Lifelines for Health - The MOTIVATE Trial: The New Era of Immune Tolerance Induction

Fall/Winter 2021 I Volume 18

A CHES Publication

MOTIVATE The New Era of IMMUNE TOLERANCE INDUCTION From Joint Health: To Bone Health l Down the Vascular Pipeline Feeling Burned Out From COVID? You Are Not Alone! l Self-Care is Self-Love l And more!

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Letter From the Editors Welcome!

Have you seen the meme with a picture of beautifully colored leaves and the caption, “the trees are about to show us how lovely it is to let go”? The last two years has felt like a lesson in letting go, adjusting expectations, and embracing change. For some, it is easier than others.

If there is one thing that living with a chronic condition has taught all of us is that things seldom go the way we have planned! Like everyone else, we started the spring hopeful that we could transition back to live programming, with many precautions and modifications. Alas, it was not meant to be, and we make the best of the virtual world that just isn’t the same. We know one thing that is for certain WE MISS YOU! CHES continues to partner with the nSpiration Foundation, a 501 c 3 non-profit with a mission to provide education, support, and access to people with chronic conditions. Would you consider donating to nSpiration in your year-long giving plan to provide much needed funds for travel scholarships and hardship funds for many in our community? https://nspiration-foundation

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As always, we hope you enjoy this issue of LifeLines for Health. We are excited to share information from Dr. Robert Sidonio, coordinating investigator for the MOTIVATE trial that seeks to capture different approaches used for the management of patients with hemophilia A and inhibitors.

Dr. Joanna Davis writes about the emerging trend to take a closer look at bone health-not just joint health for those with bleeding disordersespecially hemophilia A and vWD. There is still much we do not know about the function of FVIII in the body. Check out what new therapies and companies are developing for the community. It is encouraging to see that the quest for new and innovative treatments never stops. Are you struggling with the constant uncertainty that COVID brings? You aren’t the only one-Dr. Gary McClain has some suggestions. How do you feel about the concept of self-love? Does it feel selfish to you? Are you able to embrace some self-care strategies during these stressful times to refill your emotional fuel tank?

Emily Taylor has some suggestions-and they are as easy as breathing!

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LifeLines for HealthSM Disclaimers The views and opinions of our writers are not a reflection of Comprehensive Health Education ServicesTM, Inc. (CHES) or its sponsors.

Be sure to check out our website at www.ches. education, like us on Facebook, and follow us on Instagram to stay apprised of how to keep up to date and connected to programs. If you have an idea, comment or suggestion, don’t hesitate to let us know at info@ches.education. We love to hear from you!

This newsletter is designed to provide a forum for community members to express their views from an open and honest platform. It is meant to provide a sharing of knowledge and experience to help one another. Nothing in this newsletter is meant to replace the advice of your HTC, medical professional team or insurance provider. You are always urged to seek the opinion of a healthcare professional for treatment and your specific insurance provider for information.

May the upcoming holiday season bring you closer to the things that truly matter in your life. Take the time the winter months provide us to rest and rejuvenate. Be safe, be well and we look forward to seeing you as soon as we can.

- Janet Brewer & Eric Lowe

We take your privacy very seriously. We would never disclose your personal health information without your express written consent. We would never sell nor make available our secure database to anyone.

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“I wanted a perfect ending. Now I’ve learned, the hard way, that some poems don’t rhyme, and some stories don’t have a clear beginning, middle, and end. Life is about not knowing, having to change, taking the moment, and making the best of it, without knowing what’s going to happen next.

Delicious Ambiguity. ”

Articles and pictures may not be reproduced, published, and/or placed on websites without the express written permission of CHES. In every publication of LifeLines for HealthSM, we will provide links to other websites that are not owned or controlled by CHES or its sponsors. We cannot be responsible for privacy practices of other website owners, nor can we be responsible for the accuracy of the information provided.

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— Gilda Radner 1

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Integrity, Accuracy, Empathy...

FEATURE

7 I The MOTIVATE Trial: The New Era of Immune Tolerance Induction

Immune Tolerance Induction (ITI/ITT - a treatment to eradicate inhibitors, or halt the body's tendency to reject factor replacement) began in the 80's with little change to its methods today. Dr. Robert Sidonio, Jr. (Emory University - Atlanta) is looking to change that as co-investigator of the MOTIVATE trial, which seeks out improved regimens by including study groups on the available medications including factor, non-factor, and bypassing agents.

CONTENTS COMMUNITY CHATTER 6 I Remembering Cyrus Pavri The Pavris have become a cherished family of our inhibitor camps for many years. Sadly, beloved father and husband, Cyrus unexpectedly passed this December. Our hearts go out to the family...

FAMILY MATTERS 21 I Feeling Burned Out From COVID? You Are Not Alone!

COVID seems to be on the downswing from a year ago - and especially since its inception. But that doesn't mean COVID hasn't taken its toll of us. Many people still feel stressed, anxious, exhausted, etc. It could be a little thing called Burnout.

Dr. Gary McClain explains just how burnout works followed by some coping and prevention methods.

WHAT’S NEW 17 I From Joint Health: To Bone Health For decades, the bleeding disorder community has been submerged in cautionary advice for good joint health through live sessions, reading materials, medical care teams, and even their own peers through a trade of war stories. Today, joint health still remains a priority, but as treatments evolve, so shall our awareness - this time, to BONE health as density becomes a rising concern.

BLOODLINES 29 I Down the Vascular Pipeline New medications are always developing in the pipeline and (sadly) some go. Updating yourself on both are equally important. Take a quick look to avoid any bad surprises and perhaps you'll find some pleasant ones along the way!

MIND BODY CONNECTION 31 I Self-Care is Self-Love What is self-care? Most cannot easily define it. Self-care can be better understood through exercises, rituals, and other methods as described in a self-care menu carefully comprised by yoga teacher and international retreat leader, Emily Taylor.

CONTENTS

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Education Programs Virtual programming We'd like to thank all who attend our spring webinar series concentrating on the needs of the bleeding disorder community.

To receive info on additional upcoming programs and webinars visit: https://ches.education or https://nspiration.foundation

Comprehensive Health Education Services has been serving the needs of

Tentative dates for LIVE 2022 programs are as follows: June 24-27, 2022 Camp Zeke - Lakewood, PA

July 22-24, 2022 Location: Michigan

October 14-16, 2022 Location: Michigan

and

those with rare bleeding conditions since 2009.

As long time members of the bleeding disorder community, our mission is to inspire awareness and self-reliance for patients with chronic health conditions, their families, and their communities.

More details on our programs can be found on our website: www.ches.education

Challenges have a way of bringing new opportunities

and we are excited by CHES' continued partnership with the Cold Agglutinin Disease Foundation (CADF) for their virtual conference that began January 2022.

Cold A-what you ask?

Cold Agglutinin is a rare blood disorder that causes hemolysis. Hemolysis is when healthy red blood cells are mistakenly destroyed by the body causing symptoms such as anemia, shortness of breath and bluish discoloration of the hands and feet. Cold temperatures can trigger symptoms, including air conditioning.

Think you may know someone with CAD or want to know more about it? Check out the CADF website at https://coldagglutinindisease.org/. We are thrilled to partner with this amazing group of individuals to assist in their mission to provide education and support for those managing CAD.

MY DECIDING FACTOR: Making time for what matters most.

As an adult living with von Willebrand disease (VWD), you may share a bleeding disorder with others, but you have your own life, and your own needs. You may also have your own Deciding Factor—something that drives you to talk to your healthcare provider about finding a treatment that’s right for you. For Erica, it was that her frequent bleeding episodes were taking time away from things that mattered most to her. She talked with her healthcare provider, and together they decided that VONVENDI ® [von Willebrand (Recombinant)] was right for Erica’s VWD.

