what’s new in itp 2019 · 2019. 7. 15. · development of novel agents for itp (1) • anti-cd40...

What’s New in ITP2019

David J Kuter, MD DPhilChief of Hematology

Massachusetts General HospitalProfessor of Medicine

Harvard Medical School

Conflicts of interest disclosure • Research support: Actelion (Syntimmune), Agios,

Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ)

• Consultation: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Caremark, Daiichi Sankyo, Dova, Kyowa-Kirin, Merck Sharp Dohme, Momenta., Novartis, Pfizer, Platelet Disorder Support Association, Principia, Protalex, Protalix, Rigel, Sanofi, Genzyme, Shionogi, Shire, Takeda (Bioverativ), UCB, Up-To-Date, Zafgen

• Stock holdings: Rubius• Directorships: None• Kids college fund: Empty

ITP is Due to Increased Platelet Destruction

Macrophage Containing One Platelet (red arrow) and Engulfing Another (yellow arrow)

Karpatkin S. Lancet. 1997;349:1531-1536

PI3K

SykPLCγBtK

FcγRIII

Lyn/LcK

Adapted from:Nimmerjahn F & Ravetch J. Ann Rev Immunol 2008;26:513–33

Btk, Bruton’s tyrosine kinase;PI3K, phosphatidylinositol-3 kinase;

PLCγ, phospholipase C γ; Syk, spleen tyrosine kinase

SykPLCγBtK

FcγRIII

Lyn/LcK


PI3K



PI3K

Syk

Ras

SOS

Rac

PKC

PLCγBtk

Lyn/LcK

DAG

IP3

Ca2+

Ca2+

PiP3

PP

ITAM

ER

FcγRIII

Cell activation/proliferation


Btk, Bruton’s tyrosine kinase; ER, endoplasmic reticulum;ITAM, immunoreceptor tyrosine-kinase-based activation motifs;

PI3K, phosphatidylinositol-3 kinase; PLCγ, phospholipase C γ; Syk, spleen tyrosine kinase

FcγRIII

Complex internalized

PI3K

SykPLCγBtK

Lyn/LcK




ITP is Due to Increased Megakaryocyte Apoptosis (death)

Antiplatelet ab attacks Mk

- Antiplatelet antibody- Antiplatelet lymphocyte

Lymphocyte attacks megakaryocyteMegakaryocyte undergoes apoptosis

- Platelet

Bone

Spleen

A

B

Platelet Rate

A B C

654321

NormalOnset ITPChronic ITPOld Model

Normal PlateletDestruction

C

Chronic ITPNew Model

S

Body Pool

Therapeutic Approaches to ITP• Reduce IgG

production– Corticosteroids– Azathioprine– Cyclophosphamide– Rituximab– Cyclosporine/MMF

• Remove splenic site of clearance

• Reduce Fc mediated clearance– Corticosteroids– IVIG/Anti-D IgG– Danazol– Fostamatinib

• Increase platelet production– TPO– Corticosteroids– Dapsone?

?

Response rates of some current therapies• Corticosteroids: 80-90%• IVIG: 80-90%• TPO receptor agonists: 80-90%• Rituximab: 57% (adults)• Splenectomy: 80% (60% at 10 years)• MMF, azathioprine: 45%

What’s New in ITP• New guidelines• New agents/approaches

Proposed ASH Adult ITP Guidelines - Summary

• Patient involvement in decision making• Hospital admission for newly diagnosed patients with

platelets

Proposed ASH Pediatric ITP Guidelines -Summary

• Patient involvement in decision making• Children with no or only minor bleeding not admitted to

hospital• If no or only minor bleeding, initial therapy is observation;

not corticosteroids, IVIg, or anti-D• If non-life-threatening mucosal bleed, corticosteroids

