IL-12/23 Update
George Han, MD, PhD
Instructor, Department of Dermatology
Mount Sinai Beth Israel
Icahn School of Medicine at Mount Sinai
Disclosure
• I have no relevant conflicts of interest with
regards to the topic of this talk
• Medications that are not approved by the FDA
will be discussed
Outline
• Examine the role of IL-12 and IL-23 in the pathogenesis
of psoriasis
• Review efficacy and safety updates for ustekinumab
• Discuss major upcoming IL-23 therapeutic antibodies
• Consider differences between agents within and across
classes
• Introduce a small-molecule IL-12/23 inhibitor currently
being developed
Background
• Our understanding of the pathogenesis of psoriasis is changing with
a better understanding of its immunopathogenesis
http://theartchics.com/psoriasis-vulgaris-is-an-autoimmune-disease-in-which-activated-t-cells-express-th1-cytokines/
Pathogenesis of Psoriasis
IL-12 and IL-23
Teng MWL et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21:719-29.
Ustekinumab
• FDA approved for moderate to severe plaque
psoriasis and psoriatic arthritis
• Initially approved in 2009
• 5-year safety data available
How effective is Ustekinumab?
• Generally very effective
• Long term data shows durable effect
• Very low rate of antidrug antibody formation
PHOENIX 1
9
PHOENIX 1 Overall Population: PASI 75 Responses Week 0 Through Week 244
Weeks 0 – 40
Percent of Patients
100
80
80
60
60
40
40
20
20
0
0
0
2
4
8 12 16 20 24 28 32 36 40
Week
Weeks 76 – 244
Open-label Extension**
100
72.4
72.2
72.0
61.2
62.3
63.4
76
UST 45 mg (n=382)
88
100 112 124 136 152 168 184 200 216 232 244
Week
UST 90 mg (n=384)
Note: Placebo cross-over patients are included beginning at Week 24 (i.e. 12 weeks after UST treatment). Analyses
were not conducted between Weeks 40 and 76 when the majority of the population was withdrawn from treatment per
study design. Analyses resumed at Week 76 when about half of the withdrawn patients had reinitiated UST for at least
12 weeks. Patients who reinitiated treatment after Week 76 were re-included after at least 12 weeks of re-treatment.
**After Week 76, treatment was unblinded and concomitant topicals were allowed
Kimball AB, et al. JEADV. 2013;27(12):1535-45.
PHOENIX 1
10
Overall Population: PASI 90 Responses During the Open-label Extension
(Weeks 76 – 244)*
Percentage of Patients (%)
100
80
60
40
45.8%
49.0%
35.9%
39.7%
44.9%
20
33.9%
0
76
88
100
112
124
UST 45 mg (n=382)
136
152
Week
*Evaluated every 16 weeks from Weeks 136 - 232. After Week 76, treatment
was unblinded and concomitant topicals were allowed
168
184
200
216
232
244
UST 90 mg (n=384)
Data on file, Janssen Biotech Inc.
PHOENIX 1
11
Overall Efficacy: PASI 100 Responses During the Open-label Extension
(Weeks 76 – 244)*
Percentage of Patients (%)
100
80
60
40
20.5%
26.4%
26.4%
18.1%
21.6%
20
0
15.2%
76
88
100
112
124
UST 45 mg (n=382)
Placebo crossover subjects are included after crossover to ustekinumab.
*Evaluated every 16 weeks from Weeks 152 - 232. After Week 76, treatment
was unblinded and concomitant topicals were allowed.
136
152
Week
168
184
200
216
232
244
UST 90 mg (n=384)
Data on file, Janssen Biotech Inc.
How safe is Ustekinumab?
• 3117 patients through Phase 2 trials and Phase 3 trials
(PHOENIX 1/2, ACCEPT)
• NO cases of TB or systemic fungal infection
• Serious infections at a rate of 1.1 per 100PY
• Rate of discontinuation due to infection is less than 1%
• NMSC were reported, mostly BCC>SCC (4:1)
– Notable due to concern regarding briakinumab and
increased SCC:BCC ratio
How safe is Ustekinumab?
