32
Innate Defense Regulator drugs For further information, please contact: Inimex Pharmaceuticals, Inc. 8540 Baxter Place, Burnaby, BC. V5A 4T8 Canada. 1-604-225-2251 [email protected] Innate Defense Regulator drugs (“IDRs”) John R. North. Ph.D. Chief Operating Officer

Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

Embed Size (px)

Citation preview

Page 1: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 2: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

ABIC September 2010

Slide 2

Page 3: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

ABIC September 2010

Slide 3

Page 4: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

ABIC September 2010

Slide 4

Page 5: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

ABIC September 2010

Slide 5

Page 6: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

IDRs Regulate Innate Immunity

ABIC September 2010

Slide 6

Page 7: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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.

Page 8: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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.

Page 9: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

History of IDR Discovery & Development

ABIC September 2010

Slide 9

Page 10: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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.

Page 11: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

Mechanism of Action

ABIC September 2010

Slide 11

Page 12: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 13: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 14: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

Effectiveness in Animal Models

ABIC September 2010

Slide 14

Page 15: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 16: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 17: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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.

Page 18: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 19: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 20: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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)

Page 21: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 22: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

• 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.

Page 23: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 24: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 25: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 26: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

Clinical Development

ABIC September 2010

Slide 26

Page 27: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 28: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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.

Page 29: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 30: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

“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

Page 31: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

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

Page 32: Innate Defense Regulator drugs (“IDRs”) - ABIC Web Presentations/Health... · Innate Defense Regulator drugs ... in oral mucositis scores on 7 of 14 days AND the ... incidence

For further information, please contact:Inimex Pharmaceuticals, Inc.8540 Baxter Place, Burnaby, BC.V5A 4T8 [email protected]

Thank You