Weekend reading. Oldie but a goodie From PolyMedix. Assets bought by CTIX. The birth of the Defensin Mimetics Platform! And more
"One of the holy grails of medicine is to come up with a stable, simple and easy to synthesize organic molecule, one that could be taken orally as a pill, and would function like a protein itself. This truly is one of the great holy grails of pharmaceutical research. The technology and Bill DeGrado and Mick Klein have developed achieves exactly this, using a variety of computational algorithms to mathematically design compounds which mimic the activity of proteins themselves. These compounds can be polymers, which are larger compounds that can be used as materials, and oligomers and small molecules, which can be used as drugs. Thus, biomimetics. When I had seen the success that they had achieved just the early stages of a year ago, it was light years beyond what I believe any other company has ever been able to achieve. I couldn't say no, so we had to do this".
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"Our first commercial focus is on novel antibiotic drugs and bactericidal materials. Any computational technology is only as good as the products that it generates. The only thing that matters is, does it work. In the last 20 years there have probably been over 100 different companies that have been started trying to come up with rational drug design, ways of designing drugs on first principles, compared with the old fashioned way of using combinatorial chemistry and high throughput screening, which was basically making compounds by the hundreds of thousands and throwing a lot of things against the wall and seeing what sticks. But that doesn't work, and time and history have proven that the brute force methods don't work, and the big pharmaceutical companies acknowledge that it doesn't work either. The reason it doesn't work is that the total potential number of molecules that can exist is so huge. It's been estimated that the total number of drug compounds that could possibly exist, the total number of drug structures that could possibly be designed, is about 1083, or one followed by 83 zeros. In the entire history of the pharmaceutical industry all the companies in the world in the last century have together made about 100 billion compounds. That as a percentage of total space is .000000000000000000000000000000000000000000 0000000000000000000000000000001% of all possible structures. So brute force doesn't work and brute force will never work. Rational drug design is the only way that will ultimately work. While there have been many companies that have tried rational drug design, but most of those attempts haven't been very successful. So the only value of a computational technology is not the theory, but does it work? We have a lot of very complicated molecular dynamics, course grain, and force field algorithms underlying PolyMedix, but the only thing that matters is whether they work. Is it accurate, reliable, reproducable and consistent? Can we quickly, efficiently and cost-effectively get active molecules out of it? The first target we've picked to focus on is to develop novel classes of antibiotic drugs, and with polymer derivatives, self-sterilizing materials. The target we've picked to work on is the human defenses. All multicellular life forms, all higher life forms, have what are called host defense proteins. This is the body's first life of defense against bacterial, fungal, and now known to be also viral infection. These proteins are produced in every living creature at the site where bacteria or fungi enter the body. They're potent, broad spectrum, and work uniquely by directly disrupting and rupturing bacterial cell membranes, so it's virtually impossible for bacteria to develop resistance to them. But because these are proteins, they have the same limitations that I mentioned a few moments ago of the difficulties in developing them as protein drugs. Several companies over the last decade and a half have tried to develop host defense proteins themselves as drugs, and have not succeeded because of the limitations of these proteins. Many companies have tried to come up with organic biomimetics of these host defense proteins, but have not succeeded either. Coming up with a new mechanism of action for antibiotics is a major unmet medical need. Death due to secondary bacterial infections, what are called nosocomial infections, where you check into a hospital for something and pick up a bacterial infection and die of it, is now astonishingly the fourth leading cause of death in this country. After heart disease, cancer and stroke, you have a greater chance of dying from picking up a bacterial infection in a hospital than you do of anything else. Unfortunately, there isn't a single antibiotic in use anywhere in the world today to which bacteria cannot develop, or have not already developed resistance. There are infectious disease experts who are predicting that at the rate that bacteria are developing resistance to conventional drugs, in 10-15 years the world will be at risk of uncontrollable bacterial plagues, basically epidemics of bacterial infections for which there will be no effective treatment, like the Black Death of the 14th century that wiped out half the world's population. So this is a major medical need and also a huge commercial opportunity ' coming up with a novel way of killing bacteria using a mechanism to which bacteria cannot develop a resistance. The defensin mechanism of directly disrupting bacterial cell membranes, sort of like a needle going into a balloon, is such a mechanism. Despite billions of years of evolution, bacteria are still susceptible to being destroyed by host defense proteins. That's the reason why life was able to evolve on earth. So it's a proven mechanism of action, but one that is crying out for a biomimetic compound, because the proteins themselves are just too unstable and not useful as drugs. And that's exactly what we did. We've designed oligomer and small molecule compounds that do indeed replicate the function of defensins. They've potent and broad spectrum. We've tested them against more than 25 different bacterial strains, including strains of bacteria that are resistant to antibiotics, and they work against all of them. They also have antifungal and antiviral properties and are very inexpensive and very easy to make. They're safe, selective for bacterial cells, and don't harm mammalian cells. Polymer derivatives of these compounds have been made, and we've shown that we can add them to paints, plastics and textiles to create products and surfaces that are intrinsically and permanently self-sterilizing by virtue of the material itself. The first program that we've applied this technology to addresses a tremendous market opportunity, a huge medical need, and the first one that we'll be commercializing and focused on developing. This will be the beginning for PolyMedix. Our goal is to develop these antibiotic products internally, to keep North American rights and use this as a core for building a specialty infectious disease business, and find partners to out-license international rights to. We will also out- license all the materials applications to the polymers to materials and consumer products companies, and use that cash flow as a source of near- term revenues. In the future, as we generate revenues we can apply this basic computational technology to other protein/protein targets".
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"Another reason we picked the anti-infective applications for the first product is that, relatively speaking ' and studies have shown this ' this is one of the shortest paths to getting a drug on the market. There are many reasons for this, but primarily because the clinical trials are short. This isn't a two- or three-year trial, as we often have to do in a chronic degenerative disorder like Alzheimer's or cancer. It's a very short clinical trial with a clearly defined endpoint. For someone who is in the hospital with a serious bacterial infection, like drug-resistant Staph, which we've already shown activity against, we expect the duration of dosing of the drug will be a week or two. So it's a relatively short trial, and the end point is also relatively straightforward. We're not trying to interpret whether a person's memory is a little better or a little worse. It's pretty clear: either the person is dead or alive. If you've cured them, they walk out of the hospital. Additionally, the antibiotic market is also one where a small company can successfully market a product with a relatively modest sales force and marketing effort. With a total sales and marketing force of less than 100 people, one can reach most of the hospital market. This is much more feasible for a small company ' we cannot hope to compete directly with the major pharmaceutical companies and their multi-thousand person sales forces that are needed to reach office-based primary care physicians".
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"In the first program, the antibiotic drugs, we computationally designed, synthesized and tested about 200 compounds. Of those about 70%, or 140, were biologically active, and of those about 40 or 20% were potent, broad spectrum, and nontoxic. This report card, this quantitative success rate of 70% for designing hits and 20% for coming up with druggable leads, is by any objective measure nothing short of remarkable. The typical success rate with brute force is, if you're lucky, one in 10,000 will be a hit".
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"If you look out five to 10 years from now at what PolyMedix could be doing, what diseases we would be developing treatments for, most diseases have as their underlying target a protein- protein interaction or a membrane-protein target. Biomimetic compounds for these difficult and important targets could revolutionize medicine. Our antibiotics are the first of what could be many significant new drugs. We selected antibiotics from among many possible programs because it's a huge market opportunity and an enormous unfilled medical need, and also because it's relatively fast, inexpensive, and low risk to develop".
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