared decision-making with our hematologists and the patients in the ED.

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Doris Quon, MD, PhDOrthopaedic Hemophilia Treatment Center Los Angeles, California

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Prophylaxis: The Standard of Care for Hemophilia

The benefits of prophylaxis in patients with severe hemophilia are well established

Evid

ence

• Joint Outcomes Study1

• ESPRIT trial2

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

Hemophilia A

Hemophilia B

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.

Dr. Quon: So, thank you. I am here, actually, to tell you about the management of hemophilia. So we call it “The Modern Management of Hemophilia: A Closer Look at an Evolving Treatment Paradigm.” I am going to be telling you what has evolved or developed over the last 5 years. My name is Doris Quon and I come from Los Angeles. I am from the Hemophilia Treatment Center, and that’s been my main focus.

So as Dr. Melendez said, the standard of care is really prophylaxis, and prophylaxis means prevention of bleeding. Optimal care for these patients with severe hemophilia is to replace what’s missing—at least that’s historically what’s been the goal: replace what’s missing by doing regular factor infusions. And the benefits of prophylaxis in patients with severe hemophilia has been really well established. There have been numerous studies—only two listed for hemophilia A here: the Joint Outcomes Study, which was published in 2007 and that was spearheaded by, actually, one of the doctors here at the Hemophilia Treatment Center, Dr. Marilyn Manco-Johnson. And that was the first randomized, prospective study showing the benefits of prophylaxis.

Previously, patients were treated, what we call, on-demand, meaning that, when they had a bleed, you would treat their bleeding by replacing the clotting factor. Well, what they found was that patients did better if they actually were treated beforehand to prevent bleeds from happening. And, again, the Joint Outcomes Study was the first prospective, randomized study to show better outcomes in these patients.

Modern Hemophilia Management: A Closer Look at an Evolving Treatment Paradigm

What the study did was to randomize 65 young boys aged less than 30 months to either receive prophylaxis or get aggressive on-demand treatment. So these boys were getting regular treatments and infusions, every other day, of factor. Or, when they had a bleed, they were randomized to the on-demand arm. And what they found was that, when they became 6 years of age, they did MRIs. And in the arm that had prophylaxis, 93% of them had normal joints by MRI, whereas only 55% of those boys in the on-demand arm had normal joints. So you can see, the outcome is much better when you do prophylaxis, and that really sets the stage for prophylaxis being the standard of care.

The ESPIRIT study stands for Evaluation Study on Prophylaxis: a Randomized Italian Trial. And so, that was published in 2011, confirming what was found by Dr. Marilyn Manco-Johnson—again, showing better outcomes in patients with severe hemophilia if they started prophylaxis at a younger age. For hemophilia B, Dr. Valentino published in 2014 the benefits of prophylaxis in, specifically, hemophilia B. The patients were their own controls. They would go onto 6 months of on-demand treatment and then switch over to prophylaxis. And you could see the decrease in the number of bleeds.

Major Hurdles to the Optimal Management of Hemophilia

Short in vivo half-life of standard replacement factors; adherence can become a major issue due to the need for frequent infusions t½ rFVIII: ~8-12 h

t½ rFIX: ~18-24 h

Development of inhibitors (neutralizing antibodies) to replacement factor products SIPPET study showed patients treated with PD-FVIII–containing vWF had lower incidence of inhibitors than those treated with rFVIII

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

So, again, there are many studies showing the benefits of prophylaxis—and it sounds good, but, there are also barriers to this optimal treatment of prophylaxis, and one big one is adherence. As I mentioned, you have to take these infusions and the factor is given intravenously, and the parents have to do this at home regularly. And so, you can see that adherence could be a major problem, especially given the limited half-life of these products.

For factor VIII, the half-life is 8 to 12 hours; for factor IX, it’s 18 to 24 hours. So for hemophilia A, factor VIII needs to be given, as I said, every other day or three times a week. As you can imagine, parents trying to chase down their kids to give them an IV infusion can be very difficult. And for factor VIII, it was given two to three times per week. Again, adherence is a major problem given the short half-life.



And one of the major complications of hemophilia is the development of an inhibitor—what we know as a neutralizing antibody to the replacement factor product. Basically, it’s an antidrug antibody, where you’re giving factor, but the patient develops an antibody to it, so that factor no longer works. And their treatment is through bypassing agents. And prior to 2017, there were only two treatments available for these patients with inhibitors: recombinant factor VIIa and activated prothrombin complex concentrates. The active prothrombin complex concentrates are plasma-derived, and the recombinant factor VIIa, obviously, is recombinant.

But, the SIPPET study showed that patients treated with a plasma-derived factor VIII product containing von Willebrand factor actually had a lower incidence of inhibitors than those treated with recombinant factor VIII. But the difficulty was that many of the hematologists—the pediatric hematologists—shied away from plasma-derived products because of what happened in the 80s with viral complications; some of you may remember that with the HIV and hepatitis viruses. And so, because they shied away from it, they still preferred to use recombinant products. And so, development of inhibitors is still a big problem in these patients.

Extended Half-Life Replacement Factor Products • Approved for Hemophilia A − Efmoroctocog alfa − Rurioctocog alfa pegol − Damoctocog alfa pegol − Turoctocog alfa pegol

• Approved for Hemophilia B − Eftrenonacog alfa − Albutrepenonacog alfa − Nonacog alfa pegol

• Investigational − BIVV001

Nonfactor Replacement Strategies

• Approved for hemophilia A with and without inhibitors − Emicizumab-kxwh

• Investigational − Fitusiran − Concizumab − Gene-replacement therapy

strategies for hemophilia A and B

Recent and Potential Advances in Hemophilia: How Can We Overcome These Hurdles?

So, I am going to move on to recent and potential advances in hemophilia treatment, and how we can overcome some of these barriers that we face.

Developing extended half-life products basically means that you have to take infusions less often. So as I previously said, for hemophilia A, these products were taken every other day, or three times week, with the standard factor half-lives. With the extended half-life—and you can see there are many of them—the first one was approved in 2014, which is the first product shown here. I’m not going to try to pronounce all these names for you, but suffice it to say, this is the first product produced. It’s a fusion protein, efmoroctocog alfa, and it was developed in 2014. And the subsequent products were developed. This was approved in 2015, 2018, and 2019—this year.

And there are a number of extended half-life products— which I’ll show you the mechanism of extension—as well as the clinical data for these products. It made it easier for the parents to do the

infusions, as well as for the patients to do the infusions. And so, instead of doing it three times a week, or every other day, you can do it twice a week, so you have 50 less infusions a year.

For hemophilia B, this was a bigger advance. Again, the half-life was 18 to 24 hours for the standard products, and you can move onto doing weekly prophylaxis; so it was much better. And so, the first one was, again, an Fc fusion protein, and that was developed and approved in 2014. And subsequently, we have an albumin fusion factor IX product and a PEGylated factor IX product that were approved.

And there’s one product under investigation that I think is very interesting. It’s BIVV001. It’s going to start clinical trials—phase 3 clinical trials— later this year or next year. And it has, in the phase 1 and 2 study, shown a half-life of 40 hours—and this is for hemophilia A—and it looks promising for weekly infusions. So, again, you can see where that would make it much easier for parents and patients.

The nonfactor replacements are very interesting molecules. And the first one was approved in 2017 for hemophilia A patients with inhibitors, and subsequently in 2018 for noninhibitor hemophilia A patients, and it’s known as emicizumab. And there are some investigational strategies. Most of these are in phase 3; fitusiran, concizumab, and gene therapy for hemophilia A and B, which I will briefly go over in the next few slides.

Mechanisms of Half-Life Extension in Hemophilia1

1. Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84-98.

Fc Fusion • Fc portion of human

IgG fused to factor • IgG has a long

half-life (~3 weeks)

Protein of interest Fc region

Fc region

Protein of interest

Albumin Fusion • Albumin has a long

half-life (~3 weeks)

Protein of interest Albumin

Protein of interest

Linker

PEGylation • Creates “cloud” around

attached proteins • Molecule too big to be

cleared by kidneys

PEG

PEG

PEG

So mechanisms of half-life extension in these hemophilia products. The first one I mentioned was a fusion protein, and the first product that was approved for the market for hemophilia A, as well as hemophilia B, is what we call an Fc fusion. And what you can see here is that the Fc portion of the molecule is fused to your protein of interest, shown here, and the protein of interest in hemophilia is either factor VIII or factor IX. So, the Fc portion of the human IgG is fused to the factor. And IgG has a longer half-life of 3 weeks, and that extends the half-life of the molecules.

The next one is PEGylation, and this has been commonly used for many different drugs. And what it does is, it creates a hydrophobic cloud around the attached molecule and the molecules are not cleared as quickly.

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And the last product is an albumin fusion, and this is for hemophilia B. And again, the albumin molecule, as you see here, is a larger molecule on this side, and it’s been fused to the protein of interest—and in this case, factor IX. And again, albumin has a longer half-life of 3 weeks, and so the factor IX has an extended half-life. And I’ll show you the extension of the half-lives in the next couple of slides.

0 6 12 18 24

Fc Fusion 1.5-1.7 Efmoroctocog alfa

Rurioctocog alfa pegol

Damoctocog alfa pegol 1.5

1.4-1.5

PEGylation 12.4 h 19 h

13 h 19 h

10.4 h 14.3-16 h

Approved EHL FVIII Replacement Strategies1-6

1. Powell JS et al. Blood. 2012;119:3031-3037. 2. Mahlangu J et al. Blood. 2014;123:317-325. 3. Tiede A et al. J Thromb Haemost. 2013;11:670-678. 4. Coyle TE et al. J Thromb Haemost. 2014;12:488-496. 5. Konkle BA et al. Blood. 2015;126:1078-1085. 6. Bevan DH et al. Haemophilia. 2013;19(suppl 20):10-82.

