If all goes as planned for biotechnology start-up Atox Bio Ltd., it will obtain US Food and Drug Administration (FDA) approval for its products after Phase I clinical trials. In the drug development field, this is tantamount to a revolution - Phase I clinical trials are normally only the start of a long, hard slog towards obtaining sought-after FDA marketing approval.
The reason is that Atox Bio’s first product (a superatigen antagonist) is designed to defend against terrorist attacks using biological weapons, and the FDA has an abbreviated procedure for biodefense products. This abbreviated process does not require Phase II and III clinical trials with patients to test the effectiveness of the treatment. Unsurprisingly, the FDA does not encourage companies to infect people for the purpose of the clinical trial, so there is no ethical way to conduct Phase II and III clinical trials. Biodefense products therefore undergo Phase I clinical trials while two simultaneous models on animals with similar physiologies to humans are conducted. When the process is completed, the FDA will approve the product for marketing under a biodefense label. Potential customers are the US and other national governments who buy the product for emergencies.
Atox Bio hopes to obtain FDA approval for its product in 2010, and to have $100 million in sales a year to the US government. This amount is not the company’s target, but its break-even point and a springboard towards its two real dreams that are based on its biodefense technology. One is the great dream is treating two lethal diseases: toxic shock and septic shock. The other is the immense dream: a new treatment for autoimmune disorders, such as sclerosis, arthritis, and muscle degeneration.
Atox Bio began with research into superantigens (sAg). Antigen is the generic name for substances in the body that the immune system fights. Superantigens are substances that cause an extreme and even lethal overreaction by the immune system, up to 50,000 times the regular reaction by the immunes system to an antigen. This overreaction can lead to severe physical problems and even death, says Atox Bio CEO Uri Danon.
Antigens can cause toxic shock, such as in the case of the so-called ''flesh-eating'' staphylococci bacteria. Some women may recall the phrase “toxic shock syndrome” that appeared in tampon brochures from the time when tampon use was a major cause of toxic shock, which caused diarrhea, high fever, and, in extreme cases, death.
Another, more common, superantigen-induced disease is septic shock, which has similar symptoms to toxic shock. Septic shock is usually caused by infectious bacteria or is the result of a weakened immune system, such as in cases of cancer or diabetes. Patients hospitalized after chemotherapy or dialysis can also suffer from septic shock.
The source of this problem, as mentioned above, is superantigens discharge by Staphylococcus aureus (Staph) and Streptococcus pyogenes bacteria (Strep). Superantigens cause the immune system to react in differently from the way it reacts to regular disease-inducing antigens. When an antigen (bacteria or virus) enters the body, it is absorbed by an antigen presenting cell (APC), which breaks the antigen down. An APC attaches to a T-cell, and provides it with information about the antigen. When the T-cell subsequently encounter the same antigen, it excretes substances, called cytokines, which cause inflammation reactions that kill the antigen.
In the case of a superantigen, instead of being absorbed by an APC, which then attaches to a T-cell, attaches itself to an APC and therefore to a T-cell, which results in the T-cell causing an immune and inflammation reaction 50,000 times more powerful than the T-cell’s reaction to an ordinary antigen. This reaction, called a cytokine storm, causes the terrible symptoms of toxic shock and septic shock.
“During the 1990s, many companies tried to find drugs to treat this problem,” says Danon, “but only one had any degree of success, and it can only successfully treat 6% of patients. All these drugs tried to stop the T-cell from producing one type of cytokine (usually the tumor necrosis factor (TNF) cytokine), but without success, because of the strength of the reaction. We’re operating at an earlier stage, to prevent superantigens from acting on the T-cell, thereby preventing a cytokine storm from occurring. This can be compared to trying to stop a waterfall at its base, which is a difficult task because of the immense energy of the water, rather than blocking the source of the water, where the flow is slow.
“In the past, researchers reported that superantigens attached an APC to a T-cell via two receptors. Prof. Raymond Kaempfer and Dr. Gila Arad of the Hebrew University of Jerusalem discovered another receptor, critical to the activity of superantigens, which was not previously known to be essential. Kaempfer and Arad developed peptides (short protein chains) that block only this receptor, disrupting its attachment to a superantigen, and thereby preventing the activity of the T-cell, and a subsequent cytokline storm.”
Danon says that this third receptor was uniform for all superantigen attachments to T-cells. Herein lies the technological advantage: a single molecule can stop the activity of 40 different superantigens known to science.
A company in three stages
Based on this understanding, Atox Bio found three products that it is developing on the basis of this technology platform. The first is a biodefense drug against terrorist attacks with superantigens. Before 1969, the US was developing such toxins as biological weapons, but was unable to develop an antidote or vaccine. Assuming that other countries were developing similar weapons, the US is now trying to defend itself in case of trouble.
The US Department of Defense Defense Advanced Research Projects Agency (DARPA) and US Army Medical Research and Materiel Command (USAMRMC) have provided over $6.5 million for Kaempfer and Arad basic research. Yissum Research Development Company of the Hebrew University set up Atox Bio, with Kaempfer and Arad as founders and scientists. Danon was previously project manager that developed the Copaxone chemical solution for Teva Pharmaceutical Industries Ltd. (Nasdaq:TEVA; TASE:TEVA). He is now applying his know-how to create partnerships and an outsourcing network for Atox Bio.
Atox Bio recently obtained a $5.6 million grant from the US National Institutes of Health’s National Institute of Allergy and Infectious Disease (NIAID). Although the grant is for Kaempfer’s laboratory, it will mainly be used to develop Atox Bio’s product, in cooperation with the Hebrew University.
Atox Bio is developing two follow-on products simultaneously. One is to treat toxic shock and septic shock, as mentioned above, by blocking the third receptor. The market potential for this product is estimated at hundreds of millions of dollar a year.
The second product is intended to treat autoimmune diseases, such as multiple sclerosis and arthritis, caused by T-cell overreaction. Autoimmune diseases constitute the largest potential market for Atox Bio - up to $1 billion a year.
The advantage of Atox Bio’s superantigen antangonist peptide is that it delays activity by Th1-type T-cells, which are factors in these two diseases, but does not affect other immune cells, called Th2-type T-cells, which are not factors in either toxic shock and septic shock or in autoimmune diseases. This enables treatment of these diseases, without completely foregoing the proper immune reaction.
Atox Bio intends to develop products for treating toxic shock and septic shock after completing Phase I clinical trials, and signing contracts with the US Army and other militaries. At the same time, it will offer to license its products to large pharmaceutical companies. Atox Bio will use the proceeds to develop products for the most promising field - treating autoimmune diseases.
Atox Bio does not need additional financing to reach this springboard, except for $5.5 million that it plans to raise from venture capital funds within nine months to finance the completion of two Phase I clinical trials within three years, plus one more subsequent financing round.
Published by Globes [online], Israel business news - www.globes.co.il - on November 9, 2005