New Treatments For Lupus

Joan T Merrill, M.D.

Head Clinical Pharmacology Research Program

Oklahoma Medical Research Foundation

OMRF Professor of Medicine

University of Oklahoma

Genentech/Roche UCB

GSK Questcor

EMD Serono Argos

Pfizer Abbott

Abbvie Celgene

Neovacs Ono

Cephalon Astellas

BMS Baxter

Medimmune RPS

Amgen Parexel

Lilly Eisai

Takeda Incyte

Biogenldec Exagen

Macrogenics Novo Nordisk

Kirin Jannsen

DISCLOSURES

Pathways For Modern Medical Treatment Development

Were Created in the 20th Century

Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197

Plasmacytoid DCs

Cytokines

Migrate to

target organs

Lymphoid

organization

B cells

IFN-

sBAFF aka

BLyS

T cells

Anti-dsDNA

IL 17

complement

Myeloid

Plasmacytoid

DCs

MORE BLyS in Only 50% of Patients

0

10

20

30

40

50

Normal

(n = 38)

SLE sera

(n = 40)

P <0.0001

RA

(n = 44)

P <0.001

SLE plasma

(n = 110)

P <0.0001

BLy

S P

rote

in (

ng

/mL

Zhang J et al. J Immunology. 2001;166:6-10

To What Extent is This Impacted By Background Meds?

0

10

20

30

40

50

Normal

(n = 38)

SLE sera

(n = 40)

P <0.0001

RA

(n = 44)

P <0.001

SLE plasma

(n = 110)

P <0.0001

BLy

S P

rote

in (

ng

/mL

Zhang J et al. J Immunology. 2001;166:6-10

Plaquenil

Azathioprine

MMF

MTX

STEROIDS

Navarra, et al. Lancet. 2011;377(9767):721-31

Furie, et al. Arthritis Rheum. 2011;63(12):3918-30

1 mg/kg belimumab

60

40

20

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

SR

I R

esp

on

ders

(%

)

+ + + *

+ *

+ *

+ *

+ *

+ *

+ *

* p<0.05 + p<0.05

10 mg/kg belimumab Placebo

50

40

30

20

10

0

0 4 8 16 24 32 40 48 52 60 68 76

Visit Week

% S

RI R

esp

on

de

rs

*

Belimumab –Phase III Trial Results 97-98% Had Measurable BLys, but how High?

p<0.05

SRI, SLE Responder Index

IMNL-SCT-019799

BELONG Ocrelizumab Study: Week 48 Renal Response Background Treatment with MMF vs EuroLupus

Major Difference is in the “Placebo” Group

0 75 148 N 28 64 47 84 N N

All Patients EuroLupus Mycophenolate mofetil

% P

atie

nts

20

40

60

80

100 Placebo OCR Total: Combined Doses

43

55

67 66 62

68

Mysler Arth Rheum 65; 9, 2013: 2368–2379

1 mg/kg belimumab

60

40

20

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

SR

I R

esp

on

ders

(%

)

+ + + *

+ *

+ *

+ *

+ *

+ *

+ *

* p<0.05 + p<0.05

10 mg/kg belimumab Placebo

50

40

30

20

10

0

0 4 8 16 24 32 40 48 52 60 68 76

Visit Week

% S

RI R

esp

on

de

rs

*

Belimumab – Must We Decrease

Background Medications in Very Ill patients?

p<0.05

IMNL-SCT-019799

14.4% difference

9.8% difference

Navarra SV Lancet. 2011; 377:721-731; Furie R Arth Rheum. 2011 63:3918-30 van Vollenhoven Ann Rheum Dis 2012; 71:1343-9.

1 mg/kg belimumab

60

40

20

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

SR

I R

esp

on

ders

(%

)

+ + + *

+ *

+ *

+ *

+ *

+ *

+ *

* p<0.05 + p<0.05

10 mg/kg belimumab Placebo

50

40

30

20

10

0

0 4 8 16 24 32 40 48 52 60 68 76

Visit Week

% S

RI R

esp

on

de

rs

*

Belimumab - Less Background Medication,

Better Discrimination

p<0.05

IMNL-SCT-019799

Patients With Higher Baseline Disease Activity Anti dsDNA and Low Complement

19.8% difference

14.4% difference

9.8% difference

Navarra SV Lancet. 2011; 377:721-731; Furie R Arth Rheum. 2011 63:3918-30 van Vollenhoven Ann Rheum Dis 2012; [Epub ahead of print].

