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Innate Defense Regulator drugs
For further information, please contact:Inimex Pharmaceuticals, Inc.8540 Baxter Place, Burnaby, BC.V5A 4T8 [email protected]
Innate Defense Regulator drugs (“IDRs”)
John R. North. Ph.D.
Chief Operating Officer
ABIC September 2010
Slide 2
ABIC September 2010
Slide 3
ABIC September 2010
Slide 4
ABIC September 2010
Slide 5
IDRs Regulate Innate Immunity
ABIC September 2010
Slide 6
Innate Defense Regulators (IDRs)
• The Innate Defense System is the “First Line Response” to
injury and infection:
. . . . . . not antigen- or pathogen-specific;
. . . . . . triggered by damage- or pathogen- associated molecules;
. . . . . . occurs rapidly in all tissues;
. . . . . . a major component of inflammation;
ABIC September 2010
Slide 7
• IDR drugs regulate this response and offer pre- and post-
exposure broad spectrum therapeutics to:
. . . . . . ameliorate injury;
. . . . . . fight drug-resistant infections and reduce inflammation;
. . . . . . protect immunocompromised individuals;
. . . . . . complement antibiotics.
Key features of IDRs
• Safe for multiple IV administrations;
• Rapid action - intracellular protein target is widely distributed in
body tissues and modulates multi-cellular response cascades;
• Prolonged efficacy after single exposure, but no drug
accumulation;
ABIC September 2010
Slide 8
accumulation;
• Broad-spectrum response to injury or pathogen challenge;
• Independent of adaptive immune system – effective in
immunosuppressed animals.
History of IDR Discovery & Development
ABIC September 2010
Slide 9
IDR Discovery
• Research at UBC on antimicrobial peptides, e.g. Human
LL37 (Finlay, Hancock, et al.);
• IDR-1 synthesized 2001:
• Modeled around cathelicidins, indolicidins, defensins, etc.;
• Protects animals from lethal bacterial infection but has
no intrinsic antibacterial activity:
• “Innate Defense Regulator”;
ABIC September 2010
Slide 10
• “Innate Defense Regulator”;
• Safe for systemic administration.
• IMX942 created 2005:
• Smaller, better pharmaceutical properties; additional safety
margin.
• Molecular target – Sequestosome-1 (p62) - identified
2007.
• IMX942 amelioration of mucositis recognized 2010.
Mechanism of Action
ABIC September 2010
Slide 11
TLRsTLRs
Sentinel Cell
AdaptorAdaptorProteinProtein
Altered SignalingAltered SignalingMAPK, PI3K, (NFMAPK, PI3K, (NFκκκκκκκκB)B)
C/EBP1 etcC/EBP1 etc
ChemokinesRANTES, MCP1 etc
IMX942IMX942p62p62
Bacteria at Bacteria at infection infection sitesite PAMPsPAMPs
Cellular Mechanism
NB: IDR effects
are minimal in the
absence of
stimulation
Damaged Damaged CellsCells
DAMPsDAMPs
ABIC September 2010
Slide 12
Bacteria at Bacteria at infection siteinfection site
Pathogen Killing & Clearance
Selective Effector Cell Recruitment
Controlled Inflammation
IL1ra ↑↑↑↑TNFαααα ↓↓↓↓
Wound debridement & healing
TLR TNFR
TBS
UBA
Cp62
IL-1R
MyD88 TRIF
TRAF6
IDR/p62 Molecular Mechanism of Action
ABIC September 2010
Slide 13
Cytokine/chemokine promoter region
PKCζ
NF-κB
NF-κBIκB
P Ub
NF-κB
Protein
expression
p38
C/EBPβ
C/EBPβC/EBP
p38
C/EBPβ
P
P
C/EBPβP
N
PB1
ZZZZRIP1RIP1
IMX942
Effectiveness in Animal Models
ABIC September 2010
Slide 14
100100100
Parasite: Malaria
9.5 mg/kg IMX942 IP, 4 h after S. aureus IP infection; Peritoneal bacteria counted at 24 h; 8 mice/group.
Control IMX942
4
5
6
7
8
p<0.001
Lo
g C
FU
/ml
Gram +ve
Detection
Limit
• IDRs are effective against a wide
range of pathogens;
• “Disease-modifying”, not directly
anti-pathogen;
• A single dose has a prolonged effect
– at least 72 h.
