PolyMedix Inc.
This article was originally published in Start Up
Executive Summary
PolyMedix uses a suite of proprietary, patented computational tools to create simple, easily synthesized organic small molecule compounds that mimic the activity of host defense proteins. The company's first focus is to create antibiotic candidates, and eventually, drugs for cancer and cardiovascular disease. It will seek nearer-term revenues from materials applications of its technologies.
Mimicking proteins, for drugs and materials
3701 Market Street, Suite 442
Philadelphia, PA 19104
Phone: (215) 966-6199
Web Site: www.polymedix.com
Contact: Nicholas Landekic, President & CEO
Industry Segment: Biotechnology
Business: Biomimetics, as therapeutics and for materials
Founders: Nick Landekic; William F. DeGrado, PhD
Founded: August 2002
Investors: Private investors
Financing to Date: $6 million
Employees: 8
Scientific Advisory Board: William DeGrado, Michael Klein, PhD, Joel Bennett, MD, Dewey McCafferty, PhD, Jeffrey Winkler, PhD and Mitchell Lewis, PhD (University of Pennsylvania); Gregory Tew, PhD (University of Massachusetts); Shaker Mousa, PhD (Albany Medical College)
Plenty of companies are striving to develop new antibiotics—and no wonder, given that hospital-acquired infections are now the fourth leading cause of death in the US, right after heart attacks, cancer and strokes.
The crux of the problem facing antibiotic developers rests in the fact that microorganisms have exceedingly well-developed mechanisms for evading drugs. The bugs can often recognize and pump out compounds intended to kill them, in a process known as efflux, or they can mutate the intracellular target—usually an enzyme—that a drug is designed to bind.
The founders of PolyMedix Inc. believe they can beat microbes' time-tested defense mechanisms, by mimicking and improving on the first line of defense that multi-cellular organisms from plants to fish to people deploy to fight bacteria. Nick Landekic, CEO and co-founder of the Philadelphia-based company, explains that all higher organisms produce so-called "host-defense proteins," which populate places in the body that bacteria commonly enter--such as the skin, and the mucosa in the nose, mouth and urogenital area. Over 800 such proteins have now been identified across species. In humans, they are called "defensins," while frogs produce magainins and insects utilize cecropins to fight infection.
Defensins act by physical versus chemical means to disrupt and destroy bacteria—and it's this characteristic that Landekic believes will allow protein mimics to thwart microbial defenses that lead to drug resistance.
The bacterial cell membrane "is like a balloon inside a balloon. Defensins perforate the outer layer and stick themselves in the middle," Landekic explains. This action disrupts the membrane and causes the bacterial cell to break, usually in seconds to minutes. Since defensins don't fully enter bacteria, the organisms' pumps never get a chance to work. And since bacteria have developed their cell membrane structures over millions of years, PolyMedix thinks it's unlikely the bugs will be able to mutate them.
PolyMedix isn't the first firm to hitch its star to host-defense proteins: others have tried and failed. A Philadelphia-based firm called Magainin Pharmaceuticals Inc., since re-named Genaera Corp. , began working in the late 1980s to develop magainins, after its founding scientist noticed that frogs crowded in a laboratory tank were scratching each other, but that the wounds weren't becoming infected. In the 1990s, IntraBiotics Pharmaceuticals Inc. tried to develop host-defense proteins from pigs, but these integrins, like the frogs' magainins, were seen by the body as foreign and destroyed. Both companies tried to develop their compounds for topical use, but the drawbacks made them miss the big market for systemic antibiotics. The compounds' failure as drugs also had to do with manufacturing complexity: Landekic says Magainin's and IntraBiotics' processes for synthesizing their compounds into drugs required 50 to 70 steps.
PolyMedix expects to fare better with its efforts to commercialize small molecules that mimic host-defense proteins. The firm has utilized a suite of proprietary, patented computational tools to create simple organic small molecule compounds which mimic the activity of the host defense proteins--it calls them defensin "mimetics." Landekic expects his compounds to be relatively simple to synthesize, because they are much smaller than natural host defense proteins. Additionally, they are completely synthetic small molecules made of organic building blocks, unlike proteins and peptides which are complex structures made of amino acids.
Founded in 2002, PolyMedix has already created a variety of small molecules that Landekic believes have excellent potential as drugs. The company's mimetics tend to be about 1/10th the size of native defensins, with a molecular weight ranging between 500 and 900 daltons, he says, adding that they are also easy to make. Of about 300 compounds covering 12 different antibiotic classes, about 2/3 register as hits in standard drug screens and about 1/5th are good enough to be considered leads, Landekic claims. He says the compounds have been successfully tested against more than 150 strains of gram-positive and gram-negative bacteria, as well as some fungal strains. "We've yet to find a strain we can't kill," he asserts. Landekic says his firm's mimetics were tested against 75 clinical isolates of bacteria resistant to multiple traditional antibiotics—and they worked against all strains tested. Numerous animal experiments have been encouraging as well, and have demonstrated that the lead compounds show robust activity in animal models of both disease survival as well as quantitative reduction of bacterial cell infection.
So far, all this bug-killing action seems to be occurring without engendering resistance to the compounds. Landekic notes that would-be antibiotic developers commonly do an experiment called a "serial passage," to see when resistance develops. The test involves exposing microbes to a dose of compound that's half of what's sufficient to kill them. With conventional antibiotics, after 3 to 6 rounds, it generally takes 10 to 20 times more drug to kill the bugs than was initially necessary. "But often you can't give 10 times more drug, because of toxicity," he notes. To date, he says, PolyMedix has taken its compounds through 17 passages in multiple repeats of the experiments, and they're still effective and there's still no resistance. Overall, the experimental results of PolyMedix's work have been replicated by more than a dozen labs, he notes.