Turoctocog alfa pegol 19 h 11.7 h

t½, hr

1.6

t½ extension (fold change)

rFVIII EHL rFVIII

But here are the approved molecules, extended half-life products for factor VIII. And you can see the Fc fusion protein has an extended half-life of 19 hours and it’s generally given every 3 to 5 days, or twice a week. You can see the extension is 1.5- to 1.7-fold.

The PEGylated products have varying half-lives depending on the amount of PEGylation they have. This first product is a PEGylated 20 kDa; the next product is a 60 kDa. You can see that they have longer half-lives. And the turoctocog alfa pegol is a 40 kDa PEG product. So you can see the extension shown here. And again, most of these are given anywhere from 3 to 5 days or twice a week. And I’m going to show you in the next two slides the clinical data from the clinical trials.

Clinical Data on EHL FVIII Products in Hemophilia A

Weekly prophylaxis

76%

Efmoroctocog Alfa1

Reduction in ABR vs On-Demand

• 87.3% of bleeding episodes resolved with one injection

• No subjects developed inhibitors during the study

• Most common AEs: nasopharyngitis, arthralgia, headache, and URTI

• Similar results noted in pediatric study2

Individualized prophylaxis

92%

1. Mahlangu J et al. Blood. 2014;123:317-325. 2. Young G et al. J Thromb Haemost. 2015;13:967-977. 3. Konkle BA et al. Blood. 2015;126:1078-1085.

Rurioctocog Alfa Pegol3


Twice weekly Prophylaxis

95%

• 95.9% of bleeding episodes treated with 1-2 infusions

• No subjects developed inhibitors nor experienced any unexpected AEs during the study

So generally speaking, when we do these clinical trials in hemophilia patients, what we want to see is the outcome, and what we measure for the outcome is what we call annualized bleed rate, abbreviated as ABR. And so you can see, in all of the trials, I’m going to be showing you the outcome with reduction in annualized bleed rate versus on-demand, and then the efficacy in terms of treatment of bleeds.

So here, the first product, this is the Fc fusion factor VIII molecule. You can see in the clinical trial, the ABR versus on-demand. In individualized prophylaxis, these patients were treated every 3 to 5 days depending on the treatment, so it’s individualized depending on their half-life. You get a 92% reduction compared to on-demand.

A weekly prophylaxis is actually still very good. So once-a-week treatment was a 76% reduction. And with one infusion, 87% of the bleeds resolved; 98% resolved with one or two injections. And no subjects developed inhibitors, which is the serious complication I mentioned. And the most common side effects/adverse events were nasopharyngitis, arthralgia, headache, and upper respiratory infection.

And the pediatric study showed similar results. The first PEGylated product was approved at twice weekly, and it showed a 95% reduction compared to on-demand in the annualized bleed rate, and 96% of the bleeds were treated effectively with one or two infusions. And again, safety showed no development of inhibitors or any unexpected adverse events.

Clinical Data on EHL FVIII Products in Hemophilia A (Cont’d)

Damoctocog Alfa Pegol1


• 90.6% of bleeds were controlled with ≤2 infusions

• No inhibitors were detected during the study

• Most common AEs: nasopharyngitis, headache, arthralgia, back pain, cough, epistaxis

1. Reding MT et al. J Thromb Haemost. 2017;15:411-419. 2. Giangrande P et al. Thromb Haemost. 2017;117:252-261.

Turoctocog Alfa Pegol2


Prophylaxis Once every 5 d

92%

• 83.6 % of bleeds resolved with one injection

• Frequency and types of AEs reported were as expected in this population

• One patient developed inhibitors after 93 exposure days

Prophylaxis Once every 4 d

96%

So similarly, you can see the other PEGylated products shown here: damoctocog and turoctocog. Reductions in annualized bleeding rate compared to on-demand: 92% for damoctocog alfa pegol and 96% in the turoctocog alfa pegol. You can see effective treatment. When bleeds did occur, it was effectively treated with one or two infusions; 91% of the bleeds resolved with one or two infusions with the damoctocog, and with turoctocog it was 83% with one infusion, and it was 96% also with one or two infusions. And again, in this trial—damoctocog—there were no inhibitors detected and similar types of adverse events were seen, with nasopharyngitis, headaches, arthralgias, back pain, coughing, and epistaxis. And with the turoctocog, unfortunately, 1 patient did develop an inhibitor after 93 days of exposure. So these products were approved. They were shown to be safe and effective.



0 24 48 72 96

Fc Fusion

2.4 Eftrenonacog alfa

Nonacog beta pegol ~5

PEGylation 33.8 h 82.1 h

13 h 19 h

19 h 93 h

Approved EHL FIX Replacement Strategies1-3

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.

Albutrepenonacog alfa 102 h 23.7 h

t½, hr

4.3

t½ extension (fold change)

rFIX EHL rFIX

Albumin Fusion

These are the extended half-life products for factor IX; and you can see the different extensions. The Fc fusion protein had a 2.4 extension, or a half-life of 82 hours. The PEGylated product had a half-life of 93 hours, and the albumin fusion had a half-life of 102 hours, making these, easily, weekly infusions—even up to every-2-weeks infusions.

Clinical Efficacy on EHL rFIX Products in Hemophilia B

Eftrenonacog Alfa1

• ABR reduction (vs on-demand) − Weekly prophylaxis: 83% − Inter-adjusted prophylaxis: 87%

• 90.4% of bleeding episodes resolved after one injection • No subjects developed inhibitors during study • Most common AEs: nasopharyngitis, influenza, arthralgia, URTI, headache, and

hypertension

Nonacog Beta Pegol2

• ABR reduction (vs on-demand) − Weekly prophylaxis (40 units/kg dose): 93%

• 99% of bleeding episodes resolved after one injection • No subjects developed inhibitors during study • Most common AEs: nasopharyngitis, influenza, and URTI

1. Powell JS et al. N Engl J Med. 2013;369:2313-2323. 2. Collins PW et al. Blood. 2014;124:3880-3886.

And again, just to show you the clinical data. The Fc fusion protein showed—compared to on-demand—an 83% reduction in the annualized bleed rate, and 90% of the bleeding episodes resolved after one injection, and no unexpected adverse events. The same with the PEGylated factor IX product: the annualized bleed rate was decreased by 93%; 99% of the bleeding episodes resolved after one injection and there were no unexpected adverse events.

Clinical Efficacy on EHL rFIX Products in Hemophilia B (Cont’d)1

1. Santagostino E et al. Blood. 2016;127:1761-1769.

15.4

0 0

5

10

15

20

On-Demand Prophylaxis(1x/2 wk)

Albutrepenonacog Alfa

AsB

R ↓100% vs

On-Demand

• 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection

• No patients developed antibodies or inhibitors, had related AEs, or withdrew

For the albumin fusion protein for factor IX, this was reported slightly differently. It looked at the annualized spontaneous bleed rate, as opposed to the annualized bleed rate treating all bleeds. They only looked at the spontaneous bleeds. On-demand, there were 15 bleeds versus zero spontaneous bleeds in the prophylaxis arm. And 98%-99% of the bleeding episodes were successfully treated; and again, no unexpected adverse events.

Novel Nonfactor Therapies for the Management of Hemophilia With and Without Inhibitors1

Emicizumab-kxwh

Bispecific monoclonal

antibody: bridges FIXa and FX to

restore function of missing FVIIIa

1. Hartmann J, Croteau SE. Am J Hematol. 2016;91:1252-1260.

Approved Investigational

Gene Therapy

Replacing the gene needed for

production of endogenous factor protein

Fitusiran

Small inhibitory RNA targeting antithrombin

Concizumab

Monoclonal antibody: TFPI

inhibition of FXa/TF/FVIIa

So, now we’re going to move on to some of the novel nonfactor therapies for the management of hemophilia with or without inhibitors. And the first one approved, as I mentioned previously, was emicizumab. And it’s a nonfactor, again. It’s a bispecific monoclonal antibody—and I’ll go through the mechanism; it’s a very interesting mechanism. I’ll go through it in the next couple of slides.

And there are others under clinical investigation. Most of these are in phase 3 trials. One is fitusiran, and it’s a very different mechanism of action. It’s a small inhibitory molecule that targets antithrombin; and I’m going to reach back into your memory and remind you that antithrombin is an anticoagulant, and decreases in, or deficiency in, antithrombin III results in a clotting problem. So people show up with DVTs or pulmonary emboli with antithrombin III deficiency. Concizumab is a monoclonal antibody. And it’s targeting tissue factor pathway inhibitor; so it’s inhibiting, again, an anticlotting factor or an anticoagulant. In gene therapy, the goal is to replace what’s missing; replacing the gene that’s mutated with a functional gene that’s needed for production of the endogenous clotting factor protein.

Interactions of Emicizumab-kxwh With FIXa and FX1

1. Kitazawa T et al. Thromb Haemost. 2017;117:1348-1357.

Emicizumab-kxwh

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11


So, here is the first slide on mechanism of action for emicizumab. And again, this is a bispecific monoclonal antibody. And what I’m going to do is just explain the natural role of factor VIII in the clotting cascade. So, we know that factor VIII is part of the intrinsic pathway; and the role of factor VIII is to act as a cofactor for factor IX, shown here, and factor X. So factor VIII binds naturally factor IXa and factor X. And in that binding, the factor VIII brings the activated IX close to factor X, so that the factor X molecule gets activated and then, in turn, can go and activate prothrombin to thrombin, resulting in a thrombin burst. Emicizumab mimics factor VIII, in that, one arm—it’s bispecific—one arm binds the activated factor IX. The other arm binds factor X; and in that binding, it brings the activated factor IX molecule close enough to the factor X molecule so that the factor X molecule gets activated and it can go on to activate prothrombin to thrombin, thus resulting in the thrombin burst. And that is how emicizumab works.