Broad Spectrum Anti-Infectives
ABIC September 2010
Slide 15
L. Schofield, WEHI,
Australia
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
days post-infection
% S
urv
ival
A control
B I.P. group
C I.V. group*
IMX503 injections iv
L. Schofield, WEHI,
Australia
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
days post-infection
% S
urv
ival
A control
B I.P. group
C I.V. group*
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
days post-infection
% S
urv
ival
A control
B I.P. group
C I.V. group*
IMX503 injections iv24 mg/kg IMX942 IP 24 h before Klebsiella IP
infection; survival at 24 h; 8 mice/group.
Control IMX942
0
25
50
75
100
%S
urv
iva
l
Gram -ve
MRSA Bacteremia – Therapeutic Dosing
20
40
60
80
100
Saline
Linezolid
IMX942 at +4h
IMX942 at +24h
Pe
rce
nt
su
rviv
al
ABIC September 2010
Slide 16
• CONCLUSION: Therapeutic window of 24h in this model.
1.6x107 MRSA was administered IV to female BALB/c mice (N=12 Saline, N=10 all other groups).Saline and IMX942 were given IV at the times shown; Linezolid was given orally immediately after infection.
Survival monitored for 9 days.
0 3 6 90
20
Day
IMX942 Complements Antibiotics against MRSA
20
40
60
80
100
IMX942 + Vanc
Survival
Vancomycin
ABIC September 2010
Slide 17
0 1 2 3 4 5
0
20 Vancomycin
Time (days)
IMX942 (50 mg/kg) or saline treatment was administered IV 48 h prior to inoculation with MRSA (UC6685, 8.2 × 107) to female CF-1 mice (N=10/group). Vancomycin treatment (3 mg/kg) was administered SC, 1 and 5 h after infection. Survival was monitored once daily for 5 days.
Optimization of Treatment
MRSA bacteremia
20
40
60
80
100
Saline
Linezolid 6.25mg/kg
IMX942 5mg/kg - 4h
IMX942 5mg/kg – 4h & + 48h
Perc
en
t su
rviv
al
ABIC September 2010
Slide 18
1.6x107 MRSA USA300 was administered IV to female BALB/c mice (N=20 Saline, N=10 all other groups). Saline was
administered IV 4 hours prior to bacterial challenge. IMX942 was administered either 4 hours prior to, or 4 hours prior to
and 48 hours after, bacterial challenge. Linezolid was administered IV immediately after bacterial challenge. Survival was
monitored for 14 days.
0 7 140
20 Saline
Time (Days)
Perc
en
t su
rviv
al
IMX942 Improves Neutropenic Rat Survival
20
40
60
80
100S
urv
iva
l %
Cefepime n=4
Saline n=4
IMX942 DAY 5 n=8
Control animals die of
ABIC September 2010
Slide 19
5 6 7 8 9 10 11 12 13Days after Cp0
20
Opal et al.: Female Sprague-Dawley rats were treated with IM cefamandole 4 days prior to day 0 to disrupt their GI flora. On day 0 rats were treated with 75 mg/kg cyclophosphamide IP and challenged with oral P. aeruginosa. Cyclophosphamide treatment was repeated on day 2 and P. aeruginosa challenge was repeated on days 2 and 4.
In one group of rats, 10 mg/kg IMX942 was administered IV on day 5, while other animals received saline or 40 mg/kg cefepime IM daily for 3 days.
