non-neoplastic hematology: today’s discussion management

8/24/2020

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Non-Neoplastic Hematology: Management of Rare

Bleeding DisordersAssociation of Physician Assistants in Oncology Annual Symposium

August 29, 2020

Tyler W. Buckner, MD, MScAssistant Professor

University of Colorado Division of Hematology

Today’s Discussion

•Brief background- hemophilia A and B

•Overview of changes in treatment options

•Focus on:•Emicizumab•Rebalancing therapies•Gene therapy

Pre-Presentation Questions

1. Which of the following modifications has NOTbeen used to prolong the half life of a factor VIII or factor IX medication?

A. Fusion to the Fc fragment

B. Coupling to polyethylene glycol (PEG)

C. Conjugation with hexadecanedioic acid

D. Fusion to albumin

E. Addition of the XTEN molecule

2. Which of the following medications / agents functions as a coagulation “rebalancing agent,” by reducing activity of an endogenous anticoagulant, rather than replacing or standing in for missing clotting factors?

A. Emicizumab-kxwh

B. Activated prothrombin complex concentrate

C. Eptacog alfa

D. Fitusiran

E. Recombinant factor VIII

3. Which of the following statements about gene therapy for hemophilia A and B is NOT true?

A. No AAV-based gene therapy product has been tested in patients with pre-existing anti-AAV antibodies

B. Transaminitis has been observed in every phase 3 clinical trial of AAV-based gene therapies for hemophilia A and B

C. Gene therapy has eliminated the need for regular clotting factor prophylaxis for some patients

D. Gene therapy trials for hemophilia A and B have not included anyone under age 18

E. Gene therapy has not been tested in any patient with a factor VIII or factor IX inhibitor (neutralizing antibody)

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Competing Themes

Hemophilia A and BHistory

General treatment approach

Needs and challenges

Schematic representation of normal platelet responses and the congenital disorders of

platelet function.

A. Koneti Rao, and Jagadeesh Gabbeta Arterioscler

Thromb Vasc Biol. 2000;20:285-289

Copy right © American Heart Association, Inc. All rights reserved.

Branchford, DiPaola. Making a diagnosis of VWD. ASH Education Book 2012 2012:161-167

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Hemophilia B

Hemophilia A

Protein CProtein S

Anti-thrombin

Factor III = tissue factorFactor IV = phospholipidFactor VI = Factor Va

TFPI

Background: history of treatment

1920s -1940s

1950s 1960s 1970s 1980s 1990s 2000s 2010s

Whole blood

Factor VIII describedFactor IX described

FFP

1965:Cryoprecipitate

FVIII and FIXconcentrates

Blood Safety Crisis:HIV / AIDSHCVIsolation and

Purification ofFVIII and FIX

1992: Recombinant FVIII1997: Recombinant FIX

1997: First Bypass Agent

Management Principles: FVIII / FIX Deficiency

1. Replace factor to treat bleeding

2. Prophylactic factor for severe bleeding phenotype

• Anti-fibrinolytics (tranexamic acid, aminocaproic acid)

• DDAVP for some with mild FVIII deficiency

Management Principles: Inhibitors

•High titer inhibitor (>5 Bethesda Units)• Immune tolerance induction (ITI) - factor•Bypass agent: aPCC (FEIBA) and/or rFVIIa

(NovoSeven, SEVENFACT)• On-demand or Prophylaxis

•Low titer inhibitor (<5 BU)•High dose FVIII / FIX•Plus ITI, aPCC, and/or rFVIIa

Challenges and Needs

• Immunogenicity: FVIII and FIX Inhibitors• Inhibitor management costly, difficult and not very effective

• Need for very costly intravenous medications

• Often need multiple doses to treat acute bleeding

• Prophylaxis: requires infusions every 2-3 days from age 1

Major Challenges for Inhibitor Management

• Immune Tolerance Induction (ITI): very difficult; not always successful•1/3 FVIII and 3/4 FIX inhibitor patients “fail” ITI

•aPCC and rFVIIa do not work as well as factor

•FIX inhibitors: Anaphylaxis and nephrotic syndrome

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Overview of New TreatmentsExtended half-life products

Rebalancing therapies

Substitution and new production

Extended Half-Life Clotting Factors

https://www.slideshare.net/nedevski/10-orphan-drugs-and-haemophilia

Eloctate, Alprolix Idelvion (rFIX-FP)

Adynovate, Jivi, Esperoct,Rebinyn

BIVV-001

• rFVIII-Fc (Eloctate) + VWF D’D3 domain + XTEN molecules

• Phase I / II half life: 37 hours

• Phase III results pending

rFVIII-Fc

VWF domain

XTEN

XTEN

Konkle BA et al. BIVV001: The First Investigational Factor VIII Therapy to Break Through the VWF Ceiling in Hemophilia A, with Potential for Extended Protection for One Week or Longer. Blood 2018; 132 (Supplement 1): 636.