HAVEN 1: Weekly Emicizumab-kxwh in Hemophilia A With Inhibitors1

• Most frequent AEs were injection-site reactions

• Thrombotic microangiopathy and thrombosis were reported in two participants each (in the primary analysis) − Each had received multiple

infusions of aPCC for breakthrough bleeding

• No antidrug antibodies were detected

• HAVEN 2 study showed emiciziumab-kxwh is effective and well-tolerated in pediatric patients with hemophilia A and inhibitors2,3

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 Congress (ISTH 2017). Abstract OC 24.1. 3. Young G et al. Blood. 2018;132:632.

0

5

10

15

20

25

30

Group A Group B Group C

All bleeding events Bleeding events treated with bypassing agentsTreated events of spontaneous bleeding Treated events of joint bleedingTreated events of target-joint bleeding

Annu

aliz

ed R

ate

of B

leed

ing

Even

ts

(95%

CI)

Emicizumab Prophylaxis (N = 35)

No Prophylaxis (N = 18)

Emicizumab Prophylaxis (N = 49)

87% difference in annualized rate of treated bleeding events (risk ratio = 0.13; P < .001)

And the HAVEN trials were looking at the use of emicizumab in patients with and without inhibitors. So HAVEN 1 was looking at patients with congenital hemophilia with inhibitors. Group B is the no prophylaxis group. Group A and group C are emicizumab prophylaxis.

And what you can see, they broke it down into the different types of bleeding. So the darkest bar, which is dark blue, is all types of bleeds. The lighter blue is treated bleeds And then these are—the sort of yellow-brown—are the spontaneous bleeds. These [green bars] are joint bleeds and then target joint bleeds [in purple].

And so you can see, in every type of treated bleeds—all bleeds, treated bleeds, spontaneous bleeds, target joint bleeds, or joint bleeds alone—in every category, you can see that in the emicizumab prophylaxis you get reduction in the annualized bleed rate. And again, we’re looking at annualized bleed rate; so in every category you get a reduction in the bleeds for patients on emicizumab prophylaxis. So the molecule does work.

And the most frequent adverse events were injection-site reactions. And, I have to mention, in the group with inhibitors, what they saw an unexpected adverse event was thrombotic microangiopathy and thrombotic events—two participants with thrombotic microangiopathy and two with thrombosis. And all of

these were associated with the use of the activated prothrombin complex concentrates with use for treatment of bleeds. With use of the recombinant FV11a, these were not seen. And no antidrug antibodies were detected in the HAVEN 1 trial; but in HAVEN 2 there was an antidrug antibody that was detected. And the HAVEN 2 was a pediatric study showing similar results: decreasing annualized bleed rates in patients treated with emicizumab compared to no prophylaxis.

HAVEN 3: Emicizumab-kxwh in Hemophilia A Without Inhibitors1

Outcome Emicizumab-kxwh

1/wk (n = 36)

Emicizumab-kxwh 1x/2 wk (n = 35)

No Prophylaxis

(n = 18) ABR 1.5 1.3 38.2

No treated bleeding events 56% 60% 0%

• An intra-individual comparison showed emicizumab-kxwh therapy led to a significantly lower bleeding rate than previous FVIII prophylaxis

• Most frequent AE was low-grade injection-site reaction • There were no thrombotic or thrombotic microangiopathy events,

development of antidrug antibodies, or new development of FVIII inhibitors

1. Mahlangu J et al. N Engl J Med. 2018;379:811-822.

And HAVEN 3 was use of emicizumab in congenital hemophilia patients without inhibitors, and you can see the outcomes were very similar. And here, looking at the annualized bleed rate, you can see in the no prophylaxis arm, the annualized bleed rate was 38. With emicizumab prophylaxis once weekly, the annualized bleed rate went down to 1.5, and emicizumab given once every 2 weeks was 1.3. So, again, there was greater than 90% reduction in the annualized bleed rate; 95% and 96%.

And here we talk about zero bleeding—and so no treated bleeding events. The zero bleed rate was 56% in the emicizumab given weekly and 60% in that given every 2 weeks. And what they did was an interesting intra-patient comparison.

So before the patient switched to emicizumab prophylaxis, they were on factor VIII prophylaxis, and the annualized bleed rate was approximately 4 to 5 bleeds per year. When they switched over to emicizumab, the annualized bleed rate went down to about 1.5 to 2; that represented a 67% reduction. So even compared to factor VIII prophylaxis, you can still have a better outcome with less bleeding.

And there were no unexpected adverse events. And the most common adverse event was the injection-site reaction. With the patients without inhibitors, there were no thrombotic events or thrombotic microangiopathy as seen with the patients with inhibitors.



HAVEN 4: Emicizumab-kxwh Prophylaxis Q4W in Patients With Hemophilia A1

Multicenter, Open-Label, Nonrandomized Phase 3 Study

• Most frequent treatment-related AE: injection-site reactions

• 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.

1

1.7

0.6

4.5

0 1 2 3 4 5

ABR, treated target jointbleeds

ABR, treated joint bleeds

ABR, treated spontaneousbleeds

ABR, all

ABR, treated spontaneous bleeds

ABR, treated joint bleeds

ABR, treated target joint bleeds

And HAVEN 4 was looking at emicizumab patients being treated once per month or, actually, every 28 days—so every 4 weeks. You can see that the annualized bleed rate—overall bleed rate—went down to 4.5. And you can see the different types of treated bleeds here: spontaneous bleeds, all joints bleeds, and target joint bleeds.

The most frequent adverse event was injection-site reactions, and in HAVEN 4, no development of thrombotic events or microangiopathy was seen.

Targeting Antithrombin in Hemophilia With RNAi1

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

Fitusiran

• Investigational RNAi therapy that specifically targets antithrombin mRNA (encoded by SERPINC1) to suppress the production and thereby rebalance coagulation system and promote hemostasis in hemophilia

• In murine hemophilia models, antithrombin reduction was associated with increased thrombin generation and enhanced hemostasis; suggests a potential therapeutic benefit

Hemophilia A

FVIII FVIIIa

FIX

Hemophilia B

FIX

FX

FXa

FVIIa FVII

Fitusiran

AT

FVa FV

Thrombin Prothrombin

Fibrinogen Fibrin

Blood clot

X

X X

Will flag animation for onDemand to Ops

Now we’re going to move onto another molecule that’s under investigation. It’s called fitusiran and this is an investigational, inhibitor RNA molecule that is targeted to antithrombin III and the inhibitory molecules. It suppresses the production—so you get suppression of the mRNA, which results in suppression of the protein; so you get decreased amounts of antithrombin III, and that basically rebalances the coagulation system.

So hemostasis is a balance of procoagulants and anticoagulants, where procoagulants are the clotting factors; anticoagulant antithrombin III is one example. And you can see that, here, if you have hemophilia, you are blocking the intrinsic pathway, and ultimately you get less thrombin development. You don’t get that thrombin burst. And antithrombin III, shown here, actually blocks thrombin; and if you remove that block, then you get an increase in thrombin production. So in the murine models, antithrombin reduction was associated with increased thrombin generation and that enhanced hemostasis, suggesting that there could be a potential therapeutic effect.

Targeting Antithrombin in Patients With Hemophilia A or B With Fitusiran

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 thrombin generation in participants with hemophilia A or B who did not have inhibitors1

1. Pasi K et al. N Engl J Med. 2017;377:819-828. 2. Pasi K et al. ISTH 2019. Abstract OC 11.3. 3. https://clinicaltrials.gov/ct2/show/NCT03417102. Accessed October 17, 2019. 4. https://clinicaltrials.gov/ct2/show/NCT03417245. Accessed October 17, 2019. 5. https://clinicaltrials.gov/ct2/show/NCT03974113. Accessed October 17, 2019. 6. https://clinicaltrials.gov/ct2/show/NCT03549871. Accessed October 17, 2019.

Interim analysis of phase 2 open-label extension study, which includes patients with hemophilia A or B with or without inhibitors who completed the phase 1 study, has indicated fitusiran prophylaxis provides sustained AT lowering, results in low ABR over an extended period of time, and is generally well tolerated2

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

• 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 bypassing agents6

And in the phase 1/2 trials, that’s actually what they saw. When you decreased antithrombin III production in patients with hemophilia A or B with the fitusiran, you can see in the phase 1—which was proof of concept—that it resulted in a dose-dependent lowering of antithrombin and increased thrombin generation in those patients with hemophilia A or B who did not have inhibitors; and this was confirmed in the phase 2 open-label extension study. And these included patients with hemophilia A or B with or without inhibitors. And again, they found that decreasing the antithrombin III levels increased thrombin generation, and it was well tolerated.

And now there’s an ongoing phase 3 trial looking at the use of fitusiran in patients with hemophilia A or B with inhibitors, and in patients with congenital hemophilia A or B without inhibitors. There’s also a pediatric trial, and fitusiran in patients with hemophilia A or B previously receiving bypassing agents.

Concizumab: Monoclonal Antibody Directed Against TFPI1

IX IXa

X VIII Xa

Prothrombin (II) V

Thrombin (IIa)

Fibrinogen (I) Fibrin

VIIa TF

Xa

K1 K2

K3

TFPI

K1

K2

K3 Concizumab Hemophilia

1. Hilden I et al. Blood. 2012;119:5871-5878.

Concizumab • Humanized IgG4 antibody • High affinity for Kunitz-2 domain of TFPI • Complete neutralization of TFPI inhibition of FXa/TF/FVIIa

Will flag animation for onDemand to Ops

And now moving on to concizumab, which is a monoclonal antibody, and it’s targeting tissue factor pathway inhibitor. Again, we are trying to decrease the amount of one of the anticoagulants to try to rebalance the coagulation system. So concizumab is a humanized monoclonal antibody with an affinity to the specific Kunitz-2 domain—a specific domain of the tissue factor pathway inhibitor; so it completely neutralizes the TFPI inhibition of the factor Xa/tissue factor/factor VIIa complex.

