Sarcoidosis and Biologics

Daniel Culver, DO
Department of Pulmonary, Allergy, and Critical Care Medicine
Respiratory Institute
Cleveland, OH

Sarcoidosis disclosures
• Clinical trials
– Janssen
– Pfizer
– Gilead
– Actelion
– Araim

• Research support/consulting
– Glaxo-Smith-Kline
– NHLBI
– Celgene

No medication is FDA-approved for

use in sarcoidosis
Rising sarcoidosis mortality in the
US
Non-hispanic Males: Numbers of Deaths and Age-adjusted Mortality Rates
per 1,000,000 Men
350 20

Mortality Rate per 1,000,000 Population

18
300
16
250 14
Numbers of Deaths

12
200
10
150
8
Deaths: Non- hispanic White Males
Deaths: Non- hispanic Black Males 6
100 Mortality Rates: Non- hispanic White Males
Mortality Rates: Non- hispanic Black Males 4
50
2

0 0
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
89

91

93

95

97

99

01

03

05

07
19

19

19

19

19

19

20

20

20

20
Swigris JJ. AJRCCM 2011

Sarcoidosis vs. other inflammatory

diseases in North America
25

20
Rough prevalence/1000
15 RCT/year x 100 (PubMed)
FDA approved medications
10

0
RA PS M CD SA
O S RC
RI
AS
IS
 Outline

• Review the experience

with traditional anti-TNF
medications
• Results of the recent
golimumab/ustekinumab
trial

Sarcoidosis was first recognized in

1869

Jonathan Hutchinson “Mortimer’s Malady” Caesar Boeck

1828-1913 1845-1917
Serum amyloid A hypothesis

Chen ES. Nat Rev Rheumatol 2011

 TNF: pleiotropic role in granulomas

Stenger. Ann Rheum Dis 2005

Effect of TNF antagonists on MTB-

stimulated monocytes
Median IFN gamma reduction
100
IFX
80 ADA
% of control

ETN
60

40

20

0
None Trough Peak Supra xx

Saliuo. J Infect Dis 2006; 194:486

 Main immunosuppressive options
rituximab
adalimumab
Corticosteroids cyclophosphamide infliximab
golimumab
azathioprine

1869 2013

thalidomide
pentoxifylline
Colchicum
antimalarials
Arsenic methotrexate leflunomide
Acid iron
Potassium iodide chlorambucil mycophenolate
Lead/mercury ointment

Infliximab was effective but not

earth-shattering

Mean change in % predicted FVC from baseline

4
*

0
Placebo Baughman-all Baughman- Rossman
severe (FVC
<69%)

* Patients with higher SGRQ, disease > 2 years, MRC dyspnea >1
also showed more benefit

Baughman RP. Clin Chest Med 2008 Rossman MD. SVDLD 2006
 How good is the “gold standard”
(prednisone)?
• n=53 patients treated with prednisone for 3-8 weeks
• Median FVC improvement 5.4%
• Median DLCO improvement was 10.3%
• >5% improvement of FVC was highly associated with improved
MRC dyspnea and with patient global impression of benefit

Effect of infliximab on
extrapulmonary sarcoidosis

Judson MA. Eur Respir J 2008; 31:1148

 Does ACE help?

Correlation with respiratory functional impairment in 144 non-smoking patients

Rothkrantz-Kos S. Clin Chem 2003

CXR fibrosis does not preclude a

response to infliximab
FVC (liters)

n=43
 Lazar CA. SRCCM 2010

Main points to date

• We have learned most about how to use
these agents by extrapolation
• There are no controlled trials for
comparing TNF antagonists
• Infliximab is the current standard for
sarcoidosis among the available agents
• There are inter-individual and inter-organ
differences in response
 Effect of IFX on lupus pernio

Percent with resolution, near resolution, or improvement

100%

80%

60%
Not better
Better
40%

20%

0%
AG CS CS + AG IFX n=54

Stagaki E. Chest 2008

Infliximab response rates at CCF:

four most common indications
100%

Marked benefit
50% Moderate
Minimal or none

0%
>90% able to reduce
PULM CNS SKIN SURT steroid dose
N=50
Sodhi M. Respir Med 2008
 Outline