EHL Products: Bottom Line

Factor VIII: 1.5 to 1.6-fold increase in half life

Q3-4 day infusions

Factor IX: 3 to 5-fold increase in half life

Q4-14 day infusions

In general, none of the EHL products reduce costs

CAUSES CLOT FORMATION (steps on the gas)

INHIBITS CLOT FORMATION (puts the brakes on)

Bleeding and ClottingBalanced

Rebalancing Therapies

CAUSES CLOT FORMATION

INHIBITS CLOT FORMATION

Not enough Pro-coagulants →Tendency to bleed,

Clotting is TOO SLOW




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REPLACEMENT FACTOR (more gas pedal)

1. Push more onthe gas pedal








Not enough Pro-coagulants →Tendency to bleed,

Clotting is TOO SLOW




2. Push less on the brake pedal



Rebalancing Therapies12

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Hemophilia B

Hemophilia A

Protein CProtein S

Anti-thrombin

TFPI

“Inhibit the inhibitor”

Two targets:

•Anti-thrombin (fitusiran) siRNA

•Tissue factor pathway inhibitor (concizumab, BAY 1093884*, BAX 499†)

INHIBITS CLOT FORMATION (medications “inhibit the inhibitor”)

*terminated due to thrombosis†terminated due to bleeding

Fitusiran and concizumab

•Hemophilia A or B, with or without inhibitors• Phase 3 studies enrolling

• Subcutaneous injection

•Dosing: Qday (concizumab), Qweek (fitusiran)

• Bleeding treated with FVIII, FIX, or bypass agent• Neither fitusiran nor concizumab can be used to treat bleeding

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What we don’t know

•How should we adjust dosing of factor / bypassing agent for bleeds or surgeries?

•How to respond if thrombosis occurs

•What impact do these medications have on treatment of bleeds? On ITI?

EmicizumabHow it works

Advantages, disadvantages, issues

HAVEN Studies, other updates

Emicizumab: Mechanism Emicizumab: Mechanism

ACE-910 = emicizumab = Hemlibra

Emicizumab: Mechanism Emicizumab: Advantages

• Does FVIII’s job but not neutralized by FVIII inhibitors

• Long half life → extend dosing intervals, continuous coverage

• Subcutaneous route of administration

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HAVEN 1

≥ 12 years

HA with inhibitors1

1.5 mg/kg QW

HAVEN 2

< 12 years

HA with inhibitors2

1.5 mg/kg QW3 mg/kg Q2W6 mg/kg Q4W

HAVEN 3

≥ 12 years

HA without inhibitors3

1.5 mg/kg QW3 mg/kg Q2W

HAVEN 4

≥ 12 years

HA with / without inhibitors4

6 mg/kg Q4W

1. Oldenburg J, et al. N Engl J Med 2017;377:809–18; 2. Young G, et al. Blood 2019;in press;

3. Mahlangu J, et al. N Engl J Med 2018;379:811–22;4. Pipe S, et al. Lancet Haematol 2019;6:e295–e305.

Emicizumab Clinical Trials

401 subjects across all 4 trials

Emicizumab

• Approved by FDA for use in adults and children with inhibitors aged 2 years and older in November 2017

• Commercially available as of Dec 2017 – Jan 2018

• Approved by FDA for use in patients of all ages (with and without inhibitors) in November 2018

Emicizumab: Practical Aspects

•Given as an injection under the skin

•Dosing once every 1, 2, or 4 weeks•Half-life 28 days: 5-6 months to get out of system

•Bleeding is treated with FVIII or bypassing agent• Emicizumab cannot be used to treat acute bleeding

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Emicizumab: Issues

• Interferes with one-stage FVIII activity ↑↑↑•UCH changed to chromogenic FVIII activity in 4/2019

•Should NOT use aPCC (FEIBA) while on emicizumab

•Ceiling effect: equivalent to FVIII activity 5 – 30%

Emicizumab: Issues

• In HAVEN 1, three patients developed thrombotic microangiopathy and two had VTE events

• Occurred during high dose FEIBA treatment

• Guidance for FEIBA dosing issued; no additional TMA or VTE events occurred in the trial

• No clots in any HA patient without an inhibitor

Emicizumab: Issues

•One patient death in HAVEN 1 (rectal hemorrhage)

•13 deaths and additional thrombotic events have occurred in patients on emi (reported to FDA)•Circumstances unclear / not disclosed

•Has been used (off-label) for acquired hemophilia

Gene TherapyCurrent approach and challenges

Studies and results

Future approaches

Gene Therapy: Considerations

• Increasing to >2% factor activity markedly changes the disease

• Levels > 12% effectively eliminate spontaneous bleeding

• Factor VIII levels > 150% potentially associated with thrombosis

Gene Therapy: Current Approach

• Adeno-associated virus (AAV) vector (viral genes removed)