PeerView.com/CSQ900

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You can see with hemophilia, again, you do not get activation of the Xa, which converts prothrombin to thrombin, so you get decreased thrombin generation. You can go through the extrinsic pathway with tissue factor VIIa and activated X to try to get more thrombin generation. So the intrinsic pathway is blocked in patients with hemophilia.

You can try to go around it and use the extrinsic pathway and treat patients with factor VIIa. Unfortunately, with the presence of tissue factor pathway inhibitor, it blocks the Xa and the tissue factor VIIa complex, so you don’t get thrombin generation. If you remove that block, again, you get the thrombin generation, and the thrombin burst can occur, and you get conversion of fibrinogen to fibrin. So, concizumab blocks the TFPI and then results in increased thrombin generation in those patients with hemophilia.

Key Safety Findings

• No thromboembolic events

• No AE-related withdrawals

• No safety concerns with breakthrough-bleed treatment

Key Efficacy Findings • ABR (after 24 weeks): 3.0-7.0

• All patients choose to continue to extension phase in both trials

• Concizumab exposure, free TFPI reduction, and TG potential were similar across all groups

• Concizumab exposure was associated with normalized TG potential

Phase 2 Results of SubQ Concizumab Daily in Hemophilia A and Hemophilia A/B With Inhibitors1

1. Astermark J et al. ISTH 2019. Abstract LB 01.1.

And the phase 1/2 showed the proof of concept and no unexpected safety findings—no thrombotic events, no adverse events related to this product. And the efficacy is shown here. You can see that the annualized bleed rates went down and the concizumab was given daily to patients with hemophilia A or hemophilia B with inhibitors.

rAAV Vector Genome

AAV-Mediated, Liver-Directed Gene Therapy for Hemophilia: An Overview1

1. Doshi BS, Arruda VR. Ther Adv Hematol. 2018;9:273-293.

Modifications

• Codon optimization • CpG content

Modifications

• Serotype • Empty capsids • Production system

Therapeutic Options

• Antiviral therapy • Skeletal muscle gene therapy

Therapeutic Options

• Lower vector dose • Immunosuppression

Therapeutic Options

• Plasmapheresis • Empty capsids • Immunosuppression • Novel serotype • Regional delivery

ITR

Rep Cap ITR ITR

Intron Transgene polyA ITR Promoter

AAV Genome

FVIII/FIX inhibitors

Pediatric patients Liver disease

Pre-existing neutralizing antibodies to AAV serotype

Protein production

Capsid-triggered cellular immune response

CD8+ T Cell

And so, I’m going to very quickly now go through the last thing, which is gene therapy. And gene therapy is actually close to reality in hemophilia. Some trials are in phase 3 for hemophilia A as well as hemophilia B. This is a very busy slide, but what I’m just going to

point out is that this gene therapy is a gene transfer therapy. We’re not modifying the patient’s genes at all; we’re just adding their functional gene and trying to see if this functional gene can make factor VIII or IX protein.

And we can easily assay these levels for factor VIII or factor IX. The vector that they’re using for this gene transfer is an adeno-associated virus vector and it’s liver-directed, meaning that we’re targeting the liver cells to take up the factor gene; and the reason is because it’s in the liver that all the coagulation factors are made. So, factor IX is normally made in the liver, and factor VIII is also produced in the liver.

And so, here it shows the adeno-associated virus genome. And what you can see is that we take out the viral genome, replace it with the functional gene using the inverted terminal repeat, shown here, with a polyadenylation tail and a liver-specific promoter. This vector is then infused intravenously—a one-time infusion—and then we wait to see if factor VIII is made. And currently it is working in some patients and it’s in a phase 3 larger trial.

The caveat is that you can’t use it in patients with inhibitors; so, in the red, you can’t use it in patients with inhibitors. We’re currently not using it in pediatric patients or in those patients with liver disease. So the reds are, sort of, nontargeted areas right now. And those with pre-existing neutralizing antibodies to AAV also cannot be infused with this product.

Gene Therapy Serotype Transgene Status

Valoctocogene roxaparvovec rAAV5 BDD-FVIII Phase 33,4 Recruiting4

SPK-8011 Spark 200/LK03 BDD-FVIII Phase 1/25 Recruiting5

TAK 754 (BAX 888, SHP 654) rAAV8 BDD-FVIII Phase 1/26 Recruiting6

Selected Gene Therapy for Hemophilia A: Current Status1,2

1. Miesbach W et al. Haemophilia. 2019;25:545-557. 2. Doshi BS, Arruda VR. Ther Adv Hematol. 2018;9:273-293. 3. https://clinicaltrials.gov/ct2/show/NCT03392974. Accessed October 17, 2019. 4. https://clinicaltrials.gov/ct2/show/NCT03370913. Accessed October 17, 2019. 5. https://clinicaltrials.gov/ct2/show/NCT03003533. Accessed October 17, 2019. 6. https://clinicaltrials.gov/ct2/show/NCT03370172. Accessed October 17, 2019.

So again, gene therapy is occurring in hemophilia A. These are three of the multiple trials that are going on. You can see one of them is in the phase 3. This, for short, is valrox—valoctocogene roxaparvovec. The valrox trial is in phase 3; the Spark is in a phase 1/2 and still recruiting; and the BAX 888 is also in a phase 1/2 that’s recruiting.



Gene Therapy Serotype Transgene Status

Fidanacogene elaparvove Spark100 FIX-Padua Phase 33 Recruiting3

Etranacogene dezaparvovec rAAV5 FIX-Padua Phase 34 Recruiting4

SB-FIX rAAV6 Zinc finger-FIX Phase 15 Active, not

recruiting5

Selected Gene Therapy for Hemophilia B: Current Status1,2

1. Miesbach W et al. Haemophilia. 2019;25:545-557. 2. Doshi BS, Arruda VR. Ther Adv Hematol. 2018;9:273-293. 3. https://clinicaltrials.gov/ct2/show/NCT03861273. Accessed October 17, 2019. 4. https://clinicaltrials.gov/ct2/show/NCT03569891. Accessed October 17, 2019. 5. https://clinicaltrials.gov/ct2/show/NCT02695160. Accessed October 17, 2019.

And for factor IX, these are some of the trials that are going on. You can see two of them are phase 3 trials: the Spark as well as the Unicare trials. And then there’s also one that is in phase 1; it’s still active but currently not actively recruiting patients.

Summary

• The treatment of hemophilia has evolved considerably over the past several years

• Advances in biotechnology have permitted the development of EHL replacement clotting factors for prophylaxis in patients with hemophilia A or hemophilia B

• The approval of emicizumab-kxwh has ushered in the era of nonfactor replacement for the treatment of hemophilia A with and without inhibitors

• In addition, if validated in phase 3 clinical trials, agents such as fitusiran, concizumab, and numerous gene therapies would offer patients with hemophilia A or B additional options to prevent bleeding and the development of inhibitors to FVIII or FIX

So, to quickly summarize, the treatment of hemophilia has evolved over the last 5 years, considerably. Advances in technology have permitted the development of the extended half-life products as well as nonfactor therapies for hemophilia A and B. The approval of emicizumab has really ushered in an era of nonfactor replacement therapy for prophylaxis in patients with hemophilia with inhibitors and without inhibitors. And phase 3 clinical trials are ongoing with agents such as fitusiran and concizumab. And there are numerous gene therapy trials that I showed you for hemophilia A and B, and these are going to be additional options for patients with hemophilia to prevent bleeding and the development of inhibitors to either factor VIII or IX.

PeerView.com/CSQ900

Krystin Miller, MDThe Ohio State University Department of Emergency Medicine Columbus, Ohio

15


What Can We Learn From Current Guidelines for the Treatment of Hemophilia in the Emergency Department?

MASAC Guidelines for ED Management of Individuals With Hemophilia and Other Bleeding Disorders: Triage1

This should not delay giving clotting factor concentrate replacement to the patient

Delays in administering factor concentrate can significantly impact morbidity and mortality

Individuals with known bleeding disorders should be triaged urgently

Consultation with the patient’s hematologist or a regional HTC professional is strongly advised when possible

1. National Hemophilia Foundation. MASAC Report No. 252. September 17, 2017.

Dr. Miller: So my name’s Krystin Miller. I am visiting you from the Ohio State University in Columbus, Ohio, and we’re going to switch gears a little bit from the pathophysiology and the pharmacology of how our patients with hemophilia are being treated and receiving prophylaxis—maybe on the outpatient setting with their hematologist—to what do we do with these patients when they present to your emergency department.

So we’re going to use the Medical and Scientific Advisory Council of the National Hemophilia Foundation’s guidelines for ED management to really frame the rest of the discussion today. And we’re going to start with triage. What do we do with these patients when they present to triage and we know that they have a bleeding disorder? And I think that the primary thing that we need to take away is that these patients need to be triaged urgently. These are time-sensitive diagnoses. We know that delays in administering clotting factor increase our patients’ morbidity and mortality.

So ideally, we’re giving these patients factor replacement within that first hour of suspected injury or suspected spontaneous bleed. The other thing that we should think about is consulting the patient’s hematologist or the local hemophilia treatment center if available; however, we want to make sure that that is not delaying our administration of factor concentrate. But if we have the ability, if the patient knows their hematologist’s number, if they have the

number in their cell phone to the hemophilia treatment center—which they probably do—we should be making those phone calls sooner rather than later.

