Transcript Jennifer Microbiotix DTRA Program Update

Microbiotix, Inc.
Program Update
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Overview
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Introduction
Scope of contract
Original plan
Data
Status of contract
Conclusions
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Nomenclature
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MBX-1066 (TFA salt of MBX-1336)
MBX-1162 (TFA salt of MBX-1143)
MBX-1336 (free base of MBX-1066)
MBX-1143 (free base of MBX-1162)
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Introduction – Goals of Program
• DTRA Mission: Protect the warfighter from
conventional or genetically engineered biological
threats
• Program Mission: Discover and develop broad
spectrum anti-bacterials for military use against
category A biowarfare pathogens
• Microbiotix Contract Objective : “Develop a new
class of therapeutic agents, the bis(imidazolinylindole) series discovered in preliminary
studies, for use against intracellular bacterial warfare
threats”
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Introduction – Project Strategy
• Microbiotix originally structured this
extremely rapid anti-bacterial development
program to provide the greatest chance of
success within the two year time-frame.
• The program was initially designed using the
best case scenario with no complicating issues
anticipated, based upon the data available at
contract initiation.
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Target Product Profile
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Indication: Treatment and prevention of infections from biowarfare agents
Mechanism of Action: Broad-spectrum antibacterial activity against intracellular biowarfare
agents.
Safety Profile: The benefits of treatment outweigh the risks.
MIC:
Clinical Efficacy: Must be effective in primate efficacy model.
Resistance: Compounds with new mechanisms of resistance or no resistance will be favored.
Route of Administration: Intramuscular may be more field-deployable; intravenous will be
used initially (bolus ideal; up to 1 hour infusion acceptable).
Dosing Regimen: Ideally one time dose; for multiple dosing 1 -2 times daily, no more than 34 times daily.
Dosage Form: Low volume parenteral compatible with standard intravenous solutions
Monitoring Requirements: Monitoring of serum/plasma drug concentrations should not be
required. No clinically significant adverse reactions observed in the efficacious dose range.
Product Stability: Drug product should be stable for at least 2 years.
Product Storage Conditions: The drug product ideally should be stored at room temperature.
Refrigerated or frozen drug product may be acceptable.
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Contract Scope: Specific Aims
• Aim 1: Demonstrate potent and selective inhibitory activity of
one or more bis-(imidazolinylindole) compounds in animal models
of infection.
• Aim 2: Establish the mechanism of action (MOA) of the bis(imidaolinlylindole) class of compounds.
• Aim 3: Demonstrate structure-activity relationships for the
potency and selectivity of the bis- (imidazolinylindole) class of
compounds.
• Aim 4: Conduct IND-enabling pharmacokinetic, toxicology and
safety pharmacology studies.
• Aim 5: Prepare and file an IND application for a broad-spectrum
anti-bacterial active against intracellular BW threats.
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Plan as of May 2008
Results of June-initiated toxicology and
pharmacokinetic studies will:
• Confirm lead compound
• Trigger cGMP manufacturing
• Trigger remaining IND-enabling preclinical toxicology
studies
• Trigger request for pre-IND meeting with FDA
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Product Development Course
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Six month extension requested due to compound formulation issues which
included low solubility.
Upon resolution of the formulation issues (which involved a change to the free
base form and formulation of the lead compound), Microbiotix set-up pilot GMP
manufacturing and preliminary stability studies with the lead compound, MBX1336 (free base form of MBX-1066). A pilot batch of MBX-1336 was made in April
2008. A non-GMP batch of MBX-1143 (back-up compound) was made.
In June 2008, a pharmacokinetic study was conducted using MBX-1336 and MBX1143 (free base form of MBX-1162). The study evaluated IV, IM and IP dosing of 1
and 10 mg/kg. Animals in the MBX-1336 10 mg/kg intravenous group died after
dosing. MBX-1143 was then identified as the lead candidate.
In June 2008, a toxicology study was conducted using MBX-1143 (bolus). This
study was followed by an infusion study.
In October 2008, an ADME and dog study were initiated.
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Preclinical Studies
• Pilot Toxicology
• Genetic Toxicology
– AMES
– CHO
– Rat Micronucleus
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Rat Single Dose PK
Rat Single Dose Acute Toxicity (Bolus)
Rat Single Dose Acute Toxicity (Infusion)
Rat ADME - ongoing
Dog Dose Escalation (Infusion) – ongoing
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Pilot Toxicology Study
• Single Dose Toxicity (MBX-1066, MBX-1162)
– Bolus administration
– Doses limited by solubility of MBX-1066
– Toxicity seen with higher vehicle concentrations
(20 % DMA in 5% D5W)
– MBX-1066 MTD: 5 mg/kg
– MBX-1162 MTD: 15 mg/kg
• Conclusions: Solubility limited; unclear if
formulation is contributing to toxicity
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Genetic Toxicology
• Ames Testing (MBX-1066, MBX-1162)ADD DOSES
– Completed in March 2008
– Neither compound induced mutations
• CHO Study (MBX-1143)
– Completed in August 2008
– Did not induce chromosomal aberrations
• Rat Micronucleus Study (MBX-1143)
– Completed in August 2008
– Did not increase incidence of micronucleated polychromatic
erythrocytes
• Conclusion: There were no issues in the genetic toxicology
studies. Studies support proceeding with additional studies.