• Review the experience

with traditional anti-TNF
medications
• Results of the recent
golimumab/ustekinumab
trial

Role of IL-12/23 p40 and TNF

in Sarcoidosis

Courtesy of Rosemary Watt

 Elevated TNF and IL-12p40 mRNA
in Cutaneous Lesional Skin

TNF p40

p<0.05
p<0.05
p<0.05
p<0.01
10000 1000

(relative to GAPDH)
(relative to GAPDH)

RNA expression
RNA expression

100

1000 10

100 0.1
Normal Sarcoid Sarcoid Normal Sarcoid Sarcoid
NL TL NL TL

Judson MA. JAAD 2012

Path to identify more responsive

subgroup inT48 study
Compared to Placebo
Criteria LS Mean
FVC SGRQ 6MWD
All Subjects
(n=138) 3 mg/kg +3.2 +1.0 -3
5 mg/kg +2.0 0.0 +1
 50% < FVC < 80% and
Subjects with 6MWD < 550 m
more severe
pulmonary 3 mg/kg +5.3 -3.2 -11
disease 5 mg/kg +3.2 -1.9 +4
(n=93)
Number of years
since diagnosis  2
 years
Subjects
with chronic 3 mg/kg +5.4 -3.7 -10
sarcoidosis 5 mg/kg +4.4 -5.2 +12
(n=84)
ATS dyspnea score > 1 or
 ATS dyspnea score = 1
plus post-6MW Borg  3
Subjects with
greater 3 mg/kg +5.9 -6.4 +13
symptoms 5 mg/kg +4.7 -10.4 +35
(n=73)
 Ustekinumab Mechanism of
Action
IL-23 IL-12
p19 p40 Ustekinumab p40 p35

NK or T cell
membrane

No IL-12 or IL-23 cellular activation

1275148SCD2001 Study Design

Placebo SC at Wk 0, 4, 8, 12, 16, 20 (n=60)
180 Pts with
Chronic Sarcoidosis
Primary Population: Ustekinumab (anti-IL12/23) 180 mg SC at Wk 0; 90 mg SC at Wk 8,
Pulmonary (n135) R 16, and 24 with Placebo SC at Wk 4, 12 and 20 (n=60)

Secondary Population:
Skin (n  45) Golimumab (anti-TNF ) 200 mg SC at Wk 0; 100 mg sc at Wk 4, 8, 12,
16, 20, 24 (n=60)

SC SC SC SC SC SC SC

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

Steroid Stable Phase Steroid Taper Phase

Primary Endpoint
R Secondary Efficacy and Safety
Assessments
 Sarcoidosis Subject Stratification
Scheme
Primary Population
Strata 1 + 3 (n > 135) 132

Stratum 1 Stratum 3 Stratum 2

(lung) (lung & (skin)
skin)
115 17 41

Secondary Population
Strata 2 + 3 (n > 45) 58

Primary Endpoint: Change from Baseline in

% Predicted FVC at Week 16

4
p=0.54 p=0.13
3
2.02
2
LS Mean (SE)

Improved
1.15
1

0
-0.15
GLM
-1 Placebo
(N=42)
(N=44)
UST Worsened
-2 (N=46)

* Analysis uses last observation carried forward to input missing values

 Percent Predicted FVC Responders
(≥5%) Over Time
80
Percent of Subjects (%)

60

40

20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Time (weeks)
Placebo (N=44) GLM (N=42) UST (N=46)

SPGA Responders at Week 28:

Secondary Population
60
52.9
Percent of Responders (%)

50
p=0.19
40
30.0
30

20
14.3
p=0.28
10 Placebo GLM UST
(N=20) (N=17) (N=21)
0
It’s never as simple as you think

TNF-α Knockout Models

Form defective granulomas, failing to control
infection
C. parvum model: delayed inflammatory response, followed by death

Marino MW. Proc Natl Acad Sci 1997;94:8903-8.

