• The Need:
Bacterial drug resistance is emerging as one of the most significant problems - and commercial opportunities - in medicine. This problem has arisen from many years of over-use and misuse of antibiotic agents, such as inappropriately trying to treat viral infections with antibiotics, and adding antibiotics to animal feed. Further, until very recently there has been a lack of pharmaceutical research into novel classes of antibiotic agents. The incidence of drug-resistant hospital infections is growing at an alarming rate, and strains of bacteria are now emerging that are resistant to all known antibiotic drugs.

Each year, an alarming 2,400,000+ nosocomial infections (acquired in healthcare facilities while undergoing treatment for another ailment or illness) occur in the U.S. alone. They are estimated to directly cause 30,000 deaths and contribute to another 70,000 deaths each year, over 100,000 deaths annually in total - the fourth leading cause of death in the U.S. Nosocomial infections can directly cost over $30,000 per incident and account for $4.5 billion annually in total extended care and treatment (Source: U.S. Centers for Disease Control).

• The News:
The pharmaceutical industry is now in a "catch-up" mode and feverishly attempting to discover new types of antibiotic drugs. However, most of this work is focused on synthesizing analogs of known drugs (such as cephalosporins and quinolones), which, while potentially useful for a short time, will inevitably also encounter drug resistance. The worldwide human therapeutic markets for anti-infective drugs exceeds $25 billion, and offers tremendous commercial opportunities.

PolyMedix uses a proprietary computational de novo drug design platform to design biomimetics: small molecules that mimic the activity of proteins. The first products developed using the computational platform are novel small molecule antibiotic drugs which mimic the activity of host defense proteins. These compounds are also called BAAC’s – Bactericidal Amphiphilic Antibiotic Compounds. We believe these are the first and only small molecule defensin mimetics being developed intended for use in systemic infections. These compounds mimic the mechanism of action of the host defense proteins. From a small library of a few hundred compounds, a high hit rate of biologically active compounds was produced and the first clinical IND candidate, PMX-30063, has been selected. These have broad and potent antimicrobial activity against a panel of Gram-positive and Gram-negative bacteria, including antibiotic-resistant. Our compounds:

• how potent and broad spectrum, active against over 150 Gram-positive and Gram-negative human pathogens;
• Are active against drug-resistant bacteria including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE).
• Are rapidly bactericidal, killing bacteria in a matter of minutes
• Are selective for bacterial cells versus mammalian cells
• Demonstrate antifungal and antiviral activities in addition to antibacterial
• Are simple and inexpensive to synthesize
• Have molecular weights between 500 to 1000 D.
• Show robust activity in animal models of bacterial infection with activity comparable to superior to vancomycin
• Indicate that bacterial resistance has not been observed in serial passage studies.

By mimicking the activity of the host defense proteins, PolyMedix’s compounds have a highly unique mechanism of action: directly lysing bacterial cell membranes, resulting in the destruction of the genetic machinery often responsible for bacterial resistance. Thus, it is unlikely that bacterial resistance can easily develop to these compounds. The overall approach has been the design of biomimetic polymers, oligomers, and small molecules that 1) mimic key biological properties of proteins and 2) are more stable and inexpensive to produce than natural proteins. The first application of this technology has been the design and synthesis of non-peptide mimetics of host defense proteins that exhibit potent and broad spectrum anti-microbial activity.

 Serial passage experiments demonstrate that bacterial resistance does not easily develop to the Polymedix compounds:

We believe PolyMedix compounds have potency comparable or superior to reference antibiotic drugs, with potent activity against drug-resistant bacterial strains. By offering a low likelihood of drug resistance, these compounds directly address the greatest unmet need in anti-infective therapy. As a result, these drug candidates offer a significant opportunity, and the possibility to become the standard of care for hospital infections.

