Phase 1 clinical trial of IMO-8400, an antagonist of Tolllike receptors 7, 8 and 9
Lakshmi Bhagat, Weiwen Jiang, Dong Yu, Robert D. Arbeit and Tim Sullivan
Id
Idera
Ph
Pharmaceuticals,
ti l IInc., 167 Sid
Sidney St
Street,
t C
Cambridge,
b id
MA 02139
02139, USA
Presentation Number S.85 made at FOCIS 2013, June 27-30 in Boston, MA
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© 2013 Idera Pharmaceuticals
FOCIS 2013
1
Introduction
•
IMO‐8400 is a first‐in‐class antagonist of Toll‐like Receptors (TLRs) 7, 8, and 9 in clinical development for the treatment of autoimmune diseases. IMO‐8400
9 in clinical development for the treatment of autoimmune diseases. IMO
8400 was evaluated for safety, pharmacodynamics, and pharmaco‐kinetics in a recent Phase 1 clinical trial in healthy subjects. A Phase 2 trial in patients with moderate to severe plaque psoriasis is on‐going.
•
In autoimmune diseases, damaged tissues release self nucleic acids that form complexes with antibodies, peptides, and lipids (panel to right). These complexes engage the endosomal
l
th
d
l TLRs 7, 8, and 9 in dendritic
TLR 7 8 d 9 i d d iti cells and B cells. ll
d B ll
Ligand binding activates downstream signaling cascades, resulting in the induction of pro‐inflammatory cytokines, such as IL‐12, IL‐23, IL‐17, IL‐6, and IL‐
1 thereby exacerbating the disease
1, thereby exacerbating the disease. •
Current approaches to treatment of autoimmune diseases include g
y
,
,
monoclonal antibodies against individual cytokines, such as TNF‐α, IL‐12/23, IL‐6, IL‐1β, and IL‐17, which inhibit elevated cytokines associated with disease, but also block constitutive cytokine activity. 2
© 2013 Idera Pharmaceuticals
FOCIS 2013
Induction of Cytokines and Signaling Cascades Mediated through Toll‐like Receptors is Central to the Autoimmune Disease Cycle
Receptors is Central to the Autoimmune Disease Cycle
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© 2013 Idera Pharmaceuticals
FOCIS 2013
IMO‐8400 Blocks Autoimmune Disease Cycle Upstream of Cytokine Induction
Inhibition of Inhibition
of
Cytokine Induction
IMO‐8400 blocks the induction of multiple cytokines induced by activation of TLRs 7, 8, and 9.
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© 2013 Idera Pharmaceuticals
FOCIS 2013
TLR Antagonism: Preclinical and Clinical Proof of Concept
Our approach to the treatment of autoimmune diseases involves specific inhibition of TLR responses to self nucleic acid complexes, thereby blocking the
inhibition of TLR responses to self nucleic acid complexes, thereby blocking the induction of multiple cytokines without affecting constitutive cytokine activity. As previously reported, our TLR antagonist compounds
•
inhibit endosomal
hb
d
l TLR‐mediated immune activation in cell‐based assays d
d
ll b d
and in vivo in primates,1
•
have potent activity in pre
have
potent activity in pre‐clinical
clinical models of multiple autoimmune models of multiple autoimmune
diseases including psoriasis and lupus.2
Further, IMO‐8400, an antagonist of TLR8 as well as TLRs 7 and 9, was more potent than IMO‐3100, an earlier TLR7 and 9 antagonist.3
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© 2013 Idera Pharmaceuticals
FOCIS 2013
TLR Antagonism: Preclinical and Clinical Proof of Concept In our initial clinical proof‐of‐concept Phase 2 trial in patients with moderate to severe plaque psoriasis, treatment with IMO‐3100
moderate to severe plaque psoriasis, treatment with IMO
3100 for only four for only four
weeks resulted in significant improvement in PASI scores. Further, those clinical responses were associated with improvement in psoriasis disease‐associated gene profile, including the IL‐17 pathway.4
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© 2013 Idera Pharmaceuticals
FOCIS 2013
Trial Overview
Design: Placebo‐controlled, double‐blind, randomized trial
Objectives: • Evaluate the safety and tolerability of escalating single and multiple doses of Evaluate the safety and tolerability of escalating single and multiple doses of
IMO‐8400 administered by subcutaneous injection
• Characterize the pharmacodynamic and pharmacokinetic profiles of IMO‐
8400
Three sequential single dose levels
•
,
g/ g
0.1, 0.3 and 0.6 mg/kg •
N=6 per dose level and N=6 placebo
Two sequential multiple dose levels:
Two sequential multiple dose levels:
•
0.3 and 0.6 mg/kg once weekly for 4 weeks
•
N=6
N
6 per dose level and N
per dose level and N=6
6 placebo
placebo
Site: Single US center
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© 2013 Idera Pharmaceuticals