VONVENDI • Is used in adults (age 18 and older) diagnosed with VWD to treat and control bleeding episodes and prevent excessive bleeding during and after surgery Erica Surprise, AZ Diagnosed with VWD in 1981

Are you ready to ask about VONVENDI for your VWD? Visit VONVENDI.com to learn more.

• Is the first and only recombinant von Willebrand factor (VWF), meaning it is manufactured without human plasma or blood

• May be used with or without a recombinant factor VIII (rFVIII), as instructed by your healthcare provider VONVENDI Important Risk Information Who should not use VONVENDI? You should not use VONVENDI if you: • Are allergic to any ingredients in VONVENDI. • Are allergic to mice or hamsters.

Tell your healthcare provider if you are pregnant or breastfeeding because VONVENDI may not be right for you.

Please see additional Important Risk Information below.

Important Risk Information (continued) How should I use VONVENDI? Your first dose of VONVENDI for each bleeding episode may be administered with a recombinant factor VIII as instructed by your healthcare provider.

Your healthcare provider will instruct you whether additional doses of VONVENDI with or without recombinant factor VIII are needed.

What should I tell my healthcare provider before I use VONVENDI? You should tell your healthcare provider if you: • Have or have had any medical problems.

• Take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements or herbal remedies.

• Have any allergies, including allergies to mice or hamsters.

• Are breastfeeding. It is not known if VONVENDI passes into your milk and if it can harm your baby.

• Are pregnant or planning to become pregnant. It is not known if VONVENDI can harm your unborn baby.

• Have been told that you have inhibitors to von Willebrand factor (because VONVENDI may not work for you).

• Have been told that you have inhibitors to blood coagulation factor VIII. What else should I know about VONVENDI and von Willebrand disease?

Your body can form inhibitors to von Willebrand factor or factor VIII. An inhibitor is part of the body’s normal defense system. If you form inhibitors, it may stop VONVENDI or factor VIII from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to von Willebrand factor or factor VIII. What are the possible side effects of VONVENDI? You can have an allergic reaction to VONVENDI. Call your healthcare provider right away and stop treatment if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea or fainting.

Side effects that have been reported with VONVENDI include: nausea, vomiting, tingling or burning at infusion site, chest discomfort, dizziness, hot flashes, itching, high blood pressure, muscle twitching, unusual taste, blood clots and increased heart rate.

Tell your healthcare provider about any side effects that bother you or do not go away.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see VONVENDI Consumer Brief Summary on the following page and talk to your healthcare provider.

What is VONVENDI?

® Important facts about VONVENDI : VONVENDI is a recombinant medicine used to replace low levels

What are the possible side effects of VONVENDI?

Side effects that have been reported with VONVENDI This summarizes important information about VONVENDI. Please or notleaflet properly working von Willebrand factor in people with von include: nausea, vomiting, tingling or burning at infusion site, Willebrand disease.

Von Willebrand disease is an inherited chest read it carefully before using this medicine. This information does not discomfort, dizziness, hot flashes, itching, high blood bleeding which with bloodyour doeshealthcare not clot normally. pressure, muscle twitching, unusual taste, blood clots and take the disorder place ofintalking provider. increased heart rate. These are not all the possible side effects VONVENDI is used in adults (age 18 years and older) with VONVENDI. You can ask your healthcare provider for diagnosed with von Willebrand disease to: information that is written for healthcare professionals.

• Treatisand control bleeding episodes What VONVENDI? What are the possible side effects ofeffects VONVENDI? Tell your healthcare provider about any side that bother •VONVENDI Prevent excessive bleeding during and after surgery is a recombinant medicine used to replace low levels Side or effects that been reported with VONVENDI you do not gohave away. or not properly working von Willebrand factor in people with von include: nausea, vomiting, tingling or burning at infusion site, Who should notVon useWillebrand VONVENDI? Willebrand disease. disease is an inherited chest dizziness, hotabout flashes,VONVENDI itching, high and blood Whatdiscomfort, else should I know bleeding disorder in which blood ifdoes pressure, muscle twitching, unusual taste, blood clots and You should not use VONVENDI you:not clot normally. von Willebrand increased heart rate.Disease?

These are not all the possible side effects is used adults (age in 18VONVENDI. years and older) •VONVENDI Are allergic to anyiningredients Consult with yourYou healthcare to make provider sure you for are with VONVENDI. can askprovider your healthcare diagnosed with von Willebrand disease to: • Are allergic to mice or hamsters. levels of von carefully monitored with blood tests to measure information that is written for healthcare professionals.

• Treat control bleeding Willebrand factor andprovider factor VIII so they for you.

Tell yourand healthcare provider ifepisodes you are pregnant or Tell your healthcare about any are sideright effects that bother • Prevent excessive bleeding during andnot after breastfeeding because VONVENDI may besurgery right for you.

You or may at a hemophilia treatment center you doinfuse not goVONVENDI away.

(HTC), at your healthcare provider’s office or in your home.

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• Are tohad mice ormedical hamsters. levels of von carefully bloodright testsaway to measure Haveallergic or have any problems.

Call yourmonitored healthcarewith provider if your bleeding does Willebrand factor andVONVENDI. factor VIII so they are right for you.

Tell yourany healthcare provider if you are pregnant • Take medicines, including prescription andor not stop after taking breastfeeding because VONVENDI not be right for you.

You may infuse VONVENDI at a hemophilia treatment non-prescription medicines, suchmay as over-the-counter Medicines are sometimes prescribed for purposes othercenter than (HTC), at your healthcare provider’s office or in your home. medicines, supplements or herbal remedies. those listed here. Do not use VONVENDI for a condition for You should beprescribed. trained on Do how toshare do infusions by your What I tell including my healthcare • Haveshould any allergies, allergies provider to mice or before hamsters. which it is not not VONVENDI with other healthcare provider or HTC. Many symptoms people with von Willebrand I• use people, even if they have the same that you have.

Are VONVENDI? breastfeeding. It is not known if VONVENDI passes into disease learn to infuse VONVENDI by themselves or with the You should healthcare provider your milktell andyour if it can harm your baby.if you: help of a family member.

The risk information provided here is not comprehensive. To • Have or have or hadplanning any medical problems.

Are pregnant to become pregnant. It is not Call your healthcare right away if your bleeding does learn more, talk withprovider your healthcare provider or pharmacist if VONVENDI can harmprescription your unbornand baby.

• known Take any medicines, including not stop after taking about Vonvendi.

TheVONVENDI. FDA approved product labeling can be medicines, as over-the-counter • non-prescription Have been told that you havesuch inhibitors to von Willebrand Medicines are sometimes prescribed for purposes other than found at https:\\www.shirecontent.com/ PI/PDFs/ medicines, supplements or herbal remedies. factor (because VONVENDI may not work for you). those listed here. Do not useor VONVENDI for a condition for VONVENDI_USA_ENG.pdf call 1-800-828-2088.

• Have any to to mice or hamsters. beenallergies, told thatincluding you haveallergies inhibitors blood which it is not prescribed.

Do not share VONVENDI with other You are encouraged to report negative side effects coagulation factor ItVIII. people, even if they have the same symptoms that you have.

• Are breastfeeding. is not known if VONVENDI passes into of prescription drugs to the FDA. Visit your milk and if it can harm your baby. www.fda.gov/medwatch, or call 1-800-FDA-1088.

The risk information provided here is not comprehensive. To What is the most important information • Are pregnant or planning to become pregnant. IItneed is not to learn more, talkTakeda with your healthcareCompany providerLimited. or pharmacist know about VONVENDI? known if VONVENDI can harm your unborn baby.

Copyright ©2019 Pharmaceutical 300 about Vonvendi.