• Insert target gene in viral capsids

• Infuse vector with target gene in it → goes to liver cells

• Target gene does not integrate into host DNA

• Patient cells now make target protein

(modified gene, most capsids are filled)

(and some others)

(some does)

(but may not have capacity)

(high prevalence of pre-existing immunity)

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Gene Therapy: Issues So Far

• Transaminitis• Can be associated with loss of target gene expression

• Partly due to T cell mediated immune response against viral capsid proteins (responsive to steroids)

• Partly due to increased stress on cell machinery (ER stress) (not responsive to steroids)

• Not yet tested in:• Patients with pre-existing AAV Ab (one exception)

• Patients with inhibitors

• Children

Colella et al. Mol Ther Methods Clin Devel. Vol 8, March 2018.

• Unknown durability• Earliest trials show

expression 9-10 years after single treatment

• BioMarin results attenuated over time: ~80% levels now around 20-30%

• Unclear if same therapy can be repeated

• Unknown long term risks, including insertional mutagenesis

Gene Therapy Trials

• Multiple clinical trials ongoing in FVIII and FIX gene therapy

• BioMarin (FVIII) product, valoctocogene roxaparvovec(Roctavian)• FDA decision will be announced August 20, 2020

• Planning trials with higher doses and for patients with inhibitors

• uniQure (FIX) Phase 3 results expected soon, as are others

Overall, patients had reduced bleeding and reduced use of FIX concentrate

All trials to date have shown similar effects on these outcomes

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Overall, patients had reduced bleeding and reduced use of FVIII concentrate

ProductHemophilia

type AAV (transgene)

Valactocogene roxaparvovec(BMN270)

AAAV5 (BDD-FVIII)

SPK-8011 AAAV-LK03 (BDD-FVIII)

Giroctocogene fitelparvovec(SB-525)

AAAV6(BDD-FVIII)

AAV2/8-HLP-FVIII-V3 AAAV-8(BDD-FVIII)

(BAY2599023) AAAV-hu37(BDD-FVIII)

(TAK-754, BAX-888) AAAV8(BDD-FVIII)

Etranacogene dezaparvovec(AMT-061)

BAAV5(FIX-Padua)

Fidanacogene elparvovec(PF-06838435)

BAAV-ND(FIX-Padua)

FLT180a B AAV-S3

Gene Therapy: Future Directions

• Updated / additional results of gene therapy trials are presented frequently

• Future potential approaches include • Lentiviral vectors: integrating viruses, allow for passing target gene on to

daughter cells

• Gene editing approaches

• Targeting factor production to platelets: could help in patients with inhibitors-platelets take FVIII to the site where it is needed

Multiple very promising new therapies

• Improved logistics: SQ, less frequent dosing

•Early data suggest improved efficacy

•Safety may be a concern in certain situations

•Gene therapy may offer a potential cure

•MANY unanswered questions

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List of Products Licensed in the US for Bleeding / Clotting Disorders

https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/Products-Licensed-in-the-US#IVC

White GC. Trans Am Clin Climatol Assoc. 2010;121:61-75.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917149/pdf/tacca121000061.pdf

Post-Presentation Questions

1. Which of the following modifications has NOTbeen used to prolong the half life of a factor VIII or factor IX medication?

A. Fusion to the Fc fragment

B. Coupling to polyethylene glycol (PEG)

C. Conjugation with hexadecanedioic acid

D. Fusion to albumin

E. Addition of the XTEN molecule

*CORRECT ANSWER*

2. Which of the following medications / agents functions as a coagulation “rebalancing agent,” by reducing activity of an endogenous anticoagulant, rather than replacing or standing in for missing clotting factors?

A. Emicizumab-kxwh

B. Activated prothrombin complex concentrate

C. Eptacog alfa

D. Fitusiran

E. Recombinant factor VIII

*CORRECT ANSWER*

3. Which of the following statements about gene therapy for hemophilia A and B is NOT true?

A. No AAV-based gene therapy product has been tested in patients with pre-existing anti-AAV antibodies

B. Transaminitis has been observed in every phase 3 clinical trial of AAV-based gene therapies for hemophilia A and B

C. Gene therapy has eliminated the need for regular clotting factor prophylaxis for some patients

D. Gene therapy trials for hemophilia A and B have not included anyone under age 18

E. Gene therapy has not been tested in any patient with a factor VIII or factor IX inhibitor (neutralizing antibody)

*CORRECT ANSWER*

Thank you

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https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/Products-Licensed-in-the-US#IVC

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917149/pdf/tacca121000061.pdf

non-neoplastic hematology: today’s discussion management

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