Efficacy in a Sicker Subset: Abatacept Exploratory Analysis: Proteinuria in Nephrotic Patients

31.7

63.3

73.3

79.9

16.1

61.2

75.5

84.3

34.0

40.3 43.8

52.7

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

Month 1 Month 6 Month 9 Month 12

Abatacept 30/10 mg/kg Abatacept 10/10 mg/kg Placebo

Me

dia

n %

imp

rove

me

nt

fro

m b

ase

line

U

PC

R (

mg

/mm

oL)

n= 38 36 44 33 30 37 30 37 34 30 35 33

122/298 (42%) of patients were nephrotic at baseline (UPCR >3.0 g/g)

EXPLORATORY DATA IN CLINICAL TRIALS FOR SLE AGENT Sicker Subset Less Meds REFERENCE

DHEA (Genelabs) YES Petri Arth Rheum 2002 46:1820

Riquent (LJP) Cardiel Arth Rheum 2008 58:2470

Anti-CD40L (Biogen) Biogen Inc. Press Release 2 Jan 1999

Anti-CD40L (IDEC) Kalunian Arth Rheum 2002 46:3251

Edratide (TEVA) TEVA Press release 19 Sep 2007

Rituximab (Genentech) YES (2 TRIALS) YES Merrill Arth Rheum 2010 62:222-33

Abatacept (BMS) YES (2 TRIALS) YES Merrill Arth Rheum 2010 62:3077-87

Sifalimumab (MedImm) Merrill Ann Rheum Dis 2011 70:1905

Ocrelizumab YES YES Brunetta ACR abstract 2011

Atacicept (EMD Serono) Ginzler Arth Res Ther 2012 14:R33

Blisibimod (Anthera) YES Anthera Press Release 28 Jun 2012

Rontalizumab Yes Kalunian ACR abstract 2012

Lupuzor Zimmer R Ann Rheum Dis 2013

Epratuzumab (UCB) Yes Wallace Ann Rheum Dis 2013 epub

Belimumab P3 GSK) YES Navarra Lancet. 2011; 377:721-31 Furie Arth Rheum 2011 63:3918-30

What About Genetics?

Renal Survival of Class IV LN at UNC: All patients

received standard of care with cyclophosphamide

P = .007

Years From Renal Biopsy Dooley. Kidney Int. 1997;51:1188.

n = 39

n = 51

0

20

40

60

80

100

120

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Non-African

African descent

% by Descent Group

Ginzler 1 Chan ALMS 2

African 56.4 70.7 0

27

Hisp1/Other2 14.3

Caucasian 17.1 0 39.7

Asian 5.7 100 33.2

MMF vs CYC Induction Trials: Population Differences Between

1 Trial Suggesting MMF Superiority to Cyc and 2 That Did Not

Ginzler NEJM 353:2219 2005 Appel JASN 20:1103 2009 Chan J Am Soc Neph:16:1076 2005

Response Rate by Race: ALMS Trial: Induction

Appel GB et al. J Am Soc Nephrol. 2009;20:1103-1112.

56.2 53.2

56.0 60.4

53.0

63.9

54.2

38.5

0

10

20

30

40

50

60

70

80

90

100

Overall Asian Caucasian Other

Pati

en

ts r

es

po

nd

ing

(%

)

MMF

IVC

P = 0.033

P = 0.834

P = 0.236

P = 0.575

Confirmed by TM Chan, Ginzler, Dooley

Lunar Primary Endpoint: Renal Response at week 52 Rituximab or Placebo Added to MMF

30.6

15.3

45.9

26.4 30.6

57.0

0

10

20

30

40

50

60

Complete Renal Response (CR)

Partial Renal Response (PR)

Complete + Partial (CR +PR)

Pro

po

rtio

n o

f P

atie

nts

Placebo (N=72) Rituximab (N=72)

P=0.55*

Wilcoxon Rank-sum test to compare the proportions of (CRR, PRR, NR) between rituximab and placebo

Mean MMF dose: Placebo: 2.4±0.62 g; Rituximab: 2.7±0.41 g

CRR AND PRR: 46% (PLA) vs. 57% (RTX)

Complete + Partial =57% in Rituximab Group

11.1 % Difference

Rovin Arth Rheum. 2012 64:1215-26

Lunar Pre-Specified Analysis: Proportion of Subjects Achieving Response (CR + PR) by Race

Rituximab/Placebo Added to MMF

9/20 14/20 11/23 16/29 13/26 10/19

45.0 47.8

50.0

70.0

55.0 52.6

0%

10%

20%

30%

40%

50%

60%

70%

80%

Black (n=40) Hispanic (n=52) Caucasian (n=45)

Re

spo

nse

Pro

po

rtio

n

Placebo Rituximab

25% Difference

Rovin Arth Rheum. 2012 64:1215-26

MORE BLyS vs Less BLyS Drugs or Genetics?

