Emerging MOAs in Lupus

The original anti-CD20

•Binds to CD20,leading to cell death and B cell depletion

•Significant off-label use

•Failed PIII studies in SLE and LN (trial design issues)

The original anti-CD20

•Binds to CD20,leading to cell death and B cell depletion

•Significant off-label use

•Failed PIII studies in SLE and LN (trial design issues)

B cellB cell

rituximab

CD20

Rituximab

Roche/GenentechPhase III

2nd generation anti-CD20

•BELONG trial in LN suspended due to infections

2nd generation anti-CD20

•BELONG trial in LN suspended due to infections

ocrelizumab

B cellB cell

CD20

GenentechBiogen-Idec

Ocrelizumab

Anti-CD22

Binds to CD22 (“an inhibitory B cell co-receptor”) •Cell death & partial B cell depletion•Anti-activation of B cells (“negative B cell signaling”)

Anti-CD22

Binds to CD22 (“an inhibitory B cell co-receptor”) •Cell death & partial B cell depletion•Anti-activation of B cells (“negative B cell signaling”)

B cellB cell

CD22

epratuzumab

Epratuzumab

UCBPhase III

BlyS blockade

Binds to soluble BlyS* (a B cell survival cytokine) blocking it from binding to the TACI° receptor•Inhibits B cell hyperactivity & activation•Blocks differentiation into plasma cells•Some B cell depletion

*B lymphocyte stimulator °Transmembrane activator and calcium-modulating cyclophilin ligand interactor;

BlyS blockade

Binds to soluble BlyS* (a B cell survival cytokine) blocking it from binding to the TACI° receptor•Inhibits B cell hyperactivity & activation•Blocks differentiation into plasma cells•Some B cell depletion

*B lymphocyte stimulator °Transmembrane activator and calcium-modulating cyclophilin ligand interactor;

B cellB cell

Soluble BlyS

TACIreceptor

Belimumab

Membrane-bound BlyS

Belimumab (benlysta)

HGS/GSK

Complete BlyS blockade

•Blocks BOTH soluble and membrane-bound BlyS from binding to TACI and activating the B cell•Will be available in SQ formulation

Complete BlyS blockade

•Blocks BOTH soluble and membrane-bound BlyS from binding to TACI and activating the B cell•Will be available in SQ formulation

LY2127399

LillyPhase III

B cellB cell

Soluble BlyS

TACIreceptor

Membrane-bound BlyS

LY2127399

Complete BlyS blockade

•Fusion protein: a BAFF* binding domain + Ig constant portion•Binds both soluble and membrane-bound BlyS•Will be available in a SQ formulation

Complete BlyS blockade

•Fusion protein: a BAFF* binding domain + Ig constant portion•Binds both soluble and membrane-bound BlyS•Will be available in a SQ formulation

Blisibimod

AntheraPIIb

B cellB cell

Soluble BlyS

TACIreceptor blisimibod

Membrane-bound BlyS

*B cell activating factor

Complete BlyS blockade

•Fusion protein of the TACI* receptor + Ig constant portion•Binds BlyS OR APRIL° preventing B cell activation by either ligand•PII halted in lupus nephritis; trial in SLE ongoing

*Transmembrane activator and CAML interactor (calcium-modulator and cyclophilin ligand)°A proliferation-inducing ligand

Complete BlyS blockade

•Fusion protein of the TACI* receptor + Ig constant portion•Binds BlyS OR APRIL° preventing B cell activation by either ligand•PII halted in lupus nephritis; trial in SLE ongoing

*Transmembrane activator and CAML interactor (calcium-modulator and cyclophilin ligand)°A proliferation-inducing ligand

Atacicept

MerckPIII

B cellB cell

TACIreceptor

Membrane-bound BlyS

BlyS

Atacicept

APRIL

Anti-interferon α

•Anti-IFNα receptor2 Moab•Biomarker test for IFNα gene signature (personlized medicine)