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VONVENDI can cause blood clots particularly in patients with • Have been told that you have inhibitors to von Willebrand found https:\\www.shirecontent.com/ PI/PDFs/ All rightsatreserved. with your known factors VONVENDI for blood clots. this factorrisk (because mayDiscuss not work forrisk you).

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• Have been told that you have inhibitors to blood TAKEDA and the TAKEDA logo are negative trademarksside or registered You are encouraged to report effects tradeYou can have allergic reactions to VONVENDI. Symptoms may coagulation factor VIII. marks of Takeda Pharmaceutical Company Limited. of prescription drugs to the FDA. Visit include generalized itching; rash or hives; rapid swelling of the VONVENDI is a registered trademark Baxalta Incorporated, www.fda.gov/medwatch, or call of 1-800-FDA-1088. skin or mucous membranes; chest pain or tightness; tightness

What is the most important information I need to of the throat; low blood pressure; shock; drowsiness; nausea; know about VONVENDI? vomiting; tingling, prickling, burning, or numbness of the skin;

VONVENDI cause blood particularly in patients with restlessness;can wheezing and/orclots difficulty breathing; known risk factors for blood clots.

Discuss this risk with your lightheadedness; dizziness; or fainting. If symptoms occur, healthcare provider. immediately and get emergency stop using VONVENDI treatment rightallergic away. reactions to VONVENDI. Symptoms may You can have include generalized itching; rash or hives; rapidfactor swelling of the Your body can form inhibitors to von Willebrand or factor skin An or inhibitor mucous is membranes; chest pain or tightness; tightness VIII. part of the body’s normal defense system. ofyou the form throat; low blood drowsiness; If inhibitors, theypressure; may stopshock; VONVENDI or FVIIInausea; from vomiting; tingling, prickling, burning, or numbness of the working properly. Consult with your healthcare provider to skin; make restlessness; wheezing and/or difficulty breathing; sure you are carefully monitored with blood tests for the lightheadedness; dizziness; fainting.

If symptoms development of inhibitors to or von Willebrand factor or occur, factor VIII. stop using VONVENDI immediately and get emergency treatment right away.

Your body can form inhibitors to von Willebrand factor or factor VIII. An inhibitor is part of the body’s normal defense system.

If you form inhibitors, they may stop VONVENDI or FVIII from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to von Willebrand factor or factor VIII.

a Takeda company.

Copyright ©2019 Takeda Pharmaceutical Company Limited. 300 Issued 02/2019 Shire Way, Lexington, MA 02421. 1-800-828-2088.

S48947 All rights 06/19 reserved.

TAKEDA and the TAKEDA logo are trademarks or registered trademarks of Takeda Pharmaceutical Company Limited.

VONVENDI is a registered trademark of Baxalta Incorporated, a Takeda company.

Issued 02/2019 S48947 06/19

Copyright ©2020 Takeda Pharmaceutical Company Limited.

300 Shire Way, Lexington, MA 02421. 1-800-828-2088. All rights reserved. TAKEDA and the TAKEDA logo are trademarks or registered trademarks of Takeda Pharmaceutical Company Limited. VONVENDI is a registered trademark of Baxalta Incorporated, a Takeda company.

US-VON-0055v1.0 05/20

Remembering...

Cyrus Pavri

I

t is with a heavy heart that we share with our inhibitor community the passing of Cyrus Pavri on December 4, 2021. The beloved husband of Yasmin, devoted father to Farah and Porus. The Pavris are kind, generous, dedicated members of our camp family. We came to know them through Inhibitor Summits offered by NHF, and grew to love them more as we shared time together at After the Shock: an Inhibitor Family Camp at Camp Zeke in Lakewood, PA. Cyrus will be deeply missed and our hearts and prayers remain with Yasmin, Farah and Porus.

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e n u m Im f o a r E w e The N Tolerance Induction

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By: Robert Sidonio, Jr.

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emophilia A is caused by defective or deficient coagulation factor VIII. Severity is based on the baseline FVIII level <1% (severe), 1-5% (moderate) and >5-50% (mild). Patients with severe hemophilia A are at risk for recurrent bleeding episodes including but limited to joint bleeding. Despite all the technologic improvements in manufacturing and modifications of FVIII, inhibitor development continues to be the biggest challenge in the care of hemophilia A.

Inhibitors, which develop in approximately 35% of severe haemophilia A patients, prevent the effective use of FVIII replacement therapy (the cornerstone of haemophilia A treatment) and restrict patients to less consistent and less effective bypassing agents for the treatment of bleeds or surgical coverage. Although the bispecific monoclonal antibody emicizumab (EMI) is highly effective for bleed prevention in patients with inhibitors, neither emicizumab nor bypassing agents can eradicate inhibitors. While current expert opinion and most national haemophilia organizations maintains that eradicating inhibitors by immune tolerance induction (ITI) remains an important goal, the evolving treatment options call for greater understanding of how treatment choice impacts inhibitor patient outcomes.

FEATURE

In 1977 (I was a year old at the time), the first described patient with hemophilia A and an inhibitor was tolerized utilizing a protocol that Dr. Brackmann developed in Bonn Germany. The concept was simple but nevertheless elegant. The plan was to give repeated high dose exposure to FVIII to exhaust the immune system and allowing the body to accept FVIII without developing further antibodies against it Nearly 40 years later it remains the only effective strategy for inhibitor eradication.

I recall meeting Dr. Brackmann and boldy (I know it is hard to believe) telling him that ITI in its current form is dead. After a nice discussion, we concluded - we must evolve how we eradicate inhibitors.

we must evolve how we eradicate inhibitors.

Figure 1. Immune tolerance strategies available in 2021 including novel strategies modifications under investigation.

Standard ITI Strategies

Figure 1.

Bonn protocol: high-dose regimen (FVIII 100-150 IU/kg every 12 hours until ,1BU, then FVIII 150 IU/kg)

•

Malmo protocol: high-dose regimen (FVIII continuous infusion targeting plasma levels >30 IU/dL until negative titer, then 60-90 IU/kg weekly + cyclophosphamide + IV immunoglobulin)

•

van Creveld protocol: low-dose regimen (neutralizing, then tolerizing dose)

•

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ITI combined with prophylactic emicizumab • Low dose protocol (25-50 IU FVIII/kg 3 x weekly) + emicizumab weekly • Atlanta protocol (100 IU FVIII/kg 3 x weekly) + emicizumab weekly •

Bonn protocol (100-200 IU FVIII/kg 1 x day) + emicizumab weekly

Since the advent of this ITI regimen, there have been only minor adjustments in the approach to ITI and still today there are many unresolved issues regarding ITI. First, is there a reason to consider ITI now with emicizumab prophylaxis available in most resource rich countries which is effective at mitigating bleeding regardless of inhibitor status? Second is, what is the role of von Willebrand factor (VWF) containing concentrates in ITI? Third, is how do we measure ITI futility and how do we define tolerance in the post-emicizumab era? In 2021 is there a role for ITI in the patient with hemophilia A with an inhibitor? Because emicizumab is the only available non-factor therapy available for clinical use we will focus on how it has changed the way we think about ITI and potentially obviates the need for inhibitor eradication.

As aforementioned it has become abundantly clear that the way we perform ITI must change in the upcoming decades. The pre-emicizumab ITI standard of care often required the use of a central line, daily to every other day high volume FVIII infusions, bypassing agent prophylaxis or BPA (either rFVIIa or aPCC) prophylaxis which puts a tremendous amount of burden on the family and patient. In the past 40 years, there have been multiple variations of ITI with three strategies remaining as the most widely utilized.

They can be categorized by dose intensity or more traditionally they can be categorized by the city in which it was developed (see figure 1).