FOCIS 2013
Single Ascending Dose Trial Study Events
Study Day
Event
1
Dosing
9
Vital Signs
9
3
5
8
30
9
9
9
9
9
9
9
9
9
Physical Examination
9
Safety Labs
9
Pharmacokinetics
9
Pharmacodynamics
9
Safety Monitoring
8
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© 2013 Idera Pharmaceuticals
9
9
9
9
9
9
|---- From Day 1 to Day 30 ----|
FOCIS 2013
Multiple Ascending Dose Trial Study Events
Study Day
Event
1
Dosing
9
Vital
ta Signs
Sg s
9
9
Physical Examination
9
Safety Labs
9
Pharmacokinetics
Safety Monitoring
9
2
© 2013 Idera Pharmaceuticals
9
5
9
8
15
22
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
23
24
29
57
9
9
9
9
9
9
9
9
9
|------------- From Day 1 to Day 57 -------------|
FOCIS 2013
Subject Demographics
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Single-dose Cohorts
(mg/kg)
01
0.1
03
0.3
06
0.6
PLA
Multiple-dose Cohorts
(mg/kg/wk x 4 wk)
03
0.3
06
0.6
PLA
N
Age (yr, mean)
6
43.3
6
35.8
6
39.7
6
43.7
6
39.5
6
39.2
6
38.7
BMI (Mean)
27.9
28.5
28.5
28.6
30.2
25.9
26.1
© 2013 Idera Pharmaceuticals
FOCIS 2013
Safety
Well tolerated in all treatment groups, single‐ and multiple‐dose
•
•
N
No severe adverse events (AEs), no serious AEs
d
t (AE )
i
AE
•
No treatment discontinuations
•
No changes in vital signs
No changes in vital signs
•
No patterns of changes in safety laboratory parameters Injection site reactions (ISRs) were the most common treatment‐related
Injection site reactions (ISRs) were the most common treatment
related AEs
AEs
•
•
11
•
Asymptomatic mild erythema in 15 of 30 IMO‐8400 subjects
•
Other ISRs were tenderness (N=4), pruritus (N=2), and induration (N=2)
Other AEs seen in >1 subject occurred similarly in treated and placebo groups
© 2013 Idera Pharmaceuticals
FOCIS 2013
Pharmacodynamics (PD)
•
PD of IMO‐8400 was evaluated in the single dose cohorts (IMO‐8400 0.3 or 0.6 mg/kg, or placebo)
•
Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood collected pre‐dose (Day 1) and post‐dose (Day 3 and Day 7) and cultured with TLRs 7 8 and 9 agonist5
with TLRs 7, 8, and 9 agonist
•
Supernatants were harvested after 24 hours and assayed for cytokines using multiplex antibody beads (Luminex, Invitrogen)
•
Inhibition of cytokine induction was assessed by comparing cytokine levels pre‐ and post‐treatment in treated and placebo subjects 12
© 2013 Idera Pharmaceuticals
FOCIS 2013
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Overview of PD Procedures
IMO-8400 or Placebo
D
Day
1
3
8
Blood collection
Pre-dose
------- Post-dose -------
Separation of PBMCs
Culture of PBMCs with
TLR7 agonist
TLR8 agonist
TLR9 agonist
Measure cytokine levels in culture supernatants by multiplex assay
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© 2013 Idera Pharmaceuticals
FOCIS 2013
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Pre‐dose Day 1
TLR7 Mediated
TLR8 Mediated
TLR9 M di t d
Mediated
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© 2013 Idera Pharmaceuticals
Placebo
Day 3
Day 8
Post‐Dose
IMO‐8400 at 0.3 mg/kg IMO‐8400 at 0.6 mg/kg
Day 3
Day 8
Day 3
Day 8
IL‐8
MCP‐1
MIP‐1β
RANTES
IL‐6
IL‐1RA
MIP‐1α
IL‐2R
IP‐10
IFN‐α
IL‐15
IL‐1β
IL‐12
IL‐10
TNF‐α
Percent cytokine inhibition
< 25%
> 25%
IL‐8
MCP‐1
MIP‐1β
RANTES
IL‐6
IL‐1RA
MIP‐1α
IL‐2R
IP‐10
IFN‐α
IL‐15
IL‐1β
IL‐12
IL‐10
TNF‐α
IL 8
IL‐8
MCP‐1
MIP‐1β
RANTES
IL‐6
IL‐1RA
MIP‐1α
IL‐2R
IP‐10
IFN‐α
IL‐15
IL‐1β
IL‐12
IL‐10
TNF‐α
Cytokine k
Induction
FOCIS 2013
Pharmacodynamics (PD)
•
Compared to placebo, subjects treated with IMO‐8400 showed inhibition of multiple cytokines induced by TLRs 7, 8, and 9 agonists
•
Following a single dose administration, inhibition of cytokines was sustained through Day 8
•
Inhibition of cytokine induction was dose‐dependent, with 0.6 mg/kg dose resulting in more extensive and sustained inhibition than 0.3 mg/kg dose
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© 2013 Idera Pharmaceuticals
FOCIS 2013
IMO‐8400 Treatment (Dose on Day 1)
0.6 mg/kg
0.6 mg/kg
0.3 mg/kg
Day 8
Day 8
Day 8
Day 8
Day 8
Day 8
IL‐8 MCP‐1 MIP‐1β
MIP
1β
RANTES IL‐6 IL‐1RA MIP‐1α
IL‐2R IP‐10
IFNα
IL‐15 IL‐1β
IL‐12 IL‐10 TNFα
Relative Agonist Concentration
1x
2x
1x
TLR7
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© 2013 Idera Pharmaceuticals
2x
TLR8
FOCIS 2013
1x
3x
TLR9
Percent cytokine inhibition
< 25%
> 25%
Pharmacodynamics (PD)
•
Inhibition of cytokines by IMO‐8400 is also dependent on the dose of agonist. Cytokine inhibition was decreased at 2x or 3x higher concentrations of TLR
Cytokine inhibition was decreased at 2x or 3x higher concentrations of TLR agonist.