• Relationship between levels and disease activity has been demonstrated

•Both IV and SQ being studied

Anti-interferon α

•Anti-IFNα receptor2 Moab•Biomarker test for IFNα gene signature (personlized medicine)

• Relationship between levels and disease activity has been demonstrated

•Both IV and SQ being studied

Sifalimumab

AZ/MedimmunePII

pDCpDC

Cytokines and tissue damage

Differentiation, autoantibodies

B cellB cellT cellT cell

sifalimumab

Anti-interferon α

•Anti-IFNα receptor2 moab•Biomarker test for IFNα gene signature

• Relationship between levels and disease activity has been demonstrated

•Both IV and SQ being studied

Anti-interferon α

•Anti-IFNα receptor2 moab•Biomarker test for IFNα gene signature

• Relationship between levels and disease activity has been demonstrated

•Both IV and SQ being studied

Rontalizumab

Roche/GenentechPII

pDCpDC

Cytokines and tissue damage

Differentiation, autoantibodies

B cellB cellT cellT cell

Rontalizumab

Co-stimulatory blockade

•Fusion protein of CTLA-4* + Ig constant portion•Binds with CD80/86 on B cell, thereby blocking the ability to bind to CD28 on T cell•“T cell inhibition”•Ongoing PII/III trials for lupus nephritis; PII for SLE halted

*Cytotoxic T-lymphocyte-antigen 4

Co-stimulatory blockade

•Fusion protein of CTLA-4* + Ig constant portion•Binds with CD80/86 on B cell, thereby blocking the ability to bind to CD28 on T cell•“T cell inhibition”•Ongoing PII/III trials for lupus nephritis; PII for SLE halted

*Cytotoxic T-lymphocyte-antigen 4

Abatacept

BMSPII-III

B cellB cell T cellT cell

CD80

CD86

CD28

abatacept

T cell modulation

•CD4 T cell modulation•“Modulates rather than immunosuppresses”•May have potential to be used with other lupus agents b/c of lack of B cell action•Trial endpoints: reduction in anti-dsDNA antibodies & increase in IL-10

T cell modulation

•CD4 T cell modulation•“Modulates rather than immunosuppresses”•May have potential to be used with other lupus agents b/c of lack of B cell action•Trial endpoints: reduction in anti-dsDNA antibodies & increase in IL-10

Forigermod (Lupuzor)

CephalonPIIb

T cellT cell

CD4

Anti-proliferative

•Anti-proliferative, inhibiting de novo synthesis of guanosine nucleotides (RNA)•T and B cells are more dependent on this pathway than other cell types•Off label use•In study in lupus nephritis, flare rate was 16% vs. 32% with AZT

Anti-proliferative

•Anti-proliferative, inhibiting de novo synthesis of guanosine nucleotides (RNA)•T and B cells are more dependent on this pathway than other cell types•Off label use•In study in lupus nephritis, flare rate was 16% vs. 32% with AZT

Mycophenolate mofetil (Cellcept)

Roche

B cellB cell T cellT cell

Anti-proteosome

•Proteasomes degrade intracellular proteins in a regulated manner •Inhibition of the normal degradation of intracellular proteins leads to disruption of cellular proliferation and cell death

Anti-proteosome

•Proteasomes degrade intracellular proteins in a regulated manner •Inhibition of the normal degradation of intracellular proteins leads to disruption of cellular proliferation and cell death

Proteosome inhibition

PI

Proteasomes

Anti-proteosome

•Plasmacytoid dendritic cells express TLR7 and TLR9•When bound by ligands, they produce a large amount of IFN-α

Anti-proteosome

•Plasmacytoid dendritic cells express TLR7 and TLR9•When bound by ligands, they produce a large amount of IFN-α

TLR inhibition

Dynavax/othersPI

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Laquinimod

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TWEAK

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Kinoid vaccine

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