 Paradoxical granulomatosis
53 year-old female on adalimumab for inflammatory bowel disease
develops cough and uveitis

Nascent “sarcoidosis” during

TNF therapy

• Probably less than 1% of treated patients

• More commonly reported with ETN
• Usually involve lungs, must may also
affect eyes, skin, kidney, other organs
• Typically respond to drug withdrawal

Tong D. Int Med J 2012

 Centrality of TNF?

Banchereau J. Immunity 2004

STAT1 plays a central role in

sarcoidosis
Network score = 61

Crouser ED. AMJRCCM 2009 Crouser ED. AJRCCM 2009

Transcriptional regulatory analysis

SOCS3 +
PPARy

- + - - -
-
STAT3 STAT1 LEF1

+ - +
+ + -
IRF-3 IRF-1 RUNX2

* - -
Rel-A STAT5

*Interact to promote IFN responses but do not bind each other.

 Rationale for ustekinumab in
treatment of sarcoidosis
• Serum concentrations of IL-12p40 and
IFN-g are significantly higher in
1
pulmonary sarcoidosis

• IL-12p40 protein is expressed in

epithelioid cells and macrophages of
sarcoid lungs2

• IL-12p40 levels are significantly higher NL

in BALF and serum from sarcoid
patients. IL-12p40 levels paralleled the
clinical course of sarcoidosis, with the
highest levels detected in BALF from
patients with persistent disease
C0168T48

• IL-12 receptor mRNA significantly

increased on BAL cells from sarcoidosis
patients compared to normal controls3 1Shigehara
2Shigehara
et al, Clin Exp Immunol, 2003, 132:152-7
et al, J Immunol, 2001, 166:642-9
3Taha et al, AJRCM, 1999, 160:1119-23

Major Inclusion Criteria

• Both Populations (Lung and Skin)
– Dx of sarcoidosis for  2 years
– Histologically proven disease
– Symptomatic despite current background therapy

• Primary Population (Lung)

– Stage 2, 3, or 4 [with interstitial infiltrates w/o
cavitating disease]
– FVC 45% to 80% predicted
– 6MWD between 100m - 550m
– MRC dyspnea score >2
 Trial Endpoints
• Primary Endpoint:
– Change from baseline in % predicted FVC at Week
16 in primary population
• Ustekinumab vs. placebo
• Golimumab vs. placebo

• Major Secondary Endpoints at Week 28

– 6 Min Walk (primary population)
– SGRQ Total Score (primary population)
– Proportion of responders (“Clear” or “Minimal”) by
Skin Physician Global Assessment (in secondary
population)
– % Predicted FVC (primary population)

Number of Subjects by
Stratification Factors
Placebo Golimumab Ustekinumab Total
Randomized subjects 58 55 60 173
Baseline disease organ
involvement
Lung involvement only 38 (65.5%) 38 (69.1%) 39 (65.0%) 115 (66.5%)
Both lung and skin 6 (10.3%) 4 (7.3%) 7 (11.7%) 17 (9.8%)
involvement
Skin involvement only 14 (24.1%) 13 (23.6%) 14 (23.3%) 41 (23.7%)
Prior anti-TNFα use
Yes 7 (12.1%) 6 (10.9%) 9 (15.0%) 22 (12.7%)
No 51 (87.9%) 49 (89.1%) 51 (85.0%) 151 (87.3%)
 Change in 6-Minute-Walk
Distance at Week 28: Primary
Population
p=0.90 p=0.06

Improved

Worsened

Placebo GLM UST

(N=44) (N=42) (N=46)

* Analysis uses last observation carried forward to input missing values

50% OCS Reduction at Week

28:
Primary Population
p=0.01 p=0.63

Placebo GLM UST

(N=44) (N=42) (N=46)
 Overall Conclusions
• Neither golimumab nor ustekinumab, at the
doses studied, demonstrated efficacy in
pulmonary sarcoidosis
• A trend in response following golimumab
treatment was observed in skin sarcoidosis
– However study was underpowered for this
endpoint
• A nominally greater proportion of subjects
in both active treatment groups were able
to reduce OCS dose during the taper
phase compared to the placebo group
• There were no new safety signals
observed for either golimumab nor
ustekinumab, with no evidence of
increased infection rates in either of the
active treatment groups