•
In autoimmune diseases, the concentration of the self nucleic acid complexes is significantly less than the agonist dose in the ex vivo PD assay. 17
© 2013 Idera Pharmaceuticals
FOCIS 2013
Pharmacokinetics (PK)
•
IMO‐8400 was rapidly cleared from the plasma
•
Systemic exposure to IMO‐8400 following escalating single and repeated subcutaneous doses increased approximately dose proportionately
•
There was no accumulation in plasma following repeated doses: systemic h
l
l
f ll
dd
exposure was similar after the 1st and 4th doses
•
Between‐subject variability in systemic exposure to IMO‐8400 was moderate Between‐subject
variability in systemic exposure to IMO‐8400 was moderate
to low (CV of Cmax and AUC0‐12h geometric means were 11 to 38%)
•
( g
)
pp
p
Median Tmax was 2 hr (range: 1 to 4 hr), with no apparent relationship to dose level or single versus multiple doses
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© 2013 Idera Pharmaceuticals
FOCIS 2013
Pharmacokinetics (PK)
Single‐dose
01
0.1 mg/kg
/k
03
0.3 mg/kg
/k
06
0.6 mg/kg
/k
Cmax (µg/mL)
0.324
0.651
1.49
AUC0‐12h (µg‐h/mL)
( h/ L)
1 01
1.01
3 52
3.52
8 86
8.86
Multiple‐dose
l l d
0.3 mg/kg/week
0.6 mg/kg/week
D
Dose 1
1
D
Dose 4
4
D
Dose 1
1
D
Dose 4
4
Cmax (µg/mL)
0.575
0.609
1.29
1.60
AUC0‐12h (µg‐h/mL)
( h/ L)
3 49
3.49
3 67
3.67
7 26
7.26
7 72
7.72
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© 2013 Idera Pharmaceuticals
FOCIS 2013
Comparing Pharmacodynamics and Pharmacokinetics
•
Compared to PK data, PD data is more informative about duration of activity.
•
•
PD data may also be more informative regarding dose selection. •
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Following subcutaneous injection in humans, IMO‐8400 was not detected in the plasma beyond 12 hours, whereas, in the same subjects, the ex vivo PD assay demonstrated sustained inhibition of TLR 7 8 and 9 mediated cytokine induction for up to seven days
7, 8, and 9‐mediated cytokine induction for up to seven days. For the clinical proof of concept study using IMO‐3100 in patients with moderate to severe plaque psoriasis, dose levels were selected based on PD data, which correlated well with clinical activity.
© 2013 Idera Pharmaceuticals
FOCIS 2013
Summary and Conclusions
•
IMO‐8400 is a first‐in‐class antagonist of TLRs 7, 8, and 9. •
Single and multiple doses of IMO‐8400 were well tolerated in healthy Single
and multiple doses of IMO‐8400 were well tolerated in healthy
subjects at all dose levels administered in a placebo‐controlled, double‐
blind, randomized Phase 1 clinical trial. •
PD studies show that following administration of IMO‐8400 the induction of multiple cytokines is inhibited in response to agonists of TLRs 7, 8, and 9 •
Inhibition of cytokine induction was maintained for up to seven days Inhibition
of cytokine induction was maintained for up to seven days
post‐dosing.
•
p
p
,
IMO‐8400 plasma PK showed rapid clearance, with no accumulation after four weekly doses.
•
A Phase 2 trial of IMO‐8400 in patients with moderate to severe plaque psoriasis is in progress.
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© 2013 Idera Pharmaceuticals
FOCIS 2013
References
1.
Kandimalla, E.R., et al., Nucleic Acids Res. 41, 3947, 2013
2.
Jiang, W., et al., J Invest Derm. 133, 1777, 2013; Zhu, F‐G., et al., Autoimmunity. epub ahead of print, 2013
3.
Krueger, J., Am Acad
d Dermatoll Annual Meeting, 2013
l
4.
Kimball, A., et al., Intl Invest Dermatol Meeting, 2013
5.
Wang, D., et al., J Med Chem. 52, 6871, 2009; Lan, T., et al., PNAS 104, 13750, 2007; Kandimalla, E.R., et al., PNAS 102, 6925, 2005
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© 2013 Idera Pharmaceuticals
FOCIS 2013