• 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). 

• Our Approach:  

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.
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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.
 

• Clinical Studies:

In March 2010, we completed and announced positive results from our Phase 1B clinical study which was designed as a blinded, randomized, placebo-controlled, ascending, multiple-dose study. A total of 77 healthy subjects were enrolled with 55 receiving PMX-30063 and 22 receiving placebo. The study contained three parts, each of which utilized different dosing durations including every 12, 24 or 48 hours, over five or ten days, for a planned total of five to ten doses. Doses in each part ranged from 0.08 to 0.60 mg/kg per day. The primary endpoints of the study were to further delineate the pharmacokinetics and to find the dose-limiting dose for PMX-30063 when administered as multiple doses over five days.

The results from the entire study showed no difference in tolerability or dose-limiting effects when PMX-30063 was administered every 12 or 24 hours. In addition, the dose-limiting total dose for healthy subjects was 3.0 mg/kg (0.6 mg/kg every 24 hours or 0.3 mg/kg every 12 hours). The dose-limiting effect was paresthesias (abnormal sensations of numbness and tingling), generally localized to the oral area and extremities, which were mild and non-disabling. There were no other clinically significant adverse effects reported.

To test the antimicrobial activity of PMX-30063, blood samples were drawn from healthy subjects in the study after they had been dosed with PMX-30063. Four different strains of Staphylococcus aureus bacteria, including two MRSA strains, were added to the blood samples. The results showed that PMX-30063 was bactericidal against both MSSA (methicillin-sensitive Staphylococcus aureus) and MRSA (methicillin-resistant Staphylococcus aureus, or drug-resistant Staph) starting at doses as low as 0.1 to 0.3 mg/kg. These data suggest that multiple administrations of PMX-30063 below the identified limiting-dose may have a bactericidal effect on MSSA and MRSA in human subjects.

We plan to initiate a Phase 2 clinical efficacy study with PMX-30063. The trial will be conducted in patients with any type of Staph infection, including both MSSA and MRSA strains. Patients are expected to receive multiple doses of PMX-30063 or an active comparator. The clinical target is expected to be Acute Bacterial Skin and Skin Structure Infections (ABSSSI).

In December 2008, we completed and announced positive results from our Phase 1A single dose escalation clinical study of healthy subjects receiving PMX-30063 at various dose levels. 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 limited by a subjective syndrome of paresthesias (numbness and/or tingling) often likened to dental anesthesia. 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.

[ Click here ] to view the Mechanism of Action of PMX-30063

[ Click here ] to view the PMX-30063 Antibiotic Information Package

[ Click here ] to view the PMX-30063 Antibiotic Bibliography