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
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