pseudomonas sepsisIMX942
Mucosal Protection / Reduced Infection
Mucosal weight
0.00
0.05
0.10
0.15
0.20
0.25
*p<.001*p<.001
Mu
co
sal w
eig
ht
(gm
)M
ea
n +
/- 9
5%
CI
Exp101
0
20
40
60
80
100Saline
Cefepime
IMX942 D5 10mg/kg
Percen
t su
rviv
al
10 mg/kg
SurvivalExp101
0
20
40
60
80
100Saline
Cefepime
IMX942 D5 10mg/kg
Percen
t su
rviv
al
10 mg/kg
Exp101
0
20
40
60
80
100Saline
Cefepime
IMX942 D5 10mg/kg
Percen
t su
rviv
al
10 mg/kg
Exp101
0
20
40
60
80
100Saline
Cefepime
IMX942 D5 10mg/kg
Percen
t su
rviv
al
Exp101
0
20
40
60
80
100Saline
Cefepime
IMX942 D5 10mg/kg
Percen
t su
rviv
al
10 mg/kg
Survival
IMX942
ABIC September 2010
Slide 20
STUDY DESIGN:
• Day -4: IM Cefamandole 10 mg/kg to female Sprague-Dawley rats (to disturb the gut microbiota)
• Day 0 & 3: IP Cyclophosphamide 75 mg/kg (to render leukopenic)
• Day 0, 2 & 4: 1x106 CFU/ml P. aeruginosa by orogastric feeding (pathogen repopulation of the gut)
• Day 5 (Start of fever): IV IMX942 10 mg/kg (Survival N=8, mucosal weight N=9) or IV Saline
(Survival N=8, mucosal weight N=9).
• Days 6, 7, 8: IM Cefepime 25mg/kg (Survival N=4, mucosal weight N=11).
Summary:
• IMX942-enhanced survival (green), correlates with protection of the GI barrier (increased mucosal weight);
• Data support both Mucositis and Febrile Neutropenia as potential IMX942 indications.
Contr
ol
IMX94
2
Cef
epim
e
0.00
Treatment Group
0 100 200 3000
Time (Hours)
0 100 200 3000
Time (Hours)
0 100 200 3000
Time (Hours)
0 100 200 3000
Time (Hours)
0 100 200 3000
Time (Hours)
Skin Damage & Infection
Ulceration Score at 48 h
0.0
0.5
1.0
1.5
2.0
Ulc
era
tio
n S
co
re
Saline administered IV 4 hrs prior to infection
Linezolid (12mg/kg) administered PO at 0 and 24h after infection
ABIC September 2010
Slide 21
STUDY DESIGN:
Day -1: remove fur; Day 0 -4h: IMX942 or saline IV; Day 0 0h: Tape strip & infect (MRSA
USA 300); Day 0 & 1 & 2: Linezolid treatment; Day 2 & 4: Photographs. No effect was
observed on bacterial counts in biopsies with either IMX942 or antibiotic Tx (N=6/group).
Summary:
• IMX942 significantly reduced ulceration and swelling of the epithelial barrier.
Swelling Score at 96 h
0.0
0.5
1.0
1.5
2.0
2.5
Sw
ellin
g S
co
re
IMX942 (25mg/kg) administered IV 4 hrs prior to infection
• Mucositis—Damage done to mucosa by
anticancer therapies (chemo, radiation);
• Affects 500,000 people in the US per year—40%
of chemo patients;
• Very painful—can lead to infection, sepsis, need
Side Effect of Cancer Therapies
ABIC September 2010
Slide 22
• Very painful—can lead to infection, sepsis, need
for parenteral nutrition and narcotic analgesia;
• Can lead to dose reductions in cancer treatment
which can lower efficacy.
Cell Death –
triggers:
Messages;
Signals;
AmplificationNormal
EpitheliumInitiation HealingUlceration
Pathobiology of Mucositis
Epithelium
Sub-Mucosa
Radiation Ref: S. Sonis 2004
ABIC September 2010
Slide 23
Sub-Mucosa
Basal CellFibroblast
Blood VesselInflammatory Cell
Chemotherapy
Innate response to
Damage-Associated
Molecules
IMX942 in Chemo-induced Mucositis
Oral Mucositis Score by Day
Mean Mucositis Score (+/-SEM)
2
3
4
*
* *p≤ 0.01
Vehicle Days -4, -1, 2, 5
IMX-942 Days -1, 2, 5
Duration of Severe
Mucositis
% Animal Days with a Score of 3 or Higher
4
6
8
10
12
P=0.010
ABIC September 2010
Slide 24
STUDY DESIGN:
• C3H/H3N Crl mice; N=12/grp; Day -4 & -2: 60mg/kg 5FU IP; Day 0: Chemical burn
(4x4 mm sq paper soaked in 50% acetic acid applied for 1 min); Days 1-14: monitor: oral
muco score; body wt; blood in stool; clinical obs.; Days 4 & 7: endoscopy
Summary:
Statistically significant improvement (p≤0.01) in oral mucositis scores on 7 of 14 days AND the
duration of mucositis was decreased by 50%.