• 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 guidelines as advised by their treating hematologist

MASAC Guidelines for ED Management: Assessment1

• Treatment for a suspected bleeding disorder is based on clinical history • Physical findings may be NORMAL in the early phases of most hemophilic bleeds • Spontaneous bleeding is common in individuals with severe disease

(<1% factor level)

When in doubt, administer clotting factor replacement immediately; DO NOT DELAY for imaging studies, lab results, or consultations • Treatment decisions should be based on the SUSPICION of a bleeding-related problem


We’re going to flip now to assessment. What do you do when you’ve got the patient in the room and you’re assessing your patient with a bleeding disorder, or your hemophilia patient? First and foremost—keeping in mind that our treatment for a suspected bleeding disorder is based mostly on history—so obtaining that history from the patient, but knowing that your physical exam might be normal early on, especially in the early cases of most of our minor hemophilia bleeds.

The other thing to keep in mind is that, in our patients with severe hemophilia, there is a risk—and a real risk—of spontaneous bleed. So there might not be a history of trauma; there might not be a history of injury that clues you off in that clinical history; but we should still have a high suspicion for bleed. And then, finally, relying on our patient, or the patient’s parents in the case of a pediatric patient. If they think that occult bleeding is going on, we should be administering clotting factor.

These patients and their parents know themselves and their disease process better than we do as ED physicians who are maybe seeing them for the first time. So a lot of times they’re bringing their clotting factor with them to the emergency department and, if they are—as they should be—we should be administering their clotting factor when they arrive. When in doubt, the bottom line—I’m going to be a broken record over the next several slides—when in doubt, administer clotting factor. We’re not delaying clotting factor for imaging studies and, really, the treatment of hemophilia is based on the suspicion of bleed going on.



• Routine joint bleeds DO NOT require imaging

• For the established patient, routine surveillance labs (PT, PTT, factor levels) ARE NOT indicated unless requested by the patient’s hematologist

• If an invasive procedure is required (ie, lumbar puncture, ABG, lung/joint tap) 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

MASAC Guidelines for ED Management: Diagnostic Studies1

Clotting factor should be given before any diagnostic studies are performed, especially in cases of head trauma, abdominal trauma, or suspected ICH


So what about diagnostics? A patient comes in, has a fall, has a trauma. You’re concerned for intracranial hemorrhage, you’re concerned for intra-abdominal hemorrhage, intrathoracic injury. You give the clotting factor first and then obtain your imaging studies. So we should not be delaying giving clotting factor to obtain a head CT, to obtain an abdominal CT in the cases of trauma. If it is a joint bleed, there is an obvious hemarthrosis, an obvious effusion, we do not need routine imaging and x-rays in those cases, so routine imaging is not required for joint bleeds as well as baseline labs. So, baseline PT, PTT, factor levels are not required in most cases of hemophilia patients unless that has been requested by the patient’s hematologist when you were on the phone with them. And then keep in mind, anytime you’re planning on an invasive procedure in the ED—so lumbar puncture, thoracentesis, central line, whatever it might be—clotting factor should be replaced first, up to 100%, before going forward with any of those invasive procedures in the ED.

MASAC Guidelines for ED Management: Indications for Factor Replacement Therapy1

1. Suspected bleeding into a joint or muscle 2. Any significant injury to the head, neck, mouth, or eyes, or evidence of bleeding in

these areas 3. Any new or unusual headache, particularly one following trauma 4. Severe pain or swelling at any site 5. All open wounds requiring surgical closure, wound adhesive, or wound closure

strips 6. History of an accident or trauma that might result in internal bleeding 7. Any invasive procedure or surgery 8. Heavy or persistent bleeding from any site 9. Gastrointestinal bleeding 10. Acute fractures, dislocations, and sprains


So when should our patients be getting replacement factor? We said kind of overarchingly, if there’s a suspicion for bleed, if the patient or the patient’s parents is suspicious for a bleed, this presented like their last bleed, then certainly we’re giving clotting factor. But this is a list of 10 other common scenarios that should trigger your mind and make you think about giving clotting factor in the emergency department. So any suspected bleed into a joint or a muscle, any effusion or hemarthrosis—they get clotting factor.

Any significant bleeding on the head, the neck, the face, and the oropharynx, epistaxis—they should get clotting factor. A patient comes in with a headache, especially in the setting of trauma, concern for intracranial hemorrhage—those patients should get clotting factor. Any severe pain or swelling at any site is an indication. All open wounds that are going to require repair, even if that repair is just tissue glue or wound closure strips—those patients should get factor replacement.

If a patient has a history of trauma—I think that’s the easy one—give clotting factor. Any planned invasive procedure or surgery—they get clotting factor. Any persistent or heavy bleeding, vaginal bleeding, GI bleeding—those patients are going to get factor as well. And then think about any joint injury, fracture, dislocation, sprains; those are high risk for hemarthrosis, and we’ve heard about the complications and development of a target joint and the debilitating consequences that that can have for our patients. So any joint injury should also get factor replacement therapy.

MASAC Guidelines for ED Management: Treating Patients With Hemophilia A or B Without Inhibitors1-3,a

Bleeding Type Target Percent Correction

Dose of Factor VIIIb, units/dL

Dose of Factor IXb, units/dL

Minor 25% 12.5 units/kg 25 units/kg Moderate 50% 25 units/kg 50 units/kg Severe 100% 50 units/kg 100-120 units/kg

• Minor ‒ Early hemarthrosis ‒ Mild soft tissue ‒ Mild muscular

• Moderate ‒ Definite

hemarthrosis ‒ Moderate muscular ‒ Hematuria ‒ Dental ‒ Epistaxis (rare)

• Severe ‒ CNS ‒ Retroperitoneum ‒ Retropharynx ‒ Surgery ‒ GI

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. 1. National Hemophilia Foundation. MASAC Report No. 252. September 17, 2017. 2. Factor VIII Dosing Calculator. https://mprcalc2.usbmis.com/24535.html. Accessed October 17, 2019. 3. Factor IX Dosage Calculator. https://www.empr.com/medical-calculators/factor-ix-dosage-calculator/article/170191. Accessed October 17, 2019.

So this is probably the most complicated slide in terms of our treatment algorithm, but probably one of the more important ones to keep in mind. So in deciding our dosing of clotting factor, it’s really based on the severity of the bleed. So we divide bleeding severity into minor, moderate, and severe, and we’re going to base our dosing of clotting factor on the severity of the bleed. If you remember one thing, remember the severe bleed, remember that dosing; it’s fairly easy and can be time-saving in the emergency department.

So you’re concerned about a severe bleed, intracranial hemorrhage, an RP bleed, something in the retropharynx. You’re sending your patient for surgery, for an appendectomy. You’re doing an invasive procedure in the ED, or they’ve got ongoing GI bleeding. Those are all indications to replace that patient’s factor level to 100%. In order to get there, it’s 50 units/kg of factor VIII in our hemophilia A patients and 100 to 120 units/kg of factor IX in our hemophilia B patients. So if you can remember 50 and 100 in a serious bleed, that will get you a long way in our management of these acute bleeds in the emergency department.

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For the moderate and minor bleeds, we’re replacing to a goal of 50% or 25% of factor activity; and so those numbers are there. If ever in doubt, replace to the higher level. So if you’re teetering—“Is this a moderate bleed or is this a severe bleed?”—then we should replace them to that 100%, as if they were a severe bleed. And, as always: treat first, diagnosis later. So give the clotting factor first, then get your head CT to confirm your intracranial hemorrhage, or your abdominal CT to confirm the RP bleed that you suspected on your exam.

• Treatment decisions may be more complicated • The care of inhibitor patients should be urgently discussed with the

patient's hematologist • If an individual with an inhibitor presents in a life- or limb-threatening

scenario, the safest immediate action is to prescribe:

MASAC Guidelines for ED Management: Treating Patients With Hemophilia and Inhibitors1

aPCC 75-100 units/kg

rFVIIa 90 mcg/kg

OR


What do we do with our patients that have inhibitors? As we talked about earlier, patients can develop inhibitors to their factor prophylaxis that they’re on; and so, these treatment decisions are much more complicated. Certainly, if you have the ability to talk to the patient’s hematologist, it is highly recommended that you do that; but, again, in a case of a life-threatening or a limb-threatening bleed where you don’t have the ability to do that, you’re going to think about giving one of two bypassing agents. Your options are recombinant factor VIIa or activated PCC. So those are your two bypassing agents to get around those inhibitors that the patient might have; so think about those in your treatment algorithm, but also think about talking with the patient’s hematologist.

Managing Patients With Hemophilia A on Emicizumab-kxwh Prophylaxis1

NOT used alone in patients with breakthrough bleeding episodes

• Depending on individual’s inhibitor status, patients should be treated with: − FVIII replacement product

or − Bypassing agents such as

rVIIa or aPCC (with caution)

1. Hemlibra (emicizumab-kxwh) Prescribing Information. https://www.gene.com/download/pdf/hemlibra_prescribing.pdf. Accessed October 17, 2019.

What about our patients that are on emicizumab? We heard about this monoclonal antibody and how it’s being used for prophylaxis. So what do we do when they show up to the emergency department with a bleed? The biggest thing to remember is that this drug is not to be used in breakthrough bleeding. So if the patient brings their home dose and says, “Hey, can I just give

myself my emicizumab for my bleed?”, the answer is no. These are not used for breakthrough bleeding episodes. We treat their breakthrough bleed just the same as we do any other hemophilia A patient, and it’s dependent on their inhibitor status. So if they don’t have inhibitors, we give them factor VIII, just like we would any other hemophilia A patient, dose-based on the severity of their bleed and on our goal percentage of our correction factor. If they do have an inhibitor, then we’re going to think about one of those bypassing agents, just like our standard approach to hemophilia A patients.

So the biggest take-home message for these cases is, this is for prophylaxis only and not for the acute treatment of bleeds, so treat them with factor replacement like you would any other hemophilia A patient.