– Prednisone not dexamethasone– No longer than 7 days

• IVIg = anti-D• If unresponsive first-line: TPO-RA, not rituximab or

splenectomy

anti-D, anti-D immunoglobulin; IVIg, intravenous immunoglobulinNeunert CE, Cooper N. Hematology Am Soc Hematol Educ Program 2018;2018:568−75ASH Draft Recommendations for Immune Thrombocytopenia. Available at: www.hematology.org/Clinicians/Guidelines-Quality/Documents/9106.aspx. Accessed June 2019

Development of novel agents for ITP (1) • Anti-CD40 ligand antibodies

– Reduces production of anti-platelet antibody• FcRn pathway inhibitors*

– Increase clearance of anti-platelet antibody • Sialylated IgG

– Prevents macrophage FcR from clearing platelets• Stradomers

– Recombinant Fc multimers reduce phagocytosis• Staph Protein A (PRTX-100)

– Inhibits macrophage phagocytosis

FcR, Fc receptor; FcRn, neonatal Fc receptor; Ig, immunoglobulin; Syk, spleen tyrosine kinase

Development of novel agents for ITP(2) • Fostamatinib, a Syk kinase inhibitor*

– Prevents macrophage internalization of platelets• Bruton kinase inhibitors

– Prevents macrophage internalization of platelets– Ibrutinib– PRN1008

• Recombinant TPO*– Use in pregnancy

• Lusutrombopag– Another oral TPO receptor agonist– FDA approved for thrombocytopenic chronic liver

disease patients needing procedures

Development of novel agents for ITP(3) • Avatrombopag*

– Another (better?) oral TPO receptor agonist– No food interactions or hepatic issues– FDA approved for thrombocytopenic chronic liver disease

patients needing procedures– Now approved for ITP

• Low level laser light*– Prevents megakaryocyte apoptosis

• Complement inhibitor*– Antibody against C1s

• Immunoproteasome inhibitors– KZR-616: inhibits antibody production from plasma cells

FcRn pathway inhibitors

PI3K

SykPLCγBtK

FcγRIII

Lyn/LcK




IgG structure

Kazatchkine MD & Kaveri SV. N Engl J Med 2001;345:747–55FcRn, neonatal Fc receptor;

Ig, immunoglobulin

Types of Fc receptors

FcRn

FcγR

IgG – FcRn interaction

D Kuter personal communicationFcRn, neonatal Fc receptor;

Ig, immunoglobulin

FcRn α

IgG light chain

IgG heavy chain

β2 microglobulin

FcRn is widely expressed• Placenta• Parenchymal: hepatocytes, polarized epithelial

cells, endothelial cells (protect and transport IgG and albumin)

• Hematopoietic: macrophages, dendritic cells, neutrophils, B cells (protect monomeric IgG and degrade multimeric immune complexes-IgG for antigen presentation)

• Other: lung, intestines, kidney, genitourinarytract, brain, liver

FcRn, neonatal Fc receptor; Ig, immunoglobulin

The relationship between FcRn and IgG depends on valence of IgG• Monomeric IgG (or Fc-fusion proteins): recycled and

diverted from catabolism in hematopoietic and parenchymal cells

• Multimeric IgG (or antigen-antibody IC): activates FcRn-mediated signaling and movement of IC to antigen presentation pathways in hematopoietic cells that regulate CD4+ (via MHC class II) and CD8+(via MHC class I) T cells

FcRn, neonatal Fc receptor; IC, immune complexes; Ig, immunoglobulin

The relationship between FcRn and IgG depends on valence of IgG• Monomeric IgG (or Fc-fusion proteins): recycled and

diverted from catabolism in hematopoietic and parenchymal cells

• Multimeric IgG (or antigen-antibody IC): activates FcRn-mediated signaling and movement of IC to antigen presentation pathways in hematopoietic cells that regulate CD4+ (via MHC class II) and CD8+(via MHC class I) T cells

FcRn, neonatal Fc receptor;IC, immune complexes; Ig, immunoglobulin

FcRn system

Roopenian DC & Akilesh S. Nat Rev Immunol 2007;7:715–25FcRn, neonatal Fc receptor;