Bonn protocol The most widely used in Europe is the Bonn protocol with a starting FVIII ITI dose of 100-150 IU/kg/dose twice a day until one achieves a <1 BU/mL titer then reduced to 150 IU/kg/dose daily weaning over the subsequent 1-2 years.

van Creveld protocol The van Creveld protocol is a lower dose FVIII ITI protocol in which FVIII is given 25-50 IU/kg/dose every other day or three times a week. The success rates for both protocols are similar at >70% and verified in the international ITI study.

Malmo protocol

The third strategy called the Malmo protocol is no longer widely used because of concern for lack of longterm durability of response and need for long-term hospitalization. The Malmo protocol required a protein A adsorption if titer >10 BU/mL followed by continuous FVIII infusion for up to 2 weeks to achieve recovery >30% and given with concomitant Cyclophoshamide (immunosuppressant) orally from day following an IV infusion and IVIG. I am only aware of one center in the US that continues to consider this protocol. It is no longer considered the standard of care and I strongly advise against its use with so many other options available.

FEATURE

Back in 2019 our research group developed a novel way to eradicate inhibitors (see figure 2). The concept was simple; Continue emicizumab prophylaxis and modify FVIII exposure to tolerize or eradicate the inhibitor. We felt that since FVIII and emicizumab were not synergistic in a bleed control manner and would not lead to a very high level of thrombin generation we could combine the regimens safely. With the Atlanta protocol, emicizumab prophylaxis is given every week, biweekly or monthly as per label and FVIII given at 50100 IU/kg/dose three times a week. The product choice (class and VWF containing amount) is up to the provider and patient with no evidence of a benefit with one product type over the

other. The first implementation of this protocol was conducted in a single center (our center) in seven hemophilia A patients with inhibitors, all demonstrating significant reduction of their inhibitor titer without any thrombotic or thrombotic microangiopathy (TMA) events. This new approach is called the Atlanta protocol and is under investigation with 2 clinical trials, The Emi PUPs (previously untreated patients) and Nuwiq ITI study (NCT04030052) and the MOTIVATE study.

Part B of the former study is evaluating Nuwiq 100 IU/kg/ dose three times a week for 12 months while on emicizumab prophylaxis and is currently open only in the United States.

Figure 2.

ITI

Immune Tolerance Induction ITI alone (with the human cell line-derived recombinant FVIII Nuwiq® or the plasma-derived FVIII products Octanate® or Wilate®)

Atlanta

PROTOCOL EMI

Emicizumab Loading Dose - 3 mg/kg SC weekly × 4 weeks Maintenance Dose (one of the following) - 1.5 mg/kg SC weekly - 3 mg/kg SC every 2 wk - 6 mg/kg SC every 4 wks

Figure 2. The Atlanta protocol combines emicizumab prophylaxis (loading phase followed by the maintenance phase) and high dose FVIII, typically 50-100 IU/kg/dose 3 times a week.

The international, investigator-initiated MOTIVATE study and Director of Clinical Operations at the Hemophilia of (see figures 3a/b) is collecting real-world clinical data on Georgia Center for Bleeding and Clotting Disorders, Children's the efficacy and safety of different approaches to managing Healthcare of Atlanta, Emory University, Atlanta, Georgia, haemophilia A patients with factor VIII (FVIII) inhibitors. US. MOTIVATE is registered as a non-interventional study in the US (NCT04023019) and as a MOTIVATE includes the following three treatment groups: low-interventional, pragmatic trial in Europe • ITI alone (with the human cell line-derived recombinant FVIII Nuwiq® (EudraCT No. 2019-003427-38). MOTIVATE or the plasma-derived FVIII products Octanate® or Wilate®) is led by two coordinating investigators, Dr Carmen Escuriola Ettingshausen, Director • ITI (with Nuwiq®, Octanate® or Wilate®) combined with of the Hämophilie-Zentrum Rhein Main in emicizumab prophylaxis Mörfelden-Walldorf, Germany, and Dr Robert • Non-ITI regimens: Routine prophylaxis with (1) emicizumab, (2) Sidonio Jr, Associate Professor of Pediatrics activated prothrombin complex concentrate [aPCC] or (3) rFVIIa

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Figure 3A. The MOTIVATE study is a non-interventional study in the United States, Canada, Asia and South America and a low interventional pragmatic study focused on evaluating the safety and efficacy of the Atlanta protocol compared to standard ITI and emicizumab prophylaxis. The study is sponsored by Octapharma and is registered on www.clinicaltrials. gov.

Figure 3.A

Legend Evaluated for...

Bleeeding

MOTIVATE

Treatment Groups

ITI Success Criteria 1

FVIII inhibitor titre < 0.6 BU/ml

2

FVIII recovery > 66% of normal

3

FVIII half-life > 6 h

Overall response

Definitions of ITI Success Complete success: All 3 criteria met Partial success: 2 of 3 criteria met Partial response: 1 of 3 criteria met

GROUP 1

GROUP 3 ITI with either Nuwiq®, Octanate®, or Wilate®

GROUP 2

ITI with either Nuwiq®, Octanate®, or Wilate® and emicizumab prophylaxis

Routine prophylaxis with emicizumab, aPCC, or rFVIIa with ITI

Figure 3B. The MOTIVATE study is led by Drs. Carmen Escuriola-Ettingshausen from Germany and Robert Sidonio, Jr. from the United States at Emory University and Children’s Healthcare of Atlanta. The study design allows observational evaluation over a max of 5 years.

FEATURE

Figure 3b.

Study Design Investigator-Initiated, international, multicentre, prospective* study Patients of any age with inhibitors, with or without previous unsuccessful ITI attempts Treatment at the discretion of the investigator according to routine clinical practice Follow-up: Max. 5 years

Patients from all groups are permitted to receive bypassing agents (aPCC or rFVIIa) if required for treatment of bleeding episodes or during surgery.

Patients are followed for up to five years and may switch to another treatment group if their treatment is changed by their physician. MOTIVATE aims to enroll 120 patients of any age and with haemophilia of any severity who have developed inhibitors to any FVIII product. MOTIVATE is supported by funding from Octapharma AG (Lachen, Switzerland).

The obvious question is why should one consider ITI? Firstly, the hemostatic response to bypassing agents is less consistent and predictable and the management of surgery is more complicated particularly in mitigating the risk of thrombosis. Secondly, I personally do not think it is a good idea to rely on a single therapy for prolonged period of time. When you make the decision to not consider tolerizing, you have limited your options to one effective therapy, emicizumab. Of course, again this option is highly efficacious but it may be 2 years before another nonfactor therapy option is FDA approved.

It is reasonable to not consider the Atlanta protocol if you have failed ITI multiple times prior to emicizumab and have a very high titer inhibitor (>500 BU/ml). The Atlanta protocol may not be a reasonable option. However, if you have a relatively manageable inhibitor titer (<100 BU/mL) it is worthwhile

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Overall Objectives To capture different approaches to the treatment and management of people with haemophilia A and inhibitors To document current ITI approaches To evaluate efficacy and safety of ITI, emicizumab prophylaxis, and ITI with emicizumab prophylaxis

to consider one attempt with the Atlanta protocol. Thirdly, future novel therapies such as AAV gene therapy or ex vivo gene therapy will not likely be options available to those with existing inhibitors thus limiting your option to future therapies. It is certainly a personal decision to consider ITI and specifically, the Atlanta protocol, but one you should consider with each visit to your local Hemophilia treatment center.

One of the challenges that remains if you have successfully undergone ITI using the Atlanta protocol is what to do once you have achieved tolerance as measured by a negative inhibitor titer, normalization of recovery and half-life.

This is evolving and we have proposed a strategy of a slow wean off FVIII with careful evaluation of kinetic studies (half-life and recovery) with every wean (see figure 4). Typically, we start with three times a week weaning next to twice a week, once a week, once every other week and then off typically over 12-15 months. At this point you as the patient now have the choice to choose FVIII prophylaxis or emicizumab prophylaxis.