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Single Dose Pharmacokinetic Study
• Bolus injection (MBX-1336, MBX-1143)
– IV, IM, IP administration at 1 and 10 mg/kg
– 11/12 rats in MBX-1336 IV 10 mg/kg group died within 1
minute of administration (6M, 5F)
– 1 male rat in MBX-1336 IP group died after EOI blood
collection
– PK parameters
• MBX-1336 IM and IP had BLQ plasma levels
• See other data next slide
• Conclusions: MBX-1336 caused toxicity at the high
end of the pharmacologic range; Plasma levels
provided insight into pharmacology data.
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PK Parameters
Compound
Route
Dose
(mg/kg)
Sex
Tmax
(hr)
t1/2 (hr)
Cmax
(ng/mL)
AUClast
(hr*ng/mL)
AUC0-∞
(hr*ng/mL)
MBX-1336
IV
1
M
0
41.03
6581
869
1165
MBX-1336
IV
1
F
0
NR
9565
892
918
MBX-1336
IV
10
M
NR
NR
NR
NR
NR
MBX-1336
IV
10
F
0
2.46
3516
1104
1122
MBX-1143
IV
1
M
0
1.58
13594
1674
1696
MBX-1143
IV
1
F
0
2.35
14240
1692
1698
MBX-1143
IV
10
M
0
2.65
162795
16930
16976
MBX-1143
IV
10
F
0
5.65
146200
16349
16418
MBX-1143
IP
1
M
1
5.4
52.3
435
461
MBX-1143
IP
1
F
1.5
2.79
46.3
278
296
MBX-1143
IP
10
M
6
10.47
321
4364
5789
MBX-1143
IP
10
F
6
8.85
380
4560
5663
MBX-1143
IM
1
M
4
22.45
14.5
258
490
MBX-1143
IM
1
F
6
16
17.4
346
540
MBX-1143
IM
10
M
12
NR
33.2
631
NR
MBX-1143
IM
10
F
12
NR
37.0
740
NR
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Single Dose Acute Toxicity - Bolus
• Study Design
– 6 groups of 6M, 6F
– 10, 30 , 20, 15 and 5 mg/kg and vehicle control
– Dose followed by 14 day observation period
• Results
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5 mg/kg: no issues
10 mg/kg: some clinical signs
15 mg/kg: 3M and 1F died/sac’d
20 mg/kg: 6M and 1F died/sac’d
30 mg/kg: 6M and 6F died/sac’d
• Conclusions: MBX-1143 was toxic to animals that received 15
mg/kg. It is unclear if the toxicity was related to Cmax or AUC.
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Single Dose Acute Toxicity - Bolus
Dose (mg/kg; n=6/sex/group)
5
10
15
20
M
F
M
F
M
F
M
F
M
F
Unscheduled Deaths* 0 (1) 0 (1)
0
0
0
0 (2)
3
1 (3)
6
1 (2)
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Clinical Signs
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↑
↑↑
↑
↑↑
↓
↑
↓
↓
↓↓ ↓↓
Findings
0
M
Body Weight (thru
Day 11)
Food Consumption
(Days -1 to4
compared to control)
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F
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↑↑ ↑↑
30
-
-
N/A
N/A
↓
↓
↓
↓
↓↓
↓
↓↓
↓
Clinical Pathology
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-
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+
+
+
N/A
+
N/A
N/A
Gross Pathology
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-
=
=
+
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+
+
+
+
+
Organ Weights
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-
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N/A
N/A
*Number of deaths is expressed as non-procedure related deaths (total deaths).
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Single Dose Acute Toxicity Infusion
• Study Design
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1 hour infusion
3 dose groups (10, 30 and 50 mg/kg)
2 TK groups (low and high dose)
1 vehicle control group
n=6/sex/group for all groups except control which had n=2/sex/group
• Results: All animals in 30 and 50 mg/kg dose groups
died/sac’d; 50 mg/kg male TK group died prior to end of TK
sampling.
• Conclusions: MBX-1143 was toxic by infusion at doses of 10
mg/kg. We were unsure if this was species-specific toxicity, so
we decided to evalute the compound in dogs.
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Single Dose Acute Toxicity Infusion
Findings
Dose (mg/kg; n=6/sex/group, except control n=2/sex)
0
5
10
15
M
F
M
F
M
F
M
F
Unscheduled Deaths*
0
0
0
0
6/6
6/6
6/6
6/6
Clinical Signs
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↓
feces
↓
feces
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Body Weight (thru Day 11)
↑↑
↑↑
↑
↑
↓↓
↓↓
↓↓
↓↓
Food Consumption (Days -1
to 3 compared to control)
-
-
=
=
↓
=
↓↓
↓↓
Clinical Pathology
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+
+
N/A
N/A
N/A
N/A
Gross Pathology
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-
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Organ Weights
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+
N/A
N/A
N/A
N/A
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Dose Escalation Dog Study
• Study Design
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Group 1 (1M, 1F): 0.3 mg/kg; 3 mg/kg
Group 2 (1M, 1F): 1 mg/kg; 10 mg/kg
4 days between each dose level (groups alternate)
Confirmation group
• Results
– 0.3 mg/kg: No issues during 1 week follow-up
– 1 mg/kg: No issues during 1 week follow-up
– 3 mg/kg: No issues in 4 days following dosing so 10 mg/kg group
dosed; Male found dead 9 days after 3 mg/kg dose; Female sac’d 10
days after last dose
– 10 mg/kg: Male sac’d moribund 2 days after dosing; Female found
dead 5 days after dosing
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Conclusions
• There is a toxicity issue preventing further development
– Lethal at 10-15 mg/kg in rat
– Lethal at 0.3-3.3 mg/kg in dog
• The efficacious dose is 1-10 mg/kg
• There is not an acceptable margin of safety for continued
development
• As a result, we will not continue additional animal studies and
we will not meet the IND milestone
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