Ig, immunoglobulin

FcRn is critical in IgG homeostasis –protecting it from lysosomal degradation• FcRn accounts for normal transplacental

IgG transfer• No FcRn binding of IgA, IgM or IgD, IgE• FcRn gives IgG molecules their long half-life

– Normal: ~28 day– FcRn-deficient: 1–2 days

• Mice lacking FcRn protected from autoimmune diseases because of the accelerated catabolism of pathogenic IgGs

Roopenian DC & Akilesh S. Nat Rev Immunol 2007;7:715–25FcRn, neonatal Fc receptor;

Ig, immunoglobulin

Methods to block FcRn

• Monoclonal antibodies1

• Small peptides2

• Abdegs3 – ‘sticky’ IgG with increased affinity for FcRn and slow ‘off-rate’ at pH 7

1. Liu L, et al. J Immunol 2007;178:5390–8;2. Mezo AR, et al. Proc Natl Acad Sci USA 2008;105:2337–42;3. Vaccaro C, et al. Nat Biotech 2005;23:1283–8.

Selective induction of IgG clearance in cynomologus monkey by Moab to FcRN

Ling L, et al. Eur Congress Rheumatology, Rome, IT; June 10–13, 2015. Abstract THU0057

Efficacy of M281 in mouse collagen antibody-induced arthritis

Ling L, et al. Eur Congress Rheumatology, Rome, IT; June 10–13, 2015. Abstract THU0057

FcRn inhibitors in development• ARGX-113 (efgartigimod) (Abdeg)

– ITP (NCT03102593)

• SYNT001 (MoAb)– Pemphigus (Vulgaris or Foliaceus) (NCT03075904)– Chronic, Stable Warm Autoimmune Hemolytic Anemia (WAIHA)

(NCT03075878)

• UCB7665 (Rozanolixizumab) (MoAb)– Primary Immune Thrombocytopenia (NCT02718716)– Moderate to Severe Myasthenia Gravis (NCT03052751)

• M(omenta) 281 (MoAB) – Planned

Clinicaltrials.gov. Accessed October 2017

Phase 2 ITP Study Design

Argenx press release. Available at: https://www.argenx.com/en-GB/content/press-releases/37/filter/2018// Accessed October 2018.

https://www.argenx.com/en-GB/content/press-releases/37/filter/2018/

Platelet Counts Increased

Argenx press release. Available at: https://www.argenx.com/en-GB/content/press-releases/37/filter/2018// Accessed October 2018.

https://www.argenx.com/en-GB/content/press-releases/37/filter/2018/

Future direction – FcRn inhibition• May provide continuous “plasmapheresis”• May inhibit immune feedback loops

Syk kinase inhibitionFostamatinib

PI3K

SykPLCγBtK

FcγRIII

Lyn/LcK




PI3K

Syk

Ras

SOS

Rac

PKC

PLCγBtk

Lyn/LcK

DAG

IP3

Ca2+

Ca2+

PiP3

PP

ITAM

ER

FcγRIII

Cell activation/proliferation


Btk, Bruton’s tyrosine kinase; ER, endoplasmic reticulum;ITAM, immunoreceptor tyrosine-kinase-based activation motifs;

PI3K, phosphatidylinositol-3 kinase; PLCγ, phospholipase C γ; Syk, spleen tyrosine kinase

FcγRIII

Complex internalized

PI3K

SykPLCγBtK

Lyn/LcK




R788 inhibition of Syk prevents murineantibody-mediated cytopenias

Podolanczuk A et al. Blood 2009;113:3154–60

1000

800

600

400

200

0Nil Vehicle R788

25 mg/kgR788

40 mg/kgIVIg

2 g/kg

Plat

elet

cou

nt, ×

109 /L

Unmanipulated

FIT Phase 3 (Study 047 and Study 48) —Preliminary data - enrollment

Rigel Investor Call, Jan 30, 2017

Fostamatinib: response rate ITP

Stable Response: platelet counts ≥50,000/μL on at least 4 of 6 biweekly clinic visits during weeks 14-24