Whether the Atlanta protocol strategy will be fully embraced is yet to be determined but there is a strong sense of staying the course regarding attempting to tolerize every hemophilia A patient with an inhibitor. The benefit of return to use of a FVIII for bleed control and use in surgery is one major

Fall/Winter 2021

benefit, offering a choice in therapy (FVIII versus emicizumab prophylaxis) and having more options for evolving therapies such as gene therapy which soon will be approved. If it is feasible since hemophilia A with inhibitors is a relatively rare condition I hope you consider participation in a clinical trial or observational study so we can learn whether our strategy should be considered the standard of care in the near future. Either way we will continue to advocate for the hemophilia patient community and allow freedom in treatment choice.

Additional resources:

https://www.motivatestudy.com/

https://pubmed.ncbi. nlm.nih.gov/33733033/

Figure 4. Proposed algorithm following meeting successful ITI tolerance criteria. Once a patient has achieved tolerance a wean off FVIII should be done slowly likely over 12-15 months to ensure no return of the inhibitor. The goal is to stop FVIII post ITI prophylaxis and at this point consideration of FVIII prophylaxis alone or emicizumab prophylaxis can be made.

Figure 4.

Wean no more than every 3 months and verify titer, recovery and half-life

After achieving tolerance, consider post ITI maintenance

FVIII 50 IU/kg 2x/wk

Success

ITI outcome assessment at month 18 or 33

FVIII 50 IU/kg 1x/wk

Post ITI tolerance

FVIII 50 IU/kg 2x/month

Emicizumab alone, continue to monitor for inhibitor recurrence every 12 months after verifying negative 3 months x 1

Partial response

*Always verify inhibitor status with 72 hour washout

Failure

emicizumab

Monitor inhibitor titer every 6 months & after surgery or significant BPA or FVIII exposure

Robert F. Sidonio, Jr. MD, MSc. graduated from UAB medical school, completed his pediatric residency at the University of Louisville and completed his fellowship at the University of Pittsburgh where he also obtained his Masters in Clinical Investigation. Dr. Sidonio has been the Associate Director of Hemostasis and Thrombosis at Emory University since 2014. Dr. Sidonio’s clinical and research interest is in investigating the bleeding phenotype and genotype of women with hemophilia carriage and low VWF. He is also the co-creator of the Atlanta Protocol which combines Emicizumab and FVIII for ITI. He is the co-PI of the HOG VWD project focused on characterization of children with low VWF in Georgia. He is also the PI for the Emicizumab PUP and Nuwiq ITI trial, MOTIVATE study, ATHN 9 study (severe VWD).

FEATURE

Exploring the science behind gene therapy research Gene therapy research has the potential to bring an entirely new option to people with specific genetic conditions.

Many gene therapies are in clinical trials to evaluate the possible risks and benefits for a range of conditions, including hemophilia. HemDifferently is here with gene therapy education, providing accurate information on the basics and beyond.

What questions do you have? Get them answered.

Explore gene therapy at HemDifferently.com.

No gene therapies for hemophilia have been approved for use or determined to be safe or effective.

©2020 BioMarin Pharmaceutical Inc. All Rights Reserved. MMRC-GTH-0217 3/20

THE 5 STEPS OF INVESTIGATIONAL GENE TRANSFER One method of gene therapy currently being explored in clinical trials is called gene transfer. This approach aims to introduce a working gene into the body to determine if it can produce a needed protein.

STEP 1 CREATING A WORKING GENE A working copy of a mutated gene is created in a laboratory.

STEP 2 BUILDING A THERAPEUTIC VECTOR A therapeutic vector is used to protect the working gene and serves as a transport vehicle for the gene to enter the body. The therapeutic vector is created from a neutralized virus, meaning no viral genes remain inside.

STEP 3 DELIVERING THE WORKING GENE A single, one-time infusion delivers large numbers of therapeutic vectors into the body.

STEP 4 MAKING PROTEINS Once in the body, the new working gene is designed to provide instructions for the body to make the protein it needs on its own. =Proteins.

STEP 5 MONITORING AND MANAGING HEALTH Clinical trial participants are regularly monitored to better understand the safety of the gene transfer and to evaluate its effect on the body.

MOVING

from Joint to Bone

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By: University of Miami Hemophilia Treatment Center

HEALTH

Fall/Winter 2021

T

he bleeding disorders community is very familiar with and committed to “joint health”. Pharmacokinetic evaluations, EHL versus SHL factor concentrates, novel therapies and MSKUS are now part of the vocabulary. Dialogs about prophylaxis to preserve or improve joint health occur in the HTC, in phone conversations with health care providers, and virtually (and, slowly, in person!!!) between caregivers/ patients/HCP's/MSL's, etc., etc.

But, what about “bone health”? What IS that? Isn’t it just something that older women need to worry about? How does “bone health” affect the bleeding disorders community?

It is true…. women “of a certain age” DO need to be concerned about “bone health” - loosely defined as how strong a person’s bones are - how much calcium exists in the framework of bones over a lifetime. Too little calcium translates into “weak bones”, bones which look less dense (or white) on a plain x-ray (also known as osteopenia) or even bones which are very pale looking with the suggestion of open spaces or holes (osteoporosis). Such women (and I am among their number!) need bone density evaluations (DEXASCANS), and often require calcium supplements, vitamin D supplements, perhaps other medications to enhance the deposition of calcium into the bones or decrease the loss of calcium from bones. Calcium-dense bones maintain their strength and lessen the risk of fracture. We are urged to include weightbearing exercise in our daily routine, as weight bearing helps to maintain the calcium in our bones as well.

Bones are the body’s repository or bank for the minerals, calcium, and phosphorous. Calcium and phosphorous are essential, with functions beyond the formation of bones and teeth. Bones are dynamic. There is a constant balance between the deposition of calcium and phosphorus and the release of these minerals for use by other body tissues.

WHAT’S NEW?

Osteoblasts are the cells which produce bone tissue.

Osteoclasts are the cells in the bone which are responsible for the resorption or breakdown of bone tissue.

And it turns out that Factor VIII is involved in this process of regulating the balance in the remodeling of bone tissue.

Deposition of calcium/phosphorus into our bones occurs up until age 27. At that age our bones are as “dense” as they will ever be.

From that age on, there is a loss of calcium as it is needed for other purposes, and bones become less dense. Many proteins are involved with bone metabolism: parathyroid hormone, calcitonin, growth hormone, thyroid hormone, sex hormones (estrogen and androgens), vitamin D, glucocorticosteroids produced by the body, and many other recently identified or studied “marker proteins of bone activity”. How they all fit together, and how factor VIII interacts with these is complicated and is only now being pieced together.

Before prophylaxis with factor VIII concentrate, in the era of on-demand therapy (or no therapy), the reality was that hemophiliacs, particularly severes, had low bone mineral density --- even in childhood, with the associated risks of fracture, pain, etc. Makes sense. If a PWH (person with hemophilia) is not active due to frequent bleeds, then the deposition of calcium is compromised. The inflammation induced by a bleed leads to the deterioration of bone and cartilage, further impairing bone density/ strength.

Recent research has demonstrated that Factor VIII itself is involved with the activation of osteoblasts in rabbits—leading to deposition of bone as a secondary effect of the completion of the clotting process with

Factor VIII

*Included in this process of remodeling bone tissue

the formation of thrombin. A deficiency of factor VIII leads to less thrombin production (and bleeding!) and therefore less activation of the bone-depositing osteoblasts. Factor VIII deficiency is an independent risk factor for osteoporosis! It is important to note that factor IX deficiency is not associated with increased bone resorption. However, all of this is under investigation.