0

10

20

30

40

50

Normal

(n = 38)

SLE sera

(n = 40)

P <0.0001

RA

(n = 44)

P <0.001

SLE plasma

(n = 110)

P <0.0001

BLy

S P

rote

in (

ng

/mL

Zhang J et al. J Immunology. 2001;166:6-10

RNA Expression Studies on BOLD Blood Samples: Association of IFN Signal with

AA, NA, anti-dsDNA, low complement rtPCR on 258 genes - known association with lupus 30 IFN pathway genes used for hierarchical clustering

Brightest Green

Highest expression

Healthy Average

Black Brightest Red

Lowest expression

13

6 B

loo

d R

NA

Sam

ple

s

30 IFN Pathway genes dCT+12 dCT-12 0

Seyan et al EULAR 2012

47% of BOLD Patients Had High Interferon Signature Gene Expression Using an 11 Gene Set Previously Described

centered log2-expression black = healthy mean

Pati

en

t-vis

its

Low

High

P-11

Genes

Cauc vs other p=0.012

Population % IFN High

All Patients 47%

Caucasians* 38%

Asian 50%

Afr American 65%

Nat American 69%

% with IFN High IFN Low p value

Anti dsDNA 30% 2% 0.0001

SSA/RO 30% 4% 0.0007

RNP 37% 0% 0.0001

Sm 13% 0% 0.01

Hill EULAR 2012 Merrill ACR 2013

p=0.0023

p =0.0096

Seyhan et al EULAR 2012

Impact of Interferon Signals on BLyS Levels

BLyS (pg/ml)

Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197

Plasmacytoid DCs

Cytokines

Migrate to

target organs

Lymphoid

organization

B cells

IFN-

sBAFF aka

BLyS

T cells

Anti-dsDNA

IL 17

complement

Myeloid

Plasmacytoid

DCs

FACTORS ELEVATED IFN HI/LOW p value

BLyS (TNSF13B) gene expression 0.005

BLyS protein 0.00018

IL17RA gene 0.009

IL23A gene ns

IL23 (p19) 0.02

Relationship Between Type I IFN, IL17and BLyS Pathways in SLE

Corroboration of Connections Between Type I IFN, IL17 and BLyS Pathways in Autoimmune Diseases: Ambrosi A Eur. J. Immunol. 2012. 42: 2274–2284 Mitsdoerffer M Proc Natl Acad Sci USA 107:14292–14297 Doreau A Nat Immunol 10:778–785 Vaknin-Dembinsky A Mult Scler. 2010 16:1453-7. Cuong Q Arthritis Res Ther. 2010; 12: R220 Wang H J Clin Immunol 2012 32:1007-11. Li Y J Neuroimmunol 2011 234:155-60. Merrill ACR 2013

All Patients IFN Hi IFN Lo

Marker Rx Fold decrease

p value

Fold decrease

p value

Fold decrease

p value

IL17 RA RNA

MTX 1.23 0.047 1.33 0.03 ns

MMF 1.4 0.01 ns 1.77 0.004

AZA 1.17 0.08 ns 1.3 0.03

TNSF13B BLyS RNA

Hydclq 1.64 0.09 3.6 0.001 ns

IMPACT OF COMMON SOC TREATMENTS

On Expression of IL17 and BLyS Pathway Genes

DEPENDS ON IFN GROUP

Compared to Patients Not Taking IS (All patients had SLEDAI >/=6 or >/= 2 BILAG B)

Merrill ACR 2013

Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197

Plasmacytoid DCs

Cytokines

Migrate to

target organs

Lymphoid

organization

B cells

IFN-

sBAFF aka

BLyS

T cells

Anti-dsDNA

IL 17

complement

Myeloid

Plasmacytoid

DCs

Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197

Cytokines

Migrate to

target organs

Lymphoid

organization

B cells

T cells

Anti-dsDNA

complement

Myeloid DCs

Plasmacytoid

DCs

BLyS/April Inhibitors

BELIMUMAB BLISIBIMOD

TABALUMAB

ATACICEPT

T Cell or T/B Cell Interaction Modulators

ABATACEPT

ICOS INH

Anti-IL17/23

Laquinimod

Lupuzor

Anti-IL6

B Cell Targeting

RITUXIMAB

OCRELIZUMAB

EPRATUZUMAB

IFN alpha antagonists

RONTAZLIZUMAB

SIFALIMUMAB

TLR INH

Myeloid inhibitors

GCSF INH

TNF antagonists

SICKER PATIENTS NEED MORE MEDICATIONS WON’T OBSCURE ENDPOINTS Anthera: Blisibimod

MODERATELY ILL PATIENTS LESS MEDICATIONS IMPROVE BIIOMARKER INVESTIGATION TBD: ACR 2014

SICKER PATIENTS NEED MORE MEDICATIONS WON’T OBFUSCATE ENDPOINTS Anthera: Blisibimod

MODERATELY ILL PATIENTS LESS MEDICATIONS IMPROVE BIIOMARKER INVESTIGATION TBD: ACR 2014

BETTER BIOMARKER CHARACTERIZTION Genentech: Rontalizumab TBD: ACR 2014 DOSE OPTIMIZATION BASED ON BIOMARKERS TBD: ACR 2014

PRECISION MEDICINE