Warnings and Precautions for Patients With Hemophilia A on Emicizumab-kxwh Prophylaxis1 THROMBOTIC MICROANGIOPATHY

and THROMBOEMBOLISM • Cases of thrombotic microangiopathy and

thrombotic events were reported when, on average, a cumulative amount of >100 units/kg/24 h of aPCC was administered for 24 hours or more to patients receiving emicizumab-kxwh prophylaxis

• Monitor for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered

• Discontinue aPCC and suspend dosing of emicizumab-kxwh if symptoms occur

Laboratory Coagulation Test Interference:

• Emiciziumab-kxwh interferes with ACT, aPTT, and coagulation laboratory tests based on aPTT, including one-stage aPTT-based single-factor assays, APC-R, and Bethesda assays (clotting-based) FVIII inhibitor titers

• Intrinsic pathway clotting-based laboratory tests should not be used

1. Hemlibra (emicizumab-kxwh) Prescribing Information. https://www.gene.com/download/pdf/hemlibra_prescribing.pdf. Accessed October 17, 2019.

Dr. Quon did touch on this a little bit. So we just need to keep it in our mind that, if our patient does have inhibitors, we’re treating them with activated PCC as a bypassing agent. And they’re on emicizumab; there is a risk of thrombotic microangiopathy and thromboembolism, so we just need to monitor them for those things. If we see one of these adverse events, we’re going to stop the activated PCC and we’re not going to administer additional doses of the emicizumab, and suspend that dosing. Also, remember, for our patients on this prophylaxis, your laboratory studies are not going to be reliable; so your coagulation testing and labs are not going to be reliable in the emergency department.

Every Patient Represents a Unique Challenge

A single, severity-based, therapeutic model does not represent the optimal treatment strategy for all patients with hemophilia1

Individualization of hemophilia care is recommended

Patient’s bleeding pattern Level and timing of physical activity

Condition of the patient’s musculoskeletal system

Individual pharmacokinetic profile

Central venous access Presence of target joint Patient likelihood of good adherence Psychosocial factors

Factors to consider for individualized treatment1-4

Underscores need for shared decision-making

1. Sorenson B et al. Blood Coagul Fibrinolysis. 2003;14:469-477. 2. Collins PW. Haemophilia. 2012;18(suppl 4):131-135. 3. Oldenburg J. Blood. 2015;125:2038-2044. 4. Valentino LA. Haemophilia. 2014;20:607-615.



So I think what you’ve probably seen highlighted through everything that we’ve talked about is that hemophilia is a unique disease. Every patient presents a unique challenge. There’s not a straightforward treatment algorithm for every single one of these patients. There are lots of factors that factor into this: what the patient’s bleeding pattern is, what their history is, what their musculoskeletal system condition is. Do they have the presence of target joints? What’s their timing and level of physical activity? What’s their likelihood of adhering to their outpatient regimen or your treatment protocol that you’re suggesting in the emergency department? What’s that patient’s underlying pharmacokinetic profile? Do they have inhibitors? What are they on for prophylaxis? What are the psychosocial factors that are affecting their disease management?

So each patient is unique, and I think that this really underscores the importance of talking with the patient’s hematologist and involving the patient in a shared decision-making process, because they really know themselves and their disease process better than any of us can as emergency physicians who are meeting them for the first time in our emergency department.

Goals of Shared Decision-Making1

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

Inform the patient to improve their knowledge about their own illness

Activate the patient to increase the role they assume in illness management

Promote interaction between patient and healthcare professional

So in general, when we talk about shared decision-making, we typically have three goals, and one is to increase the patient’s knowledge of their underlying disease process; two is to activate the patient to increase their role that they play in managing their illness; and then promoting that interaction between the healthcare team. So, even if it’s not hemophilia—if it’s a patient with another chronic disease process that you’re engaging in shared decision-making, these are typically our three common goals.

NQP Playbook for Shared Decision-Making1

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

Recently, the National Quality Forum developed the NQP Playbook™: Shared Decision Making in Healthcare with

input from a team of experts and recognized leaders committed to making SDM a standard of care for all patients

NQP Playbook Requirements for SDM

Clear, accurate, and unbiased medical evidence about reasonable alternatives (including no medical intervention)

and the risks/benefits of each 1

Clinician expertise in communicating and tailoring that evidence for individual patients 2

Patients’ values, goals, informed preferences, and concerns, which may include treatment burdens 3

The National Quality Partners developed a playbook on shared decision-making in healthcare, and they said that there are really three requirements of the clinician to really say that: “I have actively engaged in shared decision-making with my patient.” And so, if you can say these three things and attest to these three things, then you can say that this was truly shared decision-making with your patient; and those are that—one—you’ve provided clear and accurate unbiased medical evidence, presented reasonable alternatives to treatments, including doing nothing, and discussed the risks and benefits of those treatment options. Secondly, as a clinician, you have some expertise in communicating and tailoring that evidence to your individual patient. And then—three—as the clinician, you have been able to elicit the patient’s values and goals, their informed preferences and concerns, and you have been able to use those to help guide your treatment decisions.

Essential Steps of Shared Decision-Making1

The SHARE Approach:

Seek patient’s participation

Help patient explore and compare treatment options

Assess patient’s values and preferences

Reach a decision with patient

Evaluate patient’s decision

S

H

A

R

E

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. Accessed October 17, 2019.

So this is a nice approach and mnemonic to help you when you actually sit down with the patient and say, “We’ve got a decision to make and I would like to engage you in this process.” How do you do this practically with your patient at the bedside? And this mnemonic can kind of help guide you through it. It’s the SHARE approach.

And so the first step is to seek the patient’s participation, and a lot of times it’s as simple as saying: “Hey, you’ve got a decision to make. I would like you to be a part of making that decision. Are you willing to do that?”—and so getting the patient’s participation and permission to be engaged in that process.

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The H in SHARE is for helping the patient explore and compare the treatment options. And so this is where your expertise comes into play. So maybe it’s the case of that patient that does have inhibitors and you’re making that choice between factor VIIa and giving activated PCC as your bypassing agent. And so part of that discussion is going to be, are they on emicizumab? Is there a risk of thrombotic events? Can we talk through those risks and benefits? The H is really your job as the clinician to explain what the treatment options are and to go through those risks and benefits.

The A is to assess the patient’s values and preferences. What’s important to them? For some patients, maybe it’s “I want to get my factor replacement and I want to go home.” For some, it’s “I am bleeding into my knee. This is my target joint. I am really concerned about it and I want to do whatever I can to get this bleed stopped and protect that joint.” So, what’s important to the patient?

The R part is reaching the decision; asking the patient: “Are you ready to make a decision? What do you think is the best option based on what we’ve talked about? What aligns with your goals and your preferences?”

And then, E is evaluating that patient’s decision; so a little bit harder for us to do from the emergency department side of things. We don’t have that luxury of time to evaluate how did that decision pan out, but, certainly, our hematology colleagues can evaluate some of those decisions down the line.

• MASAC Guidelines for ED management of hemophilia recommend that suspected bleeds be treated first and diagnosed second

• 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 and underscores their role in SDM

• SDM is a model that helps clinicians and patients make joint healthcare decisions based on the best available evidence of benefits and harms of treatment options and patients’ values and preferences with regard to the treatment options

• SDM has been shown to increase the use of the treatment option that is most clearly associated with health benefits

Summary

So just to summarize what we talked about from the emergency department management side of things. I think, most importantly—if you take away nothing else from today’s talk—give factor, and give it early, and don’t delay that for diagnostic imaging, for testing, for confirmatory studies. Our job in the emergency department is to treat the suspected bleed, not treat the confirmed bleed. And then, also, to underline the importance of shared decision-making with our patients. They truly are the experts in their own disease process. Parents, patients, family members, can be your best friends in helping, using shared decision-making to come up with the best treatment plan for our patients.

Sarah Luisa Melendez, MDDoris Quon, MD, PhDKrystin Miller, MD



The Role of Shared Decision-Making in the Management of Hemophilia in the Emergency Department

PeerView.com/CSQ900

Case 1

Boy’s mother states: • He has been complaining of a mild

headache • His last FVIII infusion was 2 days ago

Key PE Findings

Boy is alert, interactive, and appears well

Does not appear to be in any distress

No scalp hematoma

Neurologic exam is normal for age

A 5-year-old boy with a history of severe hemophilia A

Receives FVIII prophylaxis 2x/week

Presents to ED after tripping over a rock while running and striking

his head

Dr. Melendez: Okay. Now, we’ll go into a couple of cases. So there’ll be three cases. So we’ll start with case number one and some common cases that we encounter in the ED. A 5-year-old boy comes in with a history of severe hemophilia A. Mom states that he normally receives factor VIII prophylaxis 3 times a week; and he was running, he tripped over a rock and hit his head—very common. The patient’s mom states that he has been complaining of a mild headache. His last factor VIII infusion was about 2 days ago. And on physical exam, he’s alert, interactive; he appears well. He doesn’t appear to be in any distress. He doesn’t have a scalp hematoma that you can appreciate, and his neurologic exam is normal.

• Is head imaging warranted?

• Does he need FVIII infusion? – If so, when should it be administered and how much?

• The patient uses rurioctocog alfa pegol at home, but mother does not have it with her – Your pharmacy only carries efmoroctocog alfa

Is it okay to switch them?

Key Questions

Dr. Melendez: Number one, is head imaging warranted in this patient?

Audience Member: How long ago did he fall? What was the time?

Dr. Melendez: He presented as soon as he fell, so less than an hour ago. So I would say, head imaging—yes, it is warranted, but maybe not right away. And does he need factor VIII infusion? And, if so, should it be administered? How much should be administered?

Audience Member: Yes. Fifty.

Dr. Miller: Fifty, perfect. Our two numbers that we need to remember. We could consider this a severe bleed with a suspicion for intracranial hemorrhage, so 50 units/kg for factor VIII; 100 to 120 units/kg for factor IX if he was a hemophilia B patient. So, great!

Dr. Melendez: Exactly. So, this is a severe bleed, so 100% correction would be where we would want him to go. And he is a severe hemophilia patient as well. The patient uses that particular factor at home.