There has been an overall improvement in bone health (density) with the adoption of prophylaxis with factor VIII concentrate. On-demand or episodic infusions do not

There has been an overall improvement in bone health (density) with the adoption of prophylaxis with factor VIII concentrate.

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result in improved bone health in the long run. This makes sense - consistently replacing the clotting factor that Hemophilia A patients lack results in both the actions of factor VIII in coagulation AND in the bone health balance.

But we know that weight-bearing exercise/activity leads to increased calcium deposition in bones, and denser, stronger bones. How much of the documented improvement in bone density in PWHA on prophy can be attributed to the increased mobility and activity that adherence to prophylaxis brings, as the number of joint bleeds decreases in any individual? It’s impossible to say, although, clearly, bone health is the result of many interactions.

We are now entering an era of non-factor therapies. Prophylaxis for both inhibitor and non-inhibitor Hemophilia A patients with emicizumab is a reality. There are other non-factor products under clinical investigation. The question has already been raised: how will bone health be affected if actual factor VIII is not being used? We don’t know. Emicizumab is not factor VIII. As far as it’s known, emicizumab provides the FVIII–like role in coagulation, but may not provide the other functions of factor VIII. As a community, both treaters and families, we recognize the improvement in joint health and lifestyle experienced by many patients prescribed emicizumab.

These patients are walking more, engaging perhaps, in more sports… in other words, improving their bone health/density through activity. (Of course, a healthy diet which includes calcium/vitamin D-rich foods or supplements helps as well!)

This question is already under study. What are other laboratory markers for bone health? Several studies already include collection of blood for evaluating not only the known markers and banking the specimens for evaluation of markers in the future as they are identified. Assessment of joint health using PT evaluations and serial musculoskeletal ultrasound exams is already underway. There will soon be studies which include monitoring of bone density through DEXASCAN imaging.

How will bone health be affected if actual factor VIII is not being used?

There will be a lot of information generated, and our knowledge base and changes to the therapeutic approach recommended for our patients will evolve.

Talk to your HTC team to determine how to maximize bone density no matter what prophylactic regimen is prescribed.

Currently, relief of pain, improvement in overall joint health, and improvement in lifestyle are accessible goals! Adherence to any available prescribed prophylactic regimen is key!

Authored by:

DEXASCAN

Maria Bastos, MD Lawrence P. Cahalin, DPT Fernando F. Corrales-Medina, MD Joanna Davis, MD Kelli A. Fraga, DPT Rachel Leeman, MD Leandro Pisani

WHAT’S NEW?

Feeling BURNED O

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Out From

by Dr. Gary McClain, PhD

I

t’s been a rough road, this COVID-19 pandemic. Right?

It’s been rough in many different ways, and I suspect we all share some of the ways in which living during these times has been challenging. As a mental health professional, I’ve been thinking and talking and presenting and writing about the mental health impact of COVID. Including COVID burnout.

The best way to begin talking about COVID burnout might be to tell you how my presentations have evolved during the pandemic. In April of 2020, I presented a webinar (from lockdown), on “Coping with COVID.” Soon followed by “Parenting During COVID.” Later in the summer of 2020, my presentation was edited to reflect “COVID Fatigue.” That fatigue stuck with us for a while and kept my presentation in circulation as a result. And then, last fall, mental health professionals began talking about COVID burnout. And that’s where we find ourselves these days, maybe with some anxiety about reentry creeping in.

So why are mental health professionals using the term “burnout” in relation to COVID? Isn’t that what happens when you are tired of your job? Well, living during a pandemic has certainly been a big job, one that we didn’t ask for. And if you look at the definition of burnout – feeling emotionally exhausted, kind of disconnected from your life, and trying not to fall into a generally negative attitude – this sure fits the way many of us are feeling right now. What about you?

Burnout creeps in over time. It results from feeling constantly bombarded by your own fears, frustrations, and anxiety, compounded by the fears, frustrations, and anxiety of the people around you. If you’re in a caregiving role – especially if you’re a parent, you are especially at risk for COVID burnout.

So, I repeat: If you’re feeling some burnout from this pandemic, you are not alone. And you are normal. Whew!

Big sigh of relief!

Yes, I’m Burned Out! So, What Can I Do?

FAMILY MATTERS

Ways to Cope with Burnout...

At this point, you may be thinking: It’s great to know I’m not alone. But I’m still feeling burned out. What next? Well, going through these difficult times with my clients has taught me a few things, so let me share some techniques for coping with burnout that I hope will help you with your own burnout recovery.

FIRST, EMPOWER YOURSELF During this pandemic, we have all been painfully aware of just how much of life is completely out of our control. As a result, it’s all too easy to fall into a “what’s going to happen to me next?” mindset. I have frequently said to my clients over the last year and a half that accepting where we don’t have control frees us up to focus on where we do have control. And taking good care of yourself is an area of life in which you do have control. It’s your choice. Let’s all power up!

TAKE A LOOK AT YOUR SELFTALK Humans are engaged every minute of the day in an ongoing dialogue with themselves.

Evaluating, judging, doing the woulda-coulda-shoulda dance, and criticizing themselves.

Constantly beating up on yourself for not being perfect is exhausting and contributes to burnout. Talk back to all that criticism with a voice of encouragement: I’m human. I am doing the best I can. I’m a work in progress and learning as I go along.

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PROJECT POSITIVITY When you find yourself falling into the "cup half empty" frame of mind, choose to make a shift. Identify what you like about your life, what’s working for you, what’s possible.

Identify the contributions you make to the people around you, along with what they bring to your life. By taking a step back, you might even recognize that the cup of life is actually half full, as well as what you can be doing to make it fuller. Focus on the big picture!

REFRAME AND SHIFT YOUR PERSPECTIVE

AKA Fake It ‘Til You Make It. We can benefit ourselves and we can benefit those around us by keeping our smile in operation. Research has shown that smiling actually produces positive hormones that help us to feel happier.

And projecting a positive attitude is a boomerang in that it motivates those around us to respond accordingly.

Smiling is a great antidote to burnout.

IDENTIFY SOURCES OF BURNOUT Your emotional exhaustion may be a warning sign that something is out of whack in your life. Take a hard look at yourself. Burnout is a generally bad feeling, but are there specific causes that can be addressed? Sure, we’ve got the restrictions and other challenges of a global pandemic. But is there something going on at work that needs to be addressed? At home? In your self-care routine? Getting down to the specifics with yourself might yield some additional answers for coping with burnout. Ask yourself questions. Take notes!

KEEP THE SUPPORT NETWORK ACTIVATED The pandemic has left us all feeling isolated. Fewer get-togethers. Zoom fatigue. Work-at-home loneliness. My clients also tell me they hesitate to talk about their feelings with friends and family out of fear of being labeled a complainer and bringing other people down. However, venting is necessary and emotionally healthy. We all need a good vent once in awhile to let out those feelings that are bouncing around inside us and, by not being released, getting bigger and stronger. Call somebody in your support network and let them know you just want to vent, that you don’t need them to fix anything and please withhold judgment. And then offer to do the same thing for them.

SEE WHERE YOU CAN SET BOUNDARIES If you are like me, you are probably getting tired of people talking about

FAMILY MATTERS

setting boundaries. It does seem that boundary setting is trendy these days. However, where burnout is concerned, setting boundaries is an important consideration. Are you wearing yourself out volunteering, signing up for meetings that don’t need to occur, agreeing to unreasonable deadlines, running yourself ragged completing tasks that could wait for another day? Consider setting boundaries, at home and at work, to conserve your emotional and physical energy. Lack of boundaries is a major contributor to burnout.

GET YOURSELF SOME DOWN TIME This is a benefit of setting boundaries. Take time to get some rest from the constant rat race. Little breaks like

actually taking time for lunch. Getting up and taking a walk around the yard or the block. Scheduling fun time with family and friends. Who knows, maybe taking a day or two off. I am especially talking to you parents here! No breaks, no rest, leads to burnout.