Overall Response: ≥1 platelet count≥50,000/μL during weeks 0-12

J Bussel et al. Am J Hematol 2018;93:921-930

Fostamatinib: platelet counts

J Bussel et al. Am J Hematol 2018;93:921-930

Fostamatinib (Tavalisse)

• Modest response rate• FDA approved for the treatment of

thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Recombinant TPO

TPO – Mechanism of Action in ITP- TPO Receptor Antiplatelet ab attacks Mk



- TPO

TPO to the rescue

rhTPO in the management of ITP in pregnancy

Kong Z, et al. Blood 2017;130:1097–103

rhTPO in the management of ITP in pregnancy: study protocol

PLT, platelet; qd, daily; qod, every other day; qw, weeklyKong Z, et al. Blood 2017;130:1097–103

Dose scheme of rhTPO

rhTPO in the management of ITP in pregnancy: results• 74% (23/31)

responded • Bleeding was absent

in 81% (25/31) of mothers

• Babies did well• Platelet counts

gradually dropped after withdrawal

Kong Z, et al. Blood 2017;130:1097–103

Recombinant TPO• Only available in China• Will probably never be approved outside of

China due to lack of safety information

Avatrombopag (AKR-501, YM-477, E5501, Doptelet)

Another (better?) oral TPO receptor agonist

TPO – Mechanism of Action in ITP- TPO Receptor Antiplatelet ab attacks Mk



- TPO

TPO to the rescue

Avatrombopag• Orally active small molecule TPO agonist• Stimulates growth of TPO-dependent lines• Increases ‘human’ platelet count in mice engrafted

with human stem cells• Effects additive to rhTPO in vitro and in vivo• In healthy humans:

– Dose-dependent rise in platelets with single and multiple doses

• No food interactions• More potent than eltrombopag• No hepatic toxicity• New data in patients with ITP

rhTPO, recombinant human thrombopoietin

Desjardins RE, et al. Blood 2006;108:abstract 477;Fukushima-Shintani M, et al. Exp Hematol 2009;82:247–54;Bussel JB, et al. Blood 2014;123:3887–94;Shih A, et al. Presse Med 2014;43:e87–95D Kuter & L Allen. Brit J Haematol 2018;183:466-478

Avatrombopag 20 mg/day x 10 days: change from baseline platelet counts

DJ Kuter & L Allen. Brit J Haematol 2018;183:466-478

Avatrombopag 20 mg/day x 10 days: change from baseline platelet counts

DJ Kuter & L Allen. Brit J Haematol 2018183:466-478.

Avatrombopag versus eltrombopag in healthy subjects

Dose (mg)

Study 002

Study 001

GSK ASH Abstract 2004

0 20 40 60 80 100 1200

100

200

300

400 E5501 daily dose for 10 days

E5501 single dose

Eltrombopag daily for 10 days

Plat

elet

cou

nt (x

1000

)m

ean

chan

ge fr

om b

asel

ine

Desjardins RE, et al. Blood 2006;108:abstract 477;Jenkins J et al. Blood 2007;109:4739–4741.

Platelet count response – Day 28

Bussel J et a. Blood 2014;123:3887-3894. Bussel J et al. Haematologica 2011;96(S2):abstract 525

Median platelet counts

Bussel J et a. Blood 2014;123:3887-3894. Bussel J et al. Haematologica 2011;96(S2):abstract 525

Avatrombopag maintained the target platelet count (50 to

Avatrombopag Phase III – Patient Disposition

Jurczak W, et al. Br J Haematol. 2018;183:479-490. Published Online, https://doi.org/10.1111/bjh.15573

https://doi.org/10.1111/bjh.15573

Primary Efficacy Analysis PBO(N=17)AVA

(N=32)Cumulative Number of Weeks with a Platelet Responsea

Mean (SD), weeks 0.1 (0.49) 12.0 (8.75)Median, weeks 0.0 12.4Min, Max 0, 2 0, 25

P-value of Wilcoxon rank sum test

Avatrombopag maintained the target platelet count (50 to

Avatrombopag Phase III – Extension Study

Jurczak W, et al. Br J Haematol. 2018;183:479-490. Published Online, https://doi.org/10.1111/bjh.15573

https://doi.org/10.1111/bjh.15573

Avatrombopag• Avatrombopag (Doptelet) is indicated for the

treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure

• Approved for treatment of ITP USA (June 27, 2019)

