Data on Novel Antibiotic Drugs Presented at ICAAC Meeting

With many strains of bacteria now immune to multiple classes of antibiotics, the needs for creating new germ fighters are enormous. Pioneering biotechnology companies are developing products that take the wiliness of bacterial superbugs into account, effectively performing an end-run around conventional antibiotics.

Scientists at PolyMedix and the University of Pennsylvania used new computer modeling approaches to design and create synthetic small organic molecules and polymers —easier to make than peptides — that have the same mechanism of action as the host defense proteins and with similar germ-fighting ability. Based on the success of this work, the University of Pennsylvania filed for several patents. PolyMedix, based in Radnor, Pennsylvania, was started in 2002 to build on this work. The Company recently made three presentations at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Washington, D.C.

The presentations demonstrate the safety and efficacy of the company’s Bacterial Amphiphilic Antibiotic Compounds (BAACs), which mimic humans’ natural defense mechanisms but are much more powerful, broader-acting and versatile – and intended to be used as systemic antibiotic drugs with a novel mechanism of action which makes bacterial resistance unlikely to develop.

BAACs are non-peptidyl molecules inspired by the activity of naturally occurring, amphiphilic antimicrobial peptides known as defensins. Like defensins, BAACs cause bacterial cell membranes to rupture, a mechanism unique among antimicrobial compounds.

While their activity mimics host defense proteins, PolyMedix’s BAACs are completely synthetic, non-peptide small molecules. BAACs are one-tenth the size of naturally-occurring defensins, hundreds of times more powerful at killing bacteria and pathogenic fungi, and as much as a thousand times more selective for bacterial vs. host cells.

Because they are synthetic, scientists can design any number of antimicrobial or pharmacokinetic properties into BAACs. These synthetic analogs have many advantages over peptides because of their small size, which increases their stability and tissue penetration, the ability to fine tune their structure for optimization of potency and safety, and their low toxicity to non-pathogenic cells.

Using advanced computational techniques; PolyMedix has identified and synthesized new BAAC antimicrobial agents – as well as antimicrobial materials useful in industry and hospitals – and has gone from starting the effort to having a drug in human clinical testing in less than 36 months and for less than $10 million. Tuft University’s Center for Drug Development estimates that the average cost of discovering a new drug is approximately $198 million in direct out-of-pocket costs and $615 million in total costs. PolyMedix’s ability to discover and advance into human clinical testing a completely new type of antibiotic drug for $10 million in direct costs (and $17 million in total costs) is an impressive demonstration of the power and efficiency of POlyMedix’s approach.

The first of four presentations relating to PolyMedix’s compounds, “In vivo efficacy and safety of a novel host defense protein mimetic, PMX30063; a candidate IV agent to treat Staphylococcal infections,” described efficacy data on PolyMedix’s lead BAAC compound in mice infected with Staphylocccus aureus, and safety data in rats.

Mice were treated beginning one hour after inoculation with Staph bacteria at doses of up to 24 mg/kg/day. The animals were monitored for viability, clinical signs, food consumption, and other signs. The lowest dose of PMX30063 resulting in maximum efficacy was 2 mg/kg twice a day. This dosage achieved reductions of up to 3.96-log reductions – a nearly 10,000-fold reduction in bacterial load– in colony forming units relative to control mice. No toxicity was observed in rats at normal doses, where the “no observable adverse effect level” (NOAEL) was found to be 12 mg/kg/day, well below the effective level in mice. PMX-30063 is currently undergoing Phase I human clinical testing.

The second poster, “In vitro antimicrobial activities of a novel host defense protein mimetic, PMX30063, against multiple isolates of Staphylococci with defined susceptibility phenotypes,” will be delivered by PolyMedix and collaborators at the University of Pennsylvania in Philadelphia.

Investigators tested PMX-30063 against 150 isolates of Staphylococcus aureus and coagulase-negative staph organisms with known antibacterial susceptibility to standard antimicrobial agents. MIC90 values, in µg/ml, for PMX30063 averaged : 1 for S. aureus, 0.5 for S. epidermidis, and 1 for S. haemolyticus. MIC ranges were nearly identical between methicillin-susceptible and –resistant strains, daptomycin non-susceptible, linezolid non-susceptible, vancomycin intermediate, and vancomycin resistant strains of S. aureus.

Importantly, serial passage of methicillin-susceptible and resistant strains of S. aureus at half the MIC for 17 passages (triplicate cultures) did not result in any change in MIC values, suggesting little or no chance for development of antimicrobial resistance. This finding is potentially of tremendous importance and significantly distinguishes PolyMedix’s PMX-30063 from all other antibiotics currently on the market or in development. This finding also provides experimental evidence to support the low likelihood of bacterial resistance developing with PMX-30063. With the continued dramatic increase in drug resistance – a study by APIC published in February 2008 revealed that 70% of bacterial infections are now drug resistant – there is an immediate and desperate need for an antibiotic with a new mechanism of action. PMX30063 also has a high selectivity for bacteria over mammalian cells, suggesting very low toxicity.

The third poster, “In vitro activity of novel biomimetic compounds against oral Candida strains,” presented by Dr. Gil Diamond of the University of Medicine and Dentistry of New Jersey, working with PolyMedix scientists, examines the activity of two broad-spectrum AMPs, PMX70004 and PMX30016, against a panel of pathogenic Candida strains. Minimum inhibitory concentrations (MICs) for the phenylalkyne PMX70004 and the arylamide PMX30016 were 0.5-1.0µg/ml against blastoconidia of azole-susceptible strains of C. albicans, C. dubliniensis, C. galabrata, C. parapsilosis, and C. tropicalis, and against azole-resistant strains of C. albicans and C. krusei. MIC against hyphae of C. albicans were 4µg/ml (for PMX70004) and 0.5µg/ml (PMX30016). The AMPs achieved rapid killing of all strains, with greater than 2-log reduction after 10 minutes at 10µg/ml, and worked synergistically with the antifungal agent itraconazole. Moreover, no increase was observed in MIC after passaging the organisms twenty times at sub-MIC concentrations – providing additional experimental evidence suggesting a low likelihood of resistance developing with PolyMedix’s compounds. This work also demonstrates additional potential uses for PolyMedix’s compounds, for the treatment of fungal infections in addition to the previous work against bacteria.

“These posters demonstrate the breadth and power of PolyMedix’s compounds , and their potential to treat a wide range of dangerous infectious agents,” commented Nicholas Landekic, CEO at PolyMedix. “The pharmaceutical industry has been playing catch-up with pathogenic bacteria and fungi for decades,” he continued. “Our antibiotic agents present a tremendous opportunity to introduce new classes of antibacterial and antifungal that work through a novel mechanism and have little potential for inducing antimicrobial resistance.”

Worldwide, infections are now the second leading cause of death, and one of the fastest growing causes of death, with approximately one hundred thousand deaths each year in the U.S. alone. The Association of Professions for Infection Control and Epidemiology (APIC) estimates that 70% of bacterial infections may now be drug resistant.

Source: Investor Relations Group