WATCH OUT FOR LESS THAN HELPFUL COPING This includes not eating healthy, not staying active, maybe drinking a little too much. Disengaging from the people around you through TV or videogames and making isolation a way of life. Keep in mind that if you are taking good care of yourself, you have that much more to give to life, and the people you care about.

And a Few Ideas on Preventing Burnout By managing your daily life better, you can also help prevent burnout in ourselves and the people around you. Here are a few ideas:

BALANCE IS EVERYTHING

ATTITUDE OF GRATITUDE

It kind of goes without saying, but still needs to be said.

An unbalanced life is a recipe for burnout, accompanied by fatigue, frustration, and resentment. Step back and decide what your balanced life needs to look like. Work, friends, activity, family, rest, fun… and then schedule some balance, every day, every week.

Start out the day by focusing your mind on something you are grateful for. Psychological research has taught us that this can improve your outlook for the rest of the day. Even something simple like that great cup of hot coffee you may have started the day with (my personal favorite). Gratitude can help shift your perspective toward what’s possible and help you to open yourself up to whatever the day brings.

BE PROACTIVE ABOUT YOUR OWN NEEDS Again, I am especially talking with parents here. Keep your own needs front and center. That doesn’t mean being selfish or not meeting your responsibilities. But it does mean paying attention to your need for rest, for people time, for learning and growth. Being aware of your own needs helps you to bring your A-game to life, because you are acting out of your best self, not your depleted, burned-out self.

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When the Going Gets Tough...

BE AWARE OF BURNOUT IN YOUR FRIENDS AND FAMILY Watch out for exhaustion, irritability, forgetfulness, pessimism, shutting down. If you sense that a loved one is experiencing burnout, reach out to them. Offer to be a listening ear while they vent, and to brainstorm some solutions. Let them know you care and are here to listen without judgment. As we have been saying repeatedly during the pandemic, we are all in this together!

REACH OUT IF YOU NEED ADDITIONAL HELP This COVID pandemic has resulted in a mental health epidemic. If you are struggling with your mental health right now – loneliness, anxiety, depression – you are sure not alone. And as we say in the mental health professions, one of the bravest things you can do is to admit that you need a helping hand and then take the next step of reaching out.

So if you or a loved one is struggling, get connected with mental health support.

Better times are ahead! But right now, we’re all worn out. And so, I’ll leave you with the words that I leave pretty much every conversation these days: Take good care of yourself!

Gary McClain, PhD is a therapist, patient advocate, and educator, specializing in helping clients deal with the emotional impact of chronic and life-threatening health conditions, as well as their families and professional caregivers. He works with them to understand and cope with their emotions, to learn about their lifestyle and treatment options, to maintain compliance with medical regimens, to communicate effectively with each other and healthcare professionals, and to listen to their own inner voice as they make decisions about the future. His website is JustGotDiagnosed.com.

FAMILY MATTERS

For the treatment of bleeding episodes in people* with hemophilia A or B with inhibitors

I’M READY TO MOVE ON Get rapid, predictable, and reliable †‡ bleed control with SEVENFACT 225 Rapid effect: 3 hour At 3 hours, 84% of mild/moderate bleeding episodes were controlled with a single dose§

Predictable response: 84% At 9 hours, 84% of mild/moderate bleeding episodes treated achieved bleed control after a single dose

Reliable control: 99.5% At 24 hours, 99.5% of mild/moderate bleeding episodes were resolved

Convenient home use: 98% 98% of bleeding episodes were treated at home As seen in the PERSEPT 1 clinical trial.

225 mcg/kg initial dose regimen in the clinical trial. § Based on voluntarily reported data from 158 bleeding events. † ‡

Summary of Selected Safety Information What is the most important information I should know about SEVENFACT? The most serious possible side effect of SEVENFACT is abnormal clotting involving blockage of blood vessels, which include stroke, blockage of the main blood vessel to the lung, and deep vein blood clots.

You should know the signs of abnormal clotting and seek medical help immediately if they occur.

Signs of clotting in places other than your site of bleeding can include new onset of swelling and pain in limbs, new onset of chest pain, shortness of breath, loss of sensation or motor power, or altered consciousness or speech.

What is SEVENFACT?

*

SEVENFACT is an injectable medicine used for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with Hemophilia A or B with inhibitors.

Injecting medicines requires special training; do not attempt to self-infuse unless you have been taught how by your healthcare provider.

Who should not use SEVENFACT (coagulation factor VIIa)?

You should not use SEVENFACT if you are allergic to rabbits, or if you have known allergies to SEVENFACT or any of its components. Seek immediate medical help if you experience hives, itching, rash, difficulty breathing with cough or wheezing, swelling around the mouth and throat, tightness of the chest, dizziness or fainting, or low blood pressure after taking SEVENFACT. Tell your healthcare provider prior to using SEVENFACT if you have begun treatment of a bleeding episode with another bypassing agent.

What should I tell my healthcare provider before I use SEVENFACT? Tell your healthcare provider if you are pregnant, are nursing, or plan to become pregnant; if you have had prior blood clots, heart disease or heart failure, abnormal heart rhythms, prior pulmonary clots, or heart surgery; or if you have or have had any other medical conditions.

What are the possible side effects of SEVENFACT? The most common adverse reactions for SEVENFACT are headache, dizziness, infusion-site discomfort, infusion-site hematoma, and infusion-related reaction and fever.

Seek immediate medical help if you have signs of a blood clot or an allergic reaction.

To report SUSPECTED ADVERSE REACTIONS or product complaints, contact HEMA Biologics at 1-855-718-4362. You may also report SUSPECTED ADVERSE REACTIONS to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Patient Product Information on the next page.

Coagulation Factor VIIa (Recombinant)-jncw

Make the move

D the Vascular o PIPELINE w n

by Janet Brewer, M.Ed

Hemab

Boston, MA and Denmark, Sweden

Formed Dec. 14, 2020, Hemab is a biotech company developing next generation therapeutics for serious underserved bleeding and thrombosis disease. Their initial focus will be on rare bleeding disorders such as Glanzmann’s Thrombasthenia (GT.)

L

ike the weather in New England, one only needs to wait 15 minutes for it to change. Similar to NE weather, pharmaceutical and product changes seem to follow a similar pattern. Read on for some new players in the bleeding disorder space, the exit of another, and updates to treatment using DDAVP.

Dr Sorensen said: “Despite the innovations seen in treatments for hemophilia A and B in the last five decades, treatments for other rare bleeding disorders such as, for example GT, are still limited to blood transfusions and acute treatments.”

He added: “We owe these patients new treatment options and Hemab is uniquely positioned to leapfrog drug development of these medicines and bring treatment paradigms into the 21st century." https://www.thepharmaletter.com/in-brief/briefhemab-receives-55-million-in-series-a-financing

Centessa-ApcinteX Cambridge, MA SerpinPC, a biologic based on the serpin family of proteins, is designed to allow more thrombin to be generated by inhibiting activated protein C (APC) thus rebalancing coagulation in hemophilia patients. SerpinPC has the potential to treat all types of hemophilia regardless of severity or inhibitor status and may also prevent bleeding associated with other bleeding disorders.

AP-0101 is an ongoing Phase 1/2a open-label clinical trial to investigate the safety, tolerability and pharmacokinetics of intravenous and subcutaneous doses of SerpinPC in healthy male volunteers and male persons with severe hemophilia (https://clinicaltrials.gov/ct2/show/ NCT04073498).

https://www.globenewswire.com/newsrelease/2021/09/09/2294194/0/en/ Centessa-Pharmaceuticals-AnnouncesPositive-Topline-Data-from-Proof-of-ConceptStudy-of-SerpinPC-in-Severe-Hemophilia-Aand-B-Patients-Not-on-Prophylaxis.html

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

APC

increased

= Thrombin

SerpinPC rebalances cascade

Stimate HEMAB Research

Glanzmann’s Treatment

In July 2020, Ferring issued a voluntary recall of Stimate due to detected out-of-specification assays results in some vials from outside the US. On Sept. 7, 2021, CSL announced that their Stimate agreement with Ferring for the responsibility of commercial, medical, distribution and product support activities had ended.