Low-level laser light therapy for thrombocytopenia

New research article: Non-invasive, low-level laser therapy for thrombocytopenia

Zhang Q, et al. Sci Transl Med 2016;8:349ra101.

Proplatelet formation in vitro

Italiano JE, et al. J Cell Biol 1999;147:1299–1312.

Proplatelet formation in vivo

Zhang L, et al. J Exp Med 2012;209:2165–2181.

Background information• Mitochondrial function important for MK growth

– Gene X-1 (IEX-1) enhances ATP synthesis in mitochondria– IEX-1 null mice develop thrombocytopenia– Mitoquinone (mitochondrial antioxidant) rescues

• Low-level laser (LLL) light activates cytochrome C oxidase in mitochondria– Increases mitochondrial function

• ↑ Membrane potential• ↑ ATP• ↓ Apoptosis

• LLL rescues IEX-1 null MKs• Isolated CD40 cells can differentiate into MK in vitro

and make platelets (proplatelets)

ATP, adenosine triphosphate.

Effect on cultured mouse MKs

FSC, forward scatter; FSChigh, high forward scatter; PPF, proplatelet-forming.Zhang Q, et al. Sci Transl Med 2016;8:349ra101.

Platelet differentiation from MKs ex vivo

Cultured MKs increase in size

h, hours; IMS, invaginated membrane system; N, nuclear.Zhang Q, et al. Sci Transl Med 2016;8:349ra101.

Transmission electron micrographs anddiameter of MKs at 0 and 24 h after LLL

Cultured MKs make more platelet-forming MKs

*Small was considered

Cultured MKs make more platelets in vitro

PLTs, platelets.Zhang Q, et al. Sci Transl Med 2016;8:349ra101.

Number of platelets 3 days after LLL

LLL to whole mouse increases ATP…• 5 minutes whole body with 810 nm laser• 30 J/m2 = 3 J/m2 to bone marrow

*Percentages of PPF-MKs were determined from at least 50 MKs per femur.Zhang Q, et al. Sci Transl Med 2016;8:349ra101.

Proportion of PPF-MKs in femur*24 h after whole-body LLL

ATP in isolated BMs1 h after whole-body LLL

… but has no effect on blood counts withdaily treatment

Zhang Q, et al. Sci Transl Med 2016;8:349ra101.

Circulating platelets and BM MKs afterLLL once every other day for 12 days

LLL increases platelets in mouse ITP model(anti-CD41 Ab)

**P

LLL light prevents MK apoptosis

- TPO receptor Antiplatelet Ab attacks MK- Antiplatelet Ab

- Antiplatelet lymphocyte

Lymphocyte attacks MKMK undergoes apoptosis

Mitochondria become less active and caspases activated

LLL light

Mitochondria rechargedMK viability increased

MK needs mitochondria

Slide courtesy of D. Kuter.

Complement inhibition

PI3K

SykPLCγBtK

FcγRIII

Lyn/LcK




SykPLCγBtK

FcγRIII

Lyn/LcK


PI3K



How complement destroys blood cells

S Berentsen & T Sundic. Biomed Res Int 2015; S Berentsen. Hematology 2016 (ASH Educational Supplement) 2016;226-231

Does complement play a role in ITP?

Y Kurata et al. Brit J Haematol 1985;60:723-733.

Platelet associated complement (PAC) in normal subjects (C) and chronic ITP patients

Y Kurata et al. Brit J Haematol 1985;60:723-733.