*
Day
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Mean Mucositis Score (+/
0
1
*
**
** *
*p≤ 0.01
% Animal Days with a Score of 3 or Higher
0
2
Vehicle Days -4, -1, 2, 5
IMX-942 Days -1, 2, 5
IMX942 in Mucositis: Study #2
Endoscopy Score
p<.05
Mean Endoscopy Colitis Score (+/-SEM)
0.5
1.0
1.5
2.0
Vehicle Days -1, 2, 5
IMX942, Days -1, 2, 5p<.001
p=.002
Mean % Weight Change (+/-SEM)
-5
0
5
Vehicle Days -1, 2, 5
IMX-942 Day -1, 2, 5
% Body Weight each Day
ABIC September 2010
Slide 25
STUDY DESIGN:
• C3H/H3N Crl mice; N=12/grp; Day -4 & -2: 60mg/kg 5FU IP; Day 0: Chemical burn
(4x4 mm sq paper soaked in 50% acetic acid applied for 1 min); Days 1-14: monitor: oral
muco score; body wt.; blood in stool; clinical bservations; Days 4 & 7: endoscopy.
Summary:
Trends in clinical endoscopy scores and body weight are consistent with oral mucositis scores. Body
weight changes in the IMX942-treated animals show statistically significant differences from vehicle.
IMX942 TREATMENT:
Day -1, 2, 5
Day 4 Day 7
Mean Endoscopy Colitis Score (+/
0.0
Day
-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Mean % Weight Change (+/
-15
-10
Clinical Development
ABIC September 2010
Slide 26
IMX942 Phase 1 Synopsis
Single Ascending Dose in healthy volunteers:
• 18-55 years; Target 30% females, non-childbearing potential;
• All cohorts: 6 active and 2 placebo. Blinded / randomised.
• PK and PD sampling;
• Six dose levels planned and completed (0.15 – 8 mg/kg);
ABIC September 2010
Slide 27
• Drug well tolerated
Multiple Ascending Dose:
• 7- daily doses;
• Cohorts of 6, each with 2 placebo. Blinded / randomised;
• PD & PK evaluations;
• Five cohorts planned and completed (0.5 – 6.5 mg/kg x7);
• Drug well tolerated
Phase 2 Proof of Concept
Planning Framework:
• Small (<100 patients) trial to establish PoC for
therapeutic impact of IMX942 on innate defense
responses in Man;
• Prophylactic setting ideal but need high
ABIC September 2010
Slide 28
• Prophylactic setting ideal but need high
incidence to keep trial size small;
• Clinical setting to be consistent with preclinical
data.
Phase 2 PoC
Patients at high risk of severe mucositis:
• Autologous SCT with high dose
chemo/radiation
ABIC September 2010
Slide 29
• Head & Neck cancer patients receiving
chemo/radiation therapy
“Hard to Treat” Skin
&
Skin Structure
Infections
Hospital-Associated
Pneumonia
Ventilator
Associated
Pneumonia
IMX942 - Clinic to Market Strategy:
Patients at risk of Mucosal Barrier Failure and Infection/Inflammation:
ABIC September 2010
Slide 30
Post-Chemo
Infection
Pneumonia
Mucositis;
Head & Neck Cancer
Oral Mucositis in
High dose chemo
MRSA Bacteremia
& Endocarditis
Recurrent
C. difficile
Infection
Medical Implications of Innate Defense Regulation
Scope:
• Control antibiotic-resistant infections
• Inflammation control
• Patients at high risk of infection:
• Recurrent infections e.g. C.Difficile
• Cancer / Stem Cell Transplant
ABIC September 2010
Slide 31
• Intensive Care Units / Infectious Disease Management
• Elderly Patients with Immune Senescence
• High risk infections; e.g. Biodefense; Malaria
• Inflammation:
• Control of inflammation while reducing susceptibility to
infectious disease
For further information, please contact:Inimex Pharmaceuticals, Inc.8540 Baxter Place, Burnaby, BC.V5A 4T8 [email protected]
Thank You