In response to patient need and the void left by Stimate in the bleeding disorder community, after consulting with MASAC, the Hemophilia Alliance Board entered into an agreement with STAQ Pharma to develop a Stimate “biosimilar.” The Alliance has been working since May 2021 to have it licensed in all 50 states and the first vials were shipped on 9/13/2021. https://www.hemophilia.org/sites/default/files/document/files/ Stimate%20External%20Comm_Agreement%20End_FINAL.pdf

Catalyst Biosciences On Nov. 12, 2021 Catalyst Biosciences announced a strategic decision to halt the clinical development of MarzAA, report data to date, and seek a buyer for its hemophilia assets. This decision came despite their Sept. 28, 2021 announcement that the FDA had granted Orphan Drug Designation (ODD) for its lead product candidate, subcutaneous Marzeptacog alfa (activated), or MarzAA, for the treatment of Factor VII Deficiency (FVIId). MarzAA was previously granted ODD and Fast Track Designation (FTD) for treatment of Hemophilia A/B with inhibitors and FTD for the treatment of FVIId. https://ir.catalystbiosciences.com/press-releases

BLOODLINES

Self-Care is

by Emily Taylor

Self-

I

often end my yoga classes with the notion that our practice isn’t really an exercise of physical ability. The goal is not to make perfect shapes with our bodies; rather, it is a practice of self- study. Each pose informs us about the way we hold on and let go, the quality of our breath, the quality of our inner dialogue. In their truest form, our mindfulness practices are innately nourishing, the very essence of self-care. But self-care comes with an unfounded correlation to selfishness, especially for parents. So, let’s take some time to de-stigmatize the idea that self-care is synonymous with self-serving and remember that the more self-love we practice, the more love we have to give.

The World Health Organization defines self-care as “the ability of individuals, families, and communities to promote health, prevent disease, maintain health, and to cope with illness and disability with or without the support of a healthcare provider.”

The key word in that definition is, “prevent,” and I would even peel it back another layer by saying that self-care is prevention from the small, sometimes undetectable internal

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meltdowns we each experience as a result of the busy world we live in. Self-care allows us to manage stress and that reduction of stress is what allows us to maintain our health.

So what constitutes self-care and where to start? I think we often assume self-care means an expensive day at the spa or something that requires a lot of time, but that is not the case when we learn to thread self-love throughout the day. Self-care is anything that allows you to slow down and

feel nourished. It can truly be as simple as taking a moment of pause, closing your eyes, and breathing deep. This can happen in the car waiting for your kids at school pick up, in your office before you walk into a meeting, or first thing in the morning before the world gets busy.

Self-care is most effective when it is a routine built into our lifestyles rather than something we scramble to do when feeling depleted. Not only does routine make it more accessible, but it also takes the energy out of trying to find a “quick fix.” You might even choose to think of it as a ritual rather than the mundane essence that the word “routine” can bring to mind.

For example, the ritual of lighting a candle you love, taking a shower and intentionally transitioning from the busy day to the evening. A ritual of slowing down.

MIND BODY CONNECTION

Self-Care Menu

I have created a menu of self-care ideas organized from more accessible, quick doses of self- care to more involved options. I hope this list serves as a tool that you can access in moments when you need it most. Mostly, I hope that this gives you the permission that’s already yours, to take time for self-love, to show up for you, so that you can continue to show up for everyone else in your life with more fuel in the tank.

Breathe When we slow down our exhales, we send a signal to the nervous system that we are okay, that we are safe, that we can rest here. It allows us to quite literally hijack our nervous system in a nourishing way. The following breath work can be both beneficial in a pinch, a moment of stress, or as a daily practice to soothe the nervous system.

DO THIS: Breath in for a count of 4, breath out for a count of 4, for three rounds. Next, breathe in for a count of 4, breath out for a count of 6 for another three rounds. Continue this breath pattern for as long as you need. This can be a great tool in a moment of stress or nervousness. I often use it before giving a speech or while experiencing turbulence on a flight.

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LIFELINES for HEALTH

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Fall/Winter 2021

Meditation

After just seven minutes of meditation, we can rewire brain patterns, moving from the deep grooves of negative talk or repetitive thoughts we often suffer from to more positive routes for the brain pathways.

DO THIS: Meditation doesn’t require anything outside of us, only that we notice when the mind wanders so we can then tether ourselves back to presence by focusing on what is currently happening in the body without judgement. It feels like a simple concept and yet it is not that easily done, so if you are new to meditation or prefer to be guided through your meditation, I am fond of the Insight Timer app which has a variety of themes and styles. I also have this free 7-minute body scan meditation that is a great starting point. https://youtu.be/V5ffNCkk7tY

Movement

Our body stores both physical and emotional tension in the body. Think about the shoulders, for example. When we are cold, uncomfortable, in a difficult conversation, our shoulders rise and constrict. Over time that becomes stored tension in the body. Exercise helps to process that tension sooner, reducing stress and preventing discomfort.

Morning Ritual

Waking up even just a few moments before the rest of your house can be a game changer. This allows you to enter the day in an intentional way rather than feeling like the day happened to you.

DO THIS: Set your alarm early so you can slowly sip your morning drink, write in a gratitude journal, or take a walk in fresh air. Return to the essence of ritual so that it feels special and just for you. Carve out space for you.

DO THIS: Find a movement style you enjoy!

That is the most important, that it feels like something to look forward to rather than something to dread. This could be a virtual yin yoga class once your kiddos are down, a morning walk around the neighborhood, an in-studio workout class, or dancing in the kitchen while you make dinner. Don’t put constrictions on it; let it be free, fulfilling, and intuitive.

Evening Ritual

Take a shower or bath to intentionally transition from the busyness of the day to the energy of the evening.

DO THIS: Try adding a fragrant bath bomb, essential oil, or shower fizzy to create an at-home spa experience. Add in self massage of the lymphatic system by bringing your fingertips to the jawline and sliding them down the side of the neck with as much pressure as it feels good. Complete a few strokes on each side. This flushing of the lymphatic system is good for our immune system, and it feels great!

Emily is a yoga teacher and international retreat leader with over a decade of teaching experience. Shortly after getting a degree in Psychology from San Diego State University, Emily completed her first 200 Hour vinyasa yoga certification. She found that the connection between mind and body wellbeing was what interested her most. Since then she has continued to deepen her studies with a 500 hour Prana Flow training, a 200 hour Hatha training, and master immersion courses.

Emily spends her day-to-day teaching private and public classes in Portland, Oregon. She also offers a variety of workshops and retreats throughout the year.

You can learn more about Emily at emilytayloryoga.com

MIND BODY CONNECTION

84 Beach Street Middleboro, MA 02346

CHES Mission To Inspire awareness and selfreliance for patients with chronic health conditions, their families, and their communities.

Editors in Chief Janet Brewer, M.Ed Eric Lowe

Editor Janet Brewer, M.Ed

Publication Designer Eric Lowe

Contributing Writers Maria Bastos, MD Janet Brewer, M.Ed Lawrence P. Cahalin, DPT Fernando F. Corrales-Medina, MD Joanna Davis, MD Kelli A. Fraga, DPT Rachel Leeman, MD Eric Lowe Gary McClain, PhD Leandro Pisani Robert Sidonio, MD Emily Taylor

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