Microbiotix, Inc. Program Update

1. Microbiotix, Inc. Program Update

2. Overview • Introduction • Scope of contract • Original plan • Data • Status of contract • Conclusions

3. 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)

4. 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”

5. 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.

6. 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.

7. 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.

8. 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

9. 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.

10. Preclinical Studies • 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

11. 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

12. 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.

13. 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.

14. PK Parameters

15. 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.

16. Single Dose Acute Toxicity - Bolus *Number of deaths is expressed as non-procedure related deaths (total deaths).

17. 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.

18. Single Dose Acute Toxicity - Infusion

19. 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

20. 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