New C1s inhibitor: BIVV009

Summary• Anti-CD40L may alter production of anti-platelet antibody• Inhibition of FcRn may provide “medical plasmapheresis”• Sialylated IVIg, stradomers and Staph Protein A may be

“super IVIg”• Syk kinase inhibition (fostamatinib) and Bruton kinase

inhibition (ibrutinib) may reduce rate of phagocytosis• Any of the these new molecules may also affect underlying

immune causes of ITP• rhuTPO may be effective in treating ITP during pregnancy• Avatrombopag may be a better oral TPO receptor agonist• Low level laser light may prevent megakaryocyte apoptosis• Complement inhibition is being tested• No treatment (yet) that ‘cures’ ITP

FcRn, neonatal Fc receptor;IVIg, intravenous immunoglobulin;

Syk, spleen tyrosine kinase

Slide Number 1Conflicts of interest disclosure ITP is Due to Increased Platelet DestructionSlide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8ITP is Due to Increased Megakaryocyte Apoptosis (death)Slide Number 10Therapeutic Approaches to ITPResponse rates of some current therapiesWhat’s New in ITP�Proposed ASH Adult ITP Guidelines - SummaryProposed ASH Pediatric ITP Guidelines - SummaryDevelopment of novel agents for ITP (1) Development of novel agents for ITP(2) Development of novel agents for ITP(3) FcRn pathway inhibitorsSlide Number 20Slide Number 21IgG structureIgG – FcRn interactionFcRn is widely expressedThe relationship between FcRn and IgG depends on valence of IgGThe relationship between FcRn and IgG depends on valence of IgGFcRn systemFcRn is critical in IgG homeostasis – protecting it from lysosomal degradationMethods to block FcRnSelective induction of IgG clearance in cynomologus monkey by Moab to FcRNEfficacy of M281 in mouse collagen antibody-induced arthritisFcRn inhibitors in developmentPhase 2 ITP Study Design Platelet Counts IncreasedPlatelet Counts IncreasedFuture direction – FcRn inhibitionSyk kinase inhibitionSlide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43R788 inhibition of Syk prevents murine antibody-mediated cytopeniasFIT Phase 3 (Study 047 and Study 48) — Preliminary data - enrollmentFostamatinib: response rate ITPFostamatinib: platelet countsFostamatinib (Tavalisse) Recombinant TPOTPO – Mechanism of Action in ITPrhTPO in the management of ITP in pregnancyrhTPO in the management of ITP in pregnancy: study protocolrhTPO in the management of ITP in pregnancy: resultsRecombinant TPOAvatrombopag (AKR-501, YM-477, E5501, Doptelet) TPO – Mechanism of Action in ITPAvatrombopagAvatrombopag 20 mg/day x 10 days: �change from baseline platelet countsAvatrombopag 20 mg/day x 10 days: �change from baseline platelet countsAvatrombopag versus eltrombopag in healthy subjectsPlatelet count response – Day 28Median platelet countsAvatrombopag Phase 2 ITP Efficacy Data:�Median Platelet Count over TimeAvatrombopag Phase III – Patient DispositionAvatrombopag Phase III – Efficacy Data – Responder AnalysisAvatrombopag Phase III – Efficacy Data – Median Platelet Count Over TimeAvatrombopag Phase III – Extension StudyAvatrombopag�New research article: Non-invasive, low-level laser therapy for thrombocytopeniaProplatelet formation in vitroProplatelet formation in vivoBackground informationEffect on cultured mouse MKsCultured MKs increase in sizeCultured MKs make more platelet-forming MKsCultured MKs make more platelets in vitroLLL to whole mouse increases ATP…… but has no effect on blood counts with�daily treatmentLLL increases platelets in mouse ITP model�(anti-CD41 Ab)LLL light prevents MK apoptosis�Slide Number 83Slide Number 84Slide Number 85Slide Number 86Slide Number 87Slide Number 88How complement destroys blood cellsDoes complement play a role in ITP?Platelet associated complement (PAC) in normal subjects (C) and chronic ITP patientsNew C1s inhibitor: BIVV009SummarySlide Number 94