Aeolus Pharmaceuticals, Inc. (AOLS)
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Pharmaceuticals antioxidant mimetic compound is effective in multiple animal models
of disease and Aeolus is currently conducting a Phase 1 trial for the treatment of ALS
Greenwood Village, CO 80111
Dr. Crapo: Aeolus is a biotech company I co-founded in the mid-90s to explore using metalloporphyrins as antioxidants. Aeolus was initially supported by a parent company called Intercardia, Inc., which eventually became Incara Pharmaceuticals Corporation. Incara had a broad drug development platform, while Aeolus concentrated on developing antioxidant mimetics. The Aeolus group, under my direction, developed these compounds through chemical synthesis and preclinical work in animal models. Aeolus eventually merged with Incara. Based on impressive results in preclinical animal models we decided to prepare our lead compound, AEOL 10150, for human clinical trials. Pharmacokinetic studies and animal toxicology were done and methods for large scale synthesis using GLP were developed. An IND (Investigational New Drug application) was filed in the summer of 2004, with the initial indication being the treatment of ALS. At about that same time a decision was made to restructure the company and I stepped in to become the Chief Executive Officer. Dr. Shayne Gad was recruited to serve as President and to oversee the development of clinical trials. We proceeded to organize the start of Phase 1 safety testing in ALS patients and added a new clinical development arm directed at cancer patients receiving radiation therapy. Other important changes included changing the name of the company to Aeolus Pharmaceuticals, Inc. (AOLS) and adding a new company office in Colorado. Aeolus is now concentrating its entire effort on creating a new class of highly effective antioxidant mimetics.
CEOCFOinterviews: Will you explain what that is?
Dr. Crapo: Oxidation is a central part of biology. Think of this as similar to a fire. A fire involves uncontrolled oxidation of organic materials. When flammable materials are combusted, they combine with oxygen from the atmosphere and create large amounts of heat and energy, which one sees in the form of fire and light. In our bodies a similar process continually occurs in every cell. The chemistry is the same except that it is controlled and takes place at a slower rate. Cellular combustion is the reason our bodies are warm. The food we eat provides the fuel and oxygen enters through our lungs and travels by the blood stream to all cells. The process of burning food molecules in a cell does not produce a flame, but does produce the heat and energy our bodies require.
Unfortunately, this process of cellular combustion can also go out of control and create unwanted oxidations that can cause damage to our cells and tissues. The body has a variety of defense mechanisms to prevent this type of injury. These defenses are called antioxidants. You can currently buy some of these antioxidants as vitamins such as vitamin E, vitamin C and beta carotene. The limitation to the vitamin antioxidants is that they are relatively low in efficiency and are not enzymatic. Our bodies also have a number of much more potent antioxidants that are enzymes and have very high rate constants for scavenging the toxic oxygen free radicals that are produced by cellular combustion processes. Our research group has been working on creating a new set of molecules that mimic the bodys most potent antioxidants enzymes. These new antioxidant molecules are essentially as powerful as the bodys native antioxidant enzymes and are about 10,000 times more potent than molecules like vitamins E and C. These new drugs are enzymatic, which means they are not consumed when they do their work. Many diseases are associated with excess oxidation. A potent antioxidant could thus be used in a large number of different clinical situations. For example, one would expect them to inhibit inflammation. Inflammation commonly leads to a tissue being red, hot and swollen. These are signs of uncontrolled oxidation in the inflamed tissue. An antioxidant can potentially prevent or limit this process.
CEOCFOinterviews: Why did you start with ALS?
Dr. Crapo: Our preclinical data on ALS (amyotrophic lateral sclerosis) was very impressive. One of the genes involved in causing ALS has been found. A mouse model of ALS has been created by transfecting the defective human gene into mice. This gene encodes for one of the bodys most powerful antioxidant enzymes; an enzyme called superoxide dismutase (SOD). When this gene is mutated, the resulting protein folds differently and then accumulates in motor neurons causing the disease ALS. When this defective gene is expressed in a mouse, the mouse develops classic signs of ALS. Dr. John Crow, at the University of Arkansas, Little Rock, gave one of our compounds, AEOL 10150, to mice with ALS and found spectacular results. In these mice our compound reduced the development of symptoms and prolonged disease-free survival. We are hopeful this compound will show similar benefits for patients with ALS.
CEOCFOinterviews: Are you ready for human trials?
Dr. Crapo: Yes, the first patients received our drug in October 2004. However, you should remember that the first trials are safety trials and are not testing efficacy. We are starting with very low doses and initially give only a single dose to test if the drug is safe.