100
Rates of Malignancies (Excluding NMSC) Through
5 Years of Follow-up Compared with SEER Population
80
54
60
40
32
22
53**
31**
22
20
0
Ustekinumab 45 mg
Ustekinumab 90 mg
Expected*
Observed**
*The expected number of patients with malignancies is based on the SEER Database (2009), adjusted for age, gender, and race.
† Indicates Standardized Incidence Ratio (SIR) with 95% CI.
**Since cervical carcinoma in situ is not captured in SEER, a single case in 90 mg is not included in this analysis.
PHOENIX 2 patients who were dose escalated from 45 mg to 90 mg were switched to the corresponding column following dose escalation.
Ustekinumab combined
Papp KA, et al. Br J Dermatol. 2013;168(4):844-854.
STELARA® (ustekinumab) Prescribing Information. Janssen Biotech, Inc.
Papp K, et al. AAD 2013. P6558.
What about pregnancy?
• Pregnancy class B
70%
60%
64.6%
53.8%
% of pregnancies
50%
40%
30%
20%
26.9%
19.2%
17 %
18.4%
10%
0%
UST Overall
(n=26)
Live Birth
Rates per pregnancy per year from 2008 CDC
Estimate11
Spontaneous Abortion
US General Population*
Elective Abortion
Schaufelberger BW., et al. AAD 2014. P7956.
Major Adverse Cardiovascular Events
• Briakinumab withdrawn, partly due to MACE and
cardiovascular deaths
• A small number of MACE in ustekinumab trials
– 5 vs 0 for placebo during initial treatment phase
• Why could there be cardiovascular risk when we
are blocking immune pathways which are
involved in atherosclerosis?
MACE
IL-12 and IL-18, produced by
macrophages (Mac), are potent
inducers of IFN-γ and promote the
differentiation of naïve T cells into
proatherogenic Th1 cells.
The Next Frontier: IL-23 Blockade
• Why specifically target IL-23?
The Next Frontier: IL-23 Blockade
• Why specifically target IL-23?
• More specific targeting can provide greater
efficacy with reduced side effects.
• IL-12 shown to be important in immunity
against TB, Candida, and Salmonella
The Next Frontier: IL-23 Blockade
• Why specifically target IL-23?
• IL-12 has anti-tumor effects while IL-23 is pro-tumorigenic
Does the science line up with experience?
• No cases of reactivation TB in ustekinumab
trials
• No evidence of increased malignancy
• Complex, redundant, and multifaceted
immune environment in autoimmune diseases
and cancer
IL-23 Inhibitors
• Tildrakizumab
• Guselkumab
• Risankizumab
Tildrakizumab
•
•
•
•
Anti-IL23p19
Entered Phase 3 trials in 2012
100mg and 200mg q12w being studied
Recombinant humanized mouse monoclonal
antibody
Tildrakizumab
Papp K et al. Tildrakizumab (MK-3222), an Anti-IL-23p19 monoclonal antibody, improves psoriasis in a phase 2b randomized placebo-controlled trial. Br J Dermatol. 2015; 173: 930-9.
Guselkumab
•
•
•
•
Anti-IL23p19
Entered Phase 3 trials in 2014
100mg q8w dosing
Fully human monoclonal antibody
Guselkumab
X-PLORE: PASI 75 through Week 40
Proportion of patients (%)
100
Adalimumab
Placebo
Guselkumab 5 mg q12w
Guselkumab 15 mg q8w
Guselkumab 50 mg q12w
Guselkumab 100 mg q8w
Guselkumab 200 mg q12w
Placebo→Guselkumab 100 q8w
80
60
40
20
0
0
4
8
12
16
20
Weeks
Callis Duffin K, et al. AAD 2014p;P8353 sponsored by Janssen.
24
28
32
36
40
Risankizumab
•
•
•
•
Anti-IL23p19
Previously known as BI-655066
Started recruiting for Phase 3 trials this year
Data exists for dosing at 0, 4, and 16 weeks as
well as a single dose administration
• Fully human monoclonal antibody
Risankizumab
Papp K, et al. EADV 2015, FC03.06 Sponsored by Boehringer Ingelheim
Risankizumab
Kreuger JG et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose,
randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015; 136: 116-124.
The Big Picture
• The new classes of biologics for psoriasis are
very effective
• How do we decide between them?
