Microbiotix, Inc. Program Update

Microbiotix, Inc. Program Update

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Overview

• Introduction• Scope of contract• Original plan• Data• Status of contract• Conclusions

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Nomenclature

• 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• 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 3-

4 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• 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, MBX-1336 (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 MBX-1143 (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

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• Pilot Toxicology • Genetic Toxicology

– AMES– CHO– Rat Micronucleus

• Rat Single Dose PK• Rat Single Dose Acute Toxicity (Bolus)• Rat Single Dose Acute Toxicity (Infusion)• Rat ADME - ongoing• Dog Dose Escalation (Infusion) – ongoing

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 ParametersCompound 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– 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

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FindingsDose (mg/kg; n=6/sex/group)

0 5 10 15 20 30M F 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) 6 6

Clinical Signs + + + + + + + + + + + +

Body Weight (thru Day 11) ↑↑ ↑↑ ↑ ↑↑ ↑ ↑↑ ↓ ↑ ↓ ↓ ↓↓ ↓↓

Food Consumption (Days -1 to4 compared to control)

- - N/A N/A ↓ ↓ ↓ ↓ ↓↓ ↓ ↓↓ ↓

Clinical Pathology - - + + + + + + N/A + N/A N/A

Gross Pathology - - = = + + + + + + + +

Organ Weights - - + + + + + + + + N/A N/A

*Number of deaths is expressed as non-procedure related deaths (total deaths).

Single Dose Acute Toxicity - Infusion

• Study Design– 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

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FindingsDose (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 - - ↓ feces

↓ feces + + + +

Body Weight (thru Day 11) ↑↑ ↑↑ ↑ ↑ ↓↓ ↓↓ ↓↓ ↓↓

Food Consumption (Days -1 to 3 compared to control) - - = = ↓ = ↓↓ ↓↓

Clinical Pathology - - + + N/A N/A N/A N/A

Gross Pathology - - + + + + + +

Organ Weights - - + + N/A N/A N/A N/A

Dose Escalation Dog Study

• Study Design– 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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