CEOCFOinterviews: Will you please tell us about your work with pancreatic cells?
Dr. Crapo: In the pancreas there are small clusters of cells called islet cells. These cells produce insulin and the insulin controls blood sugar. Injury to islet cells can cause diabetes. The childhood form of diabetes involves destruction of the islet cells in the pancreas, and therefore loss of insulin production. A new approach to the treatment of this disease involves transplantation of healthy islet cells. The way this is done is to remove and purify islets from a donor pancreas. This process of isolating islet cells exposes the islets to oxidative stress which results in the loss of most of the islets before they can be transplanted. Currently the recovery of sufficient viable islets to successfully transplant one recipient can require several donor pancreases. Dr. Jon Piganelli and his colleagues at the University of Pittsburg have found that our antioxidant mimetics can protect human islet cells during the isolation procedure and result in a much higher recovery of viable islets. The use of these antioxidant mimetics can potentially help make pancreatic islet cell transplantation practical for the cure of diabetes. In addition, if this approach works for islet cell transplant it could also help improve the preservation of other organs for transplantation.
CEOCFOinterviews: How are you funding all of this?
Dr. Crapo: Most of the work has been funded by the NIH (National Institutes of Health) and through a network of collaborations with universities across the United States. The work to prepare these new drugs for human clinical trials has been funded through Incara and Aeolus.
CEOCFOinterviews: Is it going well?
Dr. Crapo: Yes! We have given our compound to a large number of laboratories around the country and the compounds have been successfully used in a large number of animal models of disease. These include respiratory diseases, cardiovascular diseases, neurological diseases, and immunological diseases like diabetes. These antioxidant mimetics have been shown to be effective in more than twenty animal models.
CEOCFOinterviews: So, you are going to raise money for a variety of possibilities?
Dr. Crapo: The first trial is taking place in patients with ALS. We also have strong preclinical data showing that these compounds will likely have a dual action in patients with cancer who are undergoing radiation therapy. The compounds protect normal tissues from radiation-induced injury while at the same time inhibiting the regrowth of the cancer following radiation therapy. I expect that the second group of patients to receive one of these drugs will be cancer patients undergoing radiation therapy.
CEOCFOinterviews: How long until this might become commercially available?
Dr. Crapo: About 2-4 years. You have to do safety trials first, and these trials start with a single-dose escalation trial. This will lead to a multi-dose safety trial to prove the drug does not produce adverse complications in human subjects. Those two trials should take less than one year. We would then start clinical trials looking at drug efficacy. I expect the efficacy trials will take 1 to 2 years to accomplish.
CEOCFOinterviews: Will you be looking for partners?
Dr. Crapo: We are funding the initial trials through Aeolus. When these are completed we will look for a large pharmaceutical firm to partner with us and help complete the process required to move the drug into the market.
CEOCFOinterviews: It sounds like a good time for investors to be interested in the company; will you please tell them why?
Dr. Crapo: We are right on the verge. We have convincing preclinical work done, showing that these antioxidant mimetics work in multiple animal models. This is a new platform technology; there are no drugs of this nature in human therapeutics today. AEOL 10150 has now been carried through the required preclinical studies and has passed safety testing in animals, leading to FDA approval for our first human trials. The major preclinical hurdles have been solved and we are ready for safety and efficacy testing in humans.
CEOCFOinterviews: In closing, you have an extensive science and business background. How does that help in getting people to sit up and pay attention?
Dr. Crapo: I have
been involved in development of these compounds for thirty years. My first experiment was
to use an antioxidant enzyme to treat an animal model of oxidative stress in the early
1970s. I was involved in synthesizing some of the earliest forms of these drugs and
have been involved in the critical steps that have brought us to the first human clinical
trial. I have also done patient care and have been intimately involved in healthcare
administration. I find that my experience with all phases of the development and
application of these antioxidant mimetics is a great help in convincing people of the
potential for this new class of drugs. I am personally convinced by the preclinical work
done in my laboratory and in the laboratories of my colleagues that these compounds will
work. I am excited to now also have the opportunity to guide these compounds through human
We are right on the verge. We have convincing preclinical work done, showing that these antioxidant mimetics work in multiple animal models. This is a new platform technology; there are no drugs of this nature in human therapeutics today. AEOL 10150 has now been carried through the required preclinical studies and has passed safety testing in animals, leading to FDA approval for our first human trials. The major preclinical hurdles have been solved and we are ready for safety and efficacy testing in humans. - James Crapo, M.D.
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