The compounds work as well as they do, Landekic asserts, because of the computational methods PolyMedix has been able to bring to bear to design them. "Our molecules are about 20 times more potent, 50 times more selective and 10 times smaller" than natural defensins, he claims. The company's suite of proprietary tools includes a mathematical model (a force field) of the way water behaves at a molecular level—a valuable factor to consider, since water influences the shape that drugs and their targets assume, and how they interact with each other. PolyMedix gets an edge from another tool for modeling molecular dynamics, or the way molecules interact over time. Conventional modeling approaches—even those performed with huge supercomputers capable of processing tera-flops of information—generally model out an interaction for just 10 or 20 nanoseconds. Not much happens in that time, Landekic points out.
PolyMedix is modeling its compound candidates a different way, with a so-called "coarse grain" approach developed by company co-founder Mike Klein, of the University of Pennsylvania . The method does way more with less, Landekic says: a cluster of 25 PCs can do simulations for hundreds of microseconds, about 4,000 times longer than the typical current capabilities, and "that's the difference between a snapshot and a movie."
PolyMedix also possesses a set of algorithms it calls SUCCEED, for modeling and manipulating transmembrane proteins. The software has application beyond antibiotics, Landekic points out, because many drugs currently on the market—perhaps as many as 50%--are believed to target proteins that reside in cell membranes. Several start-ups founded in recent years have dedicated themselves to solving the structures of transmembrane proteins such as G-protein coupled receptors (GPCRs) but it's been tough going, because of the way these proteins wind and twist through the membrane. Landekic says SUCCEED is already helping his company's scientists see which of a protein's amino acids on the inside and the outside of the membrane can be substituted, so the structure can be solubilized and crystallized.
"So far, our founders have tried three times and succeeded three times," Landekic declares. He says Bill DeGrado of the University of Pennsylvania—who, like Klein, is a member of the National Academy of Sciences—first tried the tool on phospholamban, a target for congestive heart failure, and was able to show equivalence of the crystallized protein to the native form. DeGrado then also crystallized a potassium channel receptor, Kcsa, and showed it too had the same biological activity as the natural enzyme. Encouraging results have reportedly been obtained with a third protein, but the work hasn't been published yet.
The algorithms PolyMedix has assembled won't be able to solve every possible structure of membrane and transmembrane proteins, Landekic acknowledges, but the company believes it now has proof of principle that its technology works in this rich niche of biologically proven drug targets. While most companies' computational modeling approaches rely on in silico screening of compounds, and rational-design efforts are usually restricted to enzymes that are far less complex than proteins, Landekic thinks PolyMedix has what it takes to design molecules "based on first principles, working from within the target itself."
Eventually, PolyMedix aspires to leverage its technologies to develop drugs for cancer and cardiovascular disease. It's already made some progress in that direction: creating small molecules to mimic low-molecular-weight heparin, as well as angiogenesis inhibitors that mimic Factor Xa, and which are believed to work by blocking both VEG-F (vascular endothelial growth factor) and FGF (fibroblast growth factor). Conventional angiogenesis inhibitors, usually antibodies, block one or the other factor—and reduce the formation of new blood vessels by about 40%, Landekic points out. He says PolyMedix' candidates can block about 90% of angiogenesis in experimental models.
For now, PolyMedix is focusing on the near-term goal of preparing antibiotic candidates for clinical testing. One compound is being groomed as a topical ophthalmic drug, and might also be developed in the same aqueous solution as a treatment for acne and ear infection. A second is shaping up as an intravenous treatment for multi-drug resistant systemic bacterial infections. Both potential products fit with a corporate model geared to treating serious and acute infections: markets where the company can participate itself with a small sales team in the US, while out-licensing worldwide rights to bigger players capable of carrying oral drug formulations to large populations.
For a company just three years old, PolyMedix has accomplished a good deal—and done so at a low burn rate. The firm has spent just $4 million so far, largely, Landekic says, "by being ruthless about need-to-have, versus nice-to-have" decisions. The nearly virtual company spent the first two years of its life in space it didn't have to pay for, and now operates out of an incubator owned by the University of Pennsylvania and the City of Philadelphia.
Appreciation for the value of cash is encouraging privately funded PolyMedix to look beyond therapeutic applications for its technologies, at materials sciences. Given the length of time that infectious organisms can survive on surfaces, Landekic notes that there are many potential markets for safe antimicrobial additives. Medical uses abound: makers of catheters, IV tubes, gowns, gloves and hand lotions might all be interested, since Staphylococcus aureus is now known to be able to survive on a doorknob for 6 to 8 weeks. Industrial uses could include tabletops for hospitals, restaurants and food preparation, as well as anti-fouling coatings for boats. Consumer applications might include shampoos, deodorants, bedsheets and towels.
PolyMedix is already talking to more than 50 companies interested in licensing safe antimicrobial compounds, Landekic says. He believes materials applications are a business worth pursuing as a complement to medical treatments, with polymers appropriate for materials-science applications often being able to be cooked up all in one pot. These polymers can be thought of as linked monomers (small molecules), like beads on a necklace. The company will need monomers to create biomimetics as therapeutics anyway; might as well build the capacity to make them and turn them into relatively low-hassle products that can be sold for some materials applications as the drug candidates make their way through the clinic.
Given the rapacious terms that risk-averse venture capitalists are demanding these days for early-stage drug companies, the firm will likely explore alternative financing vehicles until it has taken its compounds into clinical development. PolyMedix hopes to initiate clinical trials with its topical and systemic antibiotic compounds in 2006.—Deborah Erickson