Efficacy vs. vancomycin in the rat thigh burden model
PMX-30063 and PMX-30016 are equally or more efficacious than vancomycin

Maximum efficacy (˜99.999% bacterial cell killing) achieved at total doses of 2-4 mg/kg

Efficacy PMX-30063 and PMX-30016 Mouse Sepsis Model: S. aureus infection
PolyMedix compounds are highly active in mouse peritonitis/sepsis model

• The Status:
In December 2008, we completed and announced positive results from our single dose escalation clinical study of healthy volunteers receiving PMX-30063 at various dose levels (Phase 1A). This ascending single-dose intravenous pharmacokinetic and safety study met the necessary Phase 1 goals of defining both a limiting single dose and the plasma distribution/elimination kinetics. In this study, the dose was not limited by any measurable clinical or laboratory parameters. A subjective syndrome of paresthesias was identified, appearing only at the higher dosages and consisting of abnormal neuronal sensations (numbness and/or tingling) often likened to dental anesthesia. These effects were graded as mild to moderate by investigators or subjects, but their reproducibility and dose-proportionality allowed dose-escalation to be successfully concluded after achieving levels well in excess of the expected therapeutic range. The effects were temporary and resolved on their own. The same study provided detailed information on the time course of the drug during and after dosing. These pharmacokinetics appear favorable for therapeutic use of the drug. The half-time for elimination from the plasma was approximately 12 to 15 hours, allowing for flexibility in dosing to obtain optimal peak and trough drug levels.

In December 2009, we completed and announced positive results from the main portion of our ascending multi-dose intravenous pharmacokinetic and safety study of healthy volunteers receiving PMX-30063 at various dose levels (Phase 1B). The Phase 1B blinded, randomized, placebo-controlled ascending multiple-dose study was designed to find the limiting tolerable dosage for PMX-30063 when administered as five daily doses, and to define the resulting plasma distribution/elimination kinetics. In this study, the limiting effects of the dose were found to be the same subjective syndrome of paresthesias identified in the previously completed Phase 1A single-dose study, which appeared only at the higher dosages and consisted of abnormal sensations often likened to dental anesthesia. These abnormal sensations of paresthesias usually begin in the oral area before branching out, and typically last from hours to days. In all cases the effects were temporary and resolved without treatment. Transient changes in liver enzymes (ALT and AST) were also observed in some subjects at higher doses. In most cases these changes were less than twice the upper limit of normal, and in all cases resolved without treatment after completion of the study. These changes were not considered clinically significant by the study physicians, and were similar to those often seen with many antibiotic and other marketed drugs.

In the first two segments of the study, 56 healthy volunteers were divided into 8 cohorts and received up to 5 doses of either PMX-30063 or placebo. The doses ranged from 0.1 mg/kg to 0.6 mg/kg per day and were administered as a single one-hour infusion every 24 or 48 hours. Dosing continued until a threshold was reached where more than one volunteer in a cohort tolerated fewer than 5 doses.

The data showed that there were minimal clinically relevant adverse effects at 0.2 mg/kg (total dose of 1.0 mg/kg), and there was no early termination of dosing until the 0.4 mg/kg level. At the 0.5 and 0.6 mg/kg doses (up to 2.5 and 3.0 mg/kg total doses, respectively), the syndrome of subjective effects became more prominent. As also seen in the previous Phase 1A clinical study, there were no objective correlates or clinical measurements associated with the sensations. Five of ten subjects intended to receive 2.5 mg/kg or more total dose tolerated that amount. These data have confirmed that a total dose of 3.0 mg/kg, given as 5 doses of 0.6 mg/kg once-daily, was the limiting dosage in this study.

Antimicrobial assays were also performed with blood samples drawn from the study subjects. In these assays, blood samples were taken from the subjects after they had been dosed with PMX-30063. Staphylococcus aureus bacteria was then added to these blood samples, to determine if the PMX-30063 in the subjects blood would have antimicrobial activity. The bacteriostatic and bactericidal activity against MSSA (methicilin-sensitive Staphylococcus aureus) and MRSA (methicillin-resistant Staphylococcus aureus, or drug-resistant Staph) strains were achieved at doses at or above 0.2 mg/kg, and largely correlated with those established in normal medium and in experimental animal studies (as seen in data presented by PolyMedix at the American Society of Microbiology ICAAC 2009 meeting). These data suggest that antimicrobial activity and bacteriostatic and bactericidal concentrations can be achieved in human subjects following multiple administrations of PMX-30063 at safe and well tolerated doses below the identified limiting dosage. Based upon the doses of PMX-30063 administered in the first two segments of the study, and blood levels of drug observed in volunteers in this study, together with our pre-clinical studies, we believe that a beneficial therapy may exist.

We have conducted our Phase 1 studies to United States standards and plan to submit an IND with the FDA before commencing Phase 2 studies in the United States, and ultimately seek regulatory approval in the United States.