Dr. Quon: Yeah. It’s an extended half-life factor, so he’s probably getting it twice a week.

Dr. Melendez: Right. But, mom doesn’t have the factor with her.

So your pharmacy at your particular ED only carries a different kind of factor. Is it okay to switch them, is the big key thing—and I know that’s a pretty common question that we have. So, is it okay to give a different factor to this patient?

Dr. Quon: So, in general, people do not like to switch factor because they think it might stimulate an inhibitor; but in cases of an emergency, I think this is what it is.

Dr. Miller: Give what you have available.

Dr. Quon: We use what is available for them.

Case 1: Management

Head CT scan obtained after efmoroctocog alfa was administered shows a small subdural hematoma without overlying skull fracture 2

After brief discussion with boy’s mother, efmoroctocog alfa administered at 50 units/kg to bring his factor level to 100% 1

Boy admitted to the PICU for serial neurologic exams and consult hematology for his treatment while in the ICU 3

21


Dr. Melendez: Yes. All right, so in this case, we discuss it with mom and we give—like we had mentioned—50 units/kg to bring his factor level up to 100% because this is a severe injury. He does get a head CT after he gets his factor administered and there’s a small subdural. There’s no overlying skull fracture. And this is where it’s consultation. Ideally, he needs to be admitted to an ICU setting for serial neurologic exams, but, also, I would make sure I call the patient’s hematologist just to let them know that he’s here. And also, that patient’s hematologist may have some more input to put in, other things to do; and then for the PICU to also follow while he’s in-house.

Case 1: Clinical Pearls

• When treating patients with hemophilia, factor replacement takes priority over imaging and other diagnostic tests

• Remember: If you are ever in doubt about how much factor a patient will need—and there is not enough time to touch base with the patient’s hematologist—correct the factor level up to 100%

• Always consult with the patient’s hematologist to coordinate disposition of discharge home vs admission for observation and continued factor infusion

Dr. Melendez: So the clinical pearls with this case are, basically: factor replacement prior to obtaining any imaging studies. Again, factor first, diagnose later—especially this patient, as he was very well-appearing.

If you’re ever in doubt on how much factor a patient needs and there’s not enough time to touch base with the patient’s hematologist, assume that they have 0% factor and just correct it to up to 100%. So, in hemophilia A, that’s the 50 units/kg, and hemophilia B the 100 to 120 units/kg. I always like to call the patient’s hematologist after I have given factor. I have the luxury of having a hematologist on call 24/7; but, ideally, it should be something that the hematologist is aware of, especially for follow-up purposes if they’re somebody who can go home.

Audience Member: What’s the big significance of giving extra factor? I mean, what are the downsides besides maybe cost?

Dr. Melendez: There really are no downsides. So if the patient—for example, in this particular case, mom gave it 2 days ago, which is in line with his prophylaxis twice a week—but, even if you treated the day before, you would still treat it as a trauma. You would give him the factor and assume that he’s at zero because he’s severe, and give him 100% correction. If he goes up to 120 or 150, there is no downside to that.

The only downside would be really older patients who might have cardiac issues and you don’t want to cause a thrombosis somewhere else; but usually the factor has a short half-life. The

standard factors have a short half-life and even, as you saw, most of the extended half-life products—for at least hemophilia A—are not that long, so the factor levels are transient.

Case 2

18-Year-Old Male Patient

Mild hemophilia B

Presents to the ED for continued bleeding of a laceration to his thumb that he sustained while

trying to cut an avocado

He has his own FIX but is unable to administer it to himself

Key PE Findings

Vital signs are within normal limits

1.5-cm laceration to proximal thumb base

Continues to ooze despite firm pressure and elevation

Dr. Melendez: On this case—pretty common that we’ll probably encounter this as well—an 18-year-old male with mild hemophilia B; he sustained a laceration to the base of his thumb after trying to cut an avocado and the knife went into his hand. He has his own factor IX, but he can’t administer it to himself. His vital signs are all within normal limits on physical exam, and you notice a 1.5-cm laceration to the proximal thumb. It continues to ooze despite pressure and elevation.

Key Questions

• The patient brought his FIX with him − Should we use it?

• Does he need FIX? − If so, how much? And when should it be administered?

Dr. Melendez: Does he need his factor? And, I think we touched upon that, that yes he does. And then, if so, how much and when should it be administered?

Dr. Miller: Yeah, so we’re going to give it sooner rather than later. I think you would consider this probably a moderate bleed, so replace to about 50%—so in this case, 50 units/kg.

Dr. Melendez: Yeah. And then he has his own factor. Should we use it?

Dr. Miller: Yes, absolutely.



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Dr. Quon: Yes. I think that you should, unless the hospital has a “no brown bag” policy—like an absolute no brownbag—and they have factor in stock; then they can use their factor. But it’s faster to actually administer the patient’s factor because it’s right there.

Case 2: Management

You administer 50 units/kg of his FIX for a correction of 50%

Hemostasis is achieved within 30 minutes, allowing for irrigation and repair of the wound

You consult with patient’s hematologist; he agrees that the patient can be discharged home, and he will follow up the next day in the office

Dr. Melendez: All right. So, like Dr. Miller said, we administer 50 units/kg. We correct him to about 50%. Within 30 minutes, hemostasis is achieved and now we can irrigate and repair the wound. And in this case—same thing—if it’s early enough and you can, or if the patient can, touch base with their hematologist just for follow-up to make sure that they can be seen, especially if it’s a patient that may not be able to come back to the ED as freely as possible to get rechecked. If they can’t go to their hematologist for any reason, I have done 24-hour rechecks, but ideally he should be in touch with the hematologist.

• Use the factor that the patient or family has with them − It will save time and may be the only factor that works

for the patient with inhibitors

• “Round up” − Due to cost, use the closest vial size to the

recommended dose and use the whole vial − Do not waste the factor


Dr. Melendez: And the key thing is that you want to use the factor that the patient has with them. It may be the only factor that works for that patient, but you should really use it. And then there’s this thing of roundup—it’s costly. Patients will often come with about 100% correction with them. If you realize that their number is in between a dose, just round up because you don’t want to waste any factor.

Dr. Quon: We just use the whole vial basically.

Dr. Melendez: The whole vial.

Dr. Quon: So, you don’t just draw out specifically and throw away half the vial; you just use up the whole vial. And again, it comes back to: overtreating is not a problem in these patients.

Case 3

• 24-year-old male patient with severe hemophilia A

• High-titer inhibitors to FVIII (>5 BU/mL)

• Receives emicizumab-kxwh prophylaxis, 1.5 mg/kg/wk

• Presents to ED with pain and swelling in his left knee that developed while at work earlier in the day

• Denies any trauma • States that his left knee tends

to bleed spontaneously

Key PE Findings

Large joint effusion and pain with flexion

Dr. Melendez: Okay. And then the last case: a 24-year-old male with severe hemophilia A. He has a high-titer inhibitor, greater than 5 BU/mL. He receives emicizumab prophylaxis 1.5 mg/kg per week. He presents to the ED with pain and swelling in his left knee that developed spontaneously while at work earlier in the day. He denies any trauma and he says that his left knee tends to be the joint that he bleeds into. So on exam you just see a large joint effusion and he has pain with flexion.

Key Questions

• Should arthrocentesis be performed for diagnostic or therapeutic purposes? – Is imaging warranted?

• How does presence of inhibitors change the management approach for this patient? – Emicizumab-kxwh? – FVIII replacement? – Bypassing agents (FVIIa or aPCC)?

• Can this patient be discharged home after treatment?

Dr. Melendez: Question: Should arthrocentesis be performed for diagnostic or therapeutic purposes? No.

Dr. Miller: Don’t stick a needle into a bleeding joint.

Dr. Quon: No.

Dr. Melendez: Yeah. And this is the patient’s target joint. Is imaging warranted?

Dr. Miller: No.

Dr. Melendez: Correct; no spontaneous bleed, no trauma. And how does the presence of inhibitors change the management approach for this patient? So he has a high-titer inhibitor. What can we do in this patient?

23


Dr. Quon: You can’t use straight factor.

Dr. Melendez: That’s the big thing, yeah—straight factor. In some patients with a low amount of inhibitor, if you have to, you can give factor at higher doses than normal. But, in this patient, since they have a severe inhibitor level, it sounds like we have to use a bypassing agent.

And then, emicizumab. Can we use that for treatment? We kind of mentioned that, no, that’s more for prophylaxis.

Do we give factor VIII replacement? We just kind of mentioned that as well. He has a severe amount of inhibitor, so no.

And then a bypassing agent. Which one should we give? And then, after they get the treatment, can they be discharged home? I think that’s a key question for the hematologist.

Case 3: Management

• Hemarthrosis is usually clinically apparent – Imaging is not necessary if a patient presents with one

spontaneously, especially if it is in a target joint

• Sometimes higher doses of FVIII may be given to patients with low titer inhibitors; however, this patient’s titer is high—treatment with FVIII product will not be effective – Patient is on emicizumab-kxwh prophylaxis, which is not used

on-demand for the treatment of spontaneous or breakthrough bleeding episodes

– Treatment with rVIIa or aPCC is necessary

Dr. Melendez: So, like we said, imaging is not necessary. Factor replacement in this patient won’t be effective, and we can’t use the emicizumab. So in this patient, we either give the recombinant factor or the aPCC.