PASI-75 at Week 16 (or Week 12*)
100
88
90
78.6
80
70
74
74
68
66
60
50
40
30
20
10
GH
0
Tildrakizumab 100mg
Tildrakizumab 200mg
Guselkumab 100mg
Risankizumab+
Ustekinumab 45mg*
Ustekinumab 90mg*
Risankizumab+: Risankizumab 180mg at 0, 4, 16 wks; 36 wk time point
PASI-75 at Week 16 (or Week 12*)
100
86.3
81.6
78.6
80
70
89.1
88
90
74
74
66
60
50
40
30
20
10
GH
0
Tildrakizumab
100mg
Tildrakizumab
200mg
Guselkumab
100mg
Risankizumab+
Ustekinumab
90mg*
Secukinumab*
Ixekizumab*
Brodalumab*
Risankizumab+: Risankizumab 180mg at 0, 4, 16 wks; 36 wk time point
PASI-90 at Week 16 (or Week 12*)
100
90
80
69
70
62
60
52
50
40
45
39
36
30
20
10
GH
0
Tildrakizumab 100mg
Tildrakizumab 200mg
Guselkumab 100mg
Risankizumab+
Ustekinumab 45mg*
Ustekinumab 90mg*
Risankizumab+: Risankizumab 180mg at 0, 4, 16 wks; 36 wk time point
PASI-90 at Week 16 (or Week 12*)
100
90
80
70.9
69
70
62
70.3
59.2
60
52
50
40
45
39
30
20
10
GH
0
Tildrakizumab
100mg
Tildrakizumab
200mg
Guselkumab
100mg
Risankizumab+
Ustekinumab
90mg*
Secukinumab*
Ixekizumab*
Brodalumab*
Risankizumab+: Risankizumab 180mg at 0, 4, 16 wks; 36 wk time point
PASI-100 at Week 16 (or Week 12*)
100
90
80
70
60
50
43
40
33
30
20
10
GH
0
Guselkumab 100mg
Risankizumab+
Risankizumab+: Risankizumab 180mg at 0, 4, 16 wks; 36 wk time point
PASI-100 at Week 16 (or Week 12*)
100
90
80
70
60
50
44.4
43
40
35.3
33
28.6
30
20
10
GH
0
Guselkumab 100mg
Risankizumab+
Risankizumab+: Risankizumab 180mg at 0, 4, 16 wks; 36 wk time point
Secukinumab*
Ixekizumab*
Brodalumab*
So what are the differences?
• Safety data is very good across the board
– Cases of nasopharyngitis, URI
• Efficacy is very good
– Patient characteristics and individual response likely a bigger
driver than drug/class differences
• Dosing regimens – frequency of injections for IL-23
inhibitors likely every 2 months, 3 months, or longer
• Insurance coverage
• What about IBD?
The IBD Story
• There have been some concerns about the
blockade of IL-17 with regards with
IBD/Crohn’s Disease
Crohn’s Disease and Secukinumab
What about IL-23 blockade?
IL-23 Blockade Ameliorates Crohn’s Disease
The IBD Story
• IL-17 blockade can worsen Crohn’s Disease
while IL-23 blockade is a promising treatment
for Crohn’s Disease
• Across large numbers of treated patients,
there does not seem to be a strong safety
signal with regards to Crohn’s Disease, but
there is some cause for caution
Apilimod
• High-throughput screening identified a
candidate that blocks IL-12 and IL-23
• Small molecule inhibitor of IL-12/IL-23p40
• Likely target is PIKfyve, a PI kinase inhibitor
– Involved in TLR signaling
– Blocks phosphotransferase activity, selectively
inhibiting IL-12/IL-23p40
Cai X et al. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chem Biol. 2013; 20: 912-21.
H&E
Open-label study
N=15 at higher dose
IL12p40
47% achieved PASI-50
13% achieved PASI-75
Summary
• The IL-12 and IL-23 pathways are involved in
the pathogenesis of psoriasis
• Therapeutic antibodies targeting IL-12/IL-23
are very effective in treating psoriasis
• There are some possible benefits of selecting
an IL-23 inhibitor, provided these agents clear
Phase III trials with no major hurdles
A Final Note
This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders
characterized by social dysfunction and suggests a co-evolutionary link between
social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.
Thank you!
[email protected]