Case 3: Management (Cont’d)

Given the complexity of this patient’s case, you decide to consult with the patient’s hematologist

Patient states he was treated with rFVIIa for a prior breakthrough bleed in the same joint, but it required multiple infusions for the bleed to resolve

After a discussion with the patient and his hematologist, a shared decision is made to administer a single dose of aPCC at 75 units/kg; a compression bandage is also placed around the patient’s knee

The patient is observed in the ED for 2 hours and reports significant improvement in his swelling and pain; he is now able to bear weight and walk in the ED; he is discharged home with close follow-up and strict return precautions

Dr. Melendez: And the patient is a complex patient. Ideally, we should be able to try to get the factor in within an hour, but I think because this patient is a little bit more complex, this would be a great patient to touch base with the hematologist. And this patient was treated with recombinant factor in the past, but it required

multiple infusions. So this patient’s a little bit more difficult to manage. So with shared decision-making with the patient, with the hematologist, we give the activated prothrombin complex concentrate at 75 units/kg, a compression bandage is placed, and then the patient is actually observed in the ED for 2 hours. It wouldn’t be wrong to necessarily admit this patient if you don’t have the luxury of observing them in the ED, or if you just can’t. But if you can, you can observe them and then, if they’re better and they feel better and they have good follow-up, they could go home if they’re doing well.

• Treating patients with hemophilia and inhibitors can be difficult; it is recommended that the physician work closely with patient’s hematologist for treatment in the ED and for disposition (home vs hospital admission)

• It is important to avoid giving more than 200 units/kg/d of aPCC in patients with hemophilia and inhibitors, as there is a thrombotic risk to the patient

– Patients with hemophilia A and inhibitors on emicizumab-kxwh prophylaxis should be administered <100 units/kg/d aPCC, especially if more than one day of treatment is necessary

– Patients with hemophilia A without inhibitors on emicizumab-kxwh prophylaxis should be treated with a FVIII product for breakthrough bleeds


Dr. Melendez: So the key thing with this particular case: it’s difficult to manage some patients with inhibitors. So more than 200 units/kg/d of the prothrombin complex in patients with inhibitors can increase the risk for thrombosis. So ideally, you want to try to not go above that. And then, in those patients on emicizumab, who take it for prophylaxis, you want to stay less than 100 units/kg/d. And then, that’s basically it with this particular case.

Any more questions at all? Okay. They do have one.

Audience Member: If he hadn’t gotten better, would you have gone down the list? Maybe then give some aminocaproic acid or TXA? Is that how you would approach it?

Dr. Quon: I would wait maybe 6 hours, and if it’s not getting better, I might try to give a recombinant VIIa. We’d try to be careful not to give the TXA too close to the activated prothrombin complex concentrates.

Audience Member: Okay.

Dr. Quon: And, at this point, I would probably admit him and monitor him because of the TMA—the thrombotic microangiopathy—because then we could watch his D-dimers, and check his platelet count, and watch his renal function, to make sure we’re not getting into that area.

Audience Member: Sounds good.



Is there anything we could do to stabilize a patient who is going to need surgery after a long transport? Are there any medications,

knowing that there might be several hours before definitive care?

Audience Question

Audience Member: I work in a critical access hospital where sometimes a surgeon is several hours away and, let’s say with this certain other patient who you know is going to need surgery and a long transport, is there anything else that we could do to stabilize him? Any other medications, knowing that there might be a several-hour delay before he gets to definitive care?

Dr. Melendez: We frequently use aminocaproic acid. That can be given as an intravenous drip. You can load them with 4 g to 5 g and then do a continuous 1 g/hr drip. A lot of times that will work for a mucosal type of bleed, like GI bleeding.

The other one is tranexamic acid. Those are antifibrinolytic agents. Actually, I had a case like this not too long ago. We do have a couple of freestanding EDs that work with our hospital system; and it was 3:00 a.m. and I get a phone call from a colleague over at the freestanding. He had a patient there, a child who was somehow running around at 3:00 a.m. and hit his head. At that freestanding ED, they didn’t have any factor at all and mom didn’t have factor, so he had called me to see if we could get the patient over to get factor.

My question was: “Well, is it quicker for mom to get the factor—because I’m assuming she lives fairly close by—to go run and get it versus the transfer to us?” My question at that point was: “What would have happened if they were visiting and maybe they didn’t have any place close by? Was there anything that we could do prior to transport before they get to us to get the factor? Is there anything, or would there be something, that you could do?”

Dr. Quon: Generally, what we try to do is have the families, the children who have hemophilia or the patient who has hemophilia, to have an emergency dose at home, and if they’re nearby, we’d tell them to go home and get it because, ultimately, that would be

faster than trying to transfer because, even though the hospital may only be 10 or 20 minutes away, with the red tape there is oftentimes a delay. So, it might be faster to go home and get the factor. Sometimes, if you don’t have that and the transfer has to happen to a tertiary center, then for at least factor IX, you can give plasma or, for factor VIII, you can give cryoprecipitate to temporize it. It depends on how fast you’re going to get these products onboard. It really depends on the timing.

Is there any role whatsoever for tranexamic acid in hemophilia?

Audience Question

Audience Member: In this day and age—one of the golden boys—any role whatsoever for TXA in hemophilia? Tranexamic acid?

Dr. Melendez: Yes. We were talking about it as a secondary agent; like, you give the factor and you’re trying to do other things, you can give the tranexamic acid. A lot of times, actually, for surgeries they’ve been doing it. They show better outcomes with bleeding in patients using tranexamic acid, so we routinely use it for all of our orthopedic procedures.

Audience Member: I work in a fairly large place, but I do 2 or 3 shifts a month in a critical access hospital and you’d be amazed what shows up in a small out-of-the-way hospital.

Dr. Quon: Actually, these antifibrinolytic agents work very well for mucosal type of bleeding. So nose epistaxis, nosebleeds—that bleed that has been going on to bring them to the hospital, usually is about an hour of epistaxis—gum bleeding, so if you’ve had a dental extraction, GI bleeding, those are perfect roles for TXA.

Dr. Miller: And, what dose would we be doing for that? Is it like the normal dose?

Dr. Quon: At least for aminocaproic acid, it’s the loading dose of 4 g and then 1 g/hr. And, there were some other questions.

Audience Q&A

Sarah Luisa Melendez, MDDoris Quon, MD, PhDKrystin Miller, MD

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Do women get hemophilia? Does menstrual bleeding require treatment?

Audience Question

Dr. Miller: Oh, yes, sure. It looks like one of the questions was, “Do women get hemophilia and does menstrual bleeding require treatment?”

Dr. Melendez: Women, they can be low-level carriers. If a woman came in saying she had hemophilia, they can truly have hemophilia and have two X chromosomes that are affected. And I know a couple women who have severe hemophilia and they’ve inherited from mom and dad the X chromosomes. So, yes, women can have it, but more commonly women carriers can have low levels.

So, 50% would be the average, but there’s this X chromosome inactivation; and you can get more of the normal X chromosome inactivated so that these carrier women show up with factor VIII or factor IX levels that are in 10%, 15%. So they can truly, by definition, have hemophilia that is less than 40% factor VIII or IX levels, and they need to be treated as if they have hemophilia and get factor replacement.

Does menstrual bleeding require treatment? I think it depends on the woman because, if the woman is bleeding and having to change every hour, I think she should be treated. You can’t go out of the house. It’s very embarrassing and the social stigma, things like that. I think that, especially for teenage girls, this is a big problem and it should actually be treated. TXA is actually a perfect example where this would be very useful. Sometimes we can use, in these mild women, DDAVP, desmopressin acetate, at high doses. It comes in a nasal spray. You talk to the hematologist at a treatment center or their private hematologist; these are all treatments that are available for women and menstrual bleeding.

If a patient is altered, how can a treating doctor figure out if they have inhibitors?

Audience Question

Dr. Melendez: I think this one is a good one. “If a patient is altered, how can a treating doctor figure out if they have inhibitors?” That’s a pretty common complaint if they are in trauma or just altered in general.

Dr. Miller: I think this is a challenge.

Dr. Melendez: Yeah, this is a real challenge.

Dr. Miller: This is a challenge for any patient that comes in altered and you have no medical history. But I think a couple of things, at least in our health system. As all of our patients that do have hemophilia have treatment plans that are on their problem list, a lot of times these patients will have cards from their hematologist with their plan, and if they have inhibitors and things. So checking wallets for any of those cards, just like you would for other forms of identification; trying to get as much information from the scene and medics as you can in terms of, is there family coming, is there a way to contact family, and making some of those phone calls. Because, certainly, family might not know, but the family might know where they get their treatment; they might know who their hematologist is. And so just relying on those other resources like you would. If you truly have no information, I think you have to assume that they don’t have inhibitors and you give them factor and go from there.

Dr. Melendez: I think the difficulty is then, if they’re on the emicizumab, they’re unconscious, and you can’t check a factor level. That, I think, is sort of a problem.

Dr. Miller: Sure.

Dr. Quon: But, checking for the wallet, IDs—almost every hemophilia treatment center sends the patients out with a wallet ID with the diagnosis and a quick treatment plan, either factor VIII, factor IX or bypassing agent, on that card of what their treatment is.



Can you speak to fitusiran and thrombotic events?

Audience Question

Dr. Quon: A specific question on fitusiran and thrombotic events. Yes. Fitusiran is the antithrombin III. Fitusiran decreases your antithrombin III level so that you’re rebalancing the coagulation system. The difficulty is, as many of you may know, antithrombin III deficiency does result in clotting and, yes, there was a reported fatal case during the clinical trial where the patient did have a thrombotic event. They did make new guidelines on how to manage these patients if a clot should occur.

Dr. Melendez: And then, I did see one more about national drug shortages and how it’s affecting the treatment.

Dr. Quon: No, because there are so many different drugs on the market right now for hemophilia. There are actually, for hemophilia A, 12 different recombinant products, and so, currently, there is no shortage. And, for hemophilia B, there are approximately six recombinant products, and that doesn’t even include the plasma-derived products that are currently on the market.

Dr. Melendez: Well, thank you so much everyone.

Dr. Quon: Yes. Thank you. Thank you for your attention.

Narrator: This activity has been jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

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

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Based on a panel discussion and on data from recent medical literature. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or supporters.

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