At medical school, students learn the connection between drugs and diseases; a headache will be treated with paracetamol, antibiotics are prescribed to fight bacteria and an inflamed appendix is removed surgically. But you may have noticed that something is missing from this equation - the patient.
From the patient’s view, it all looks completely different. Many people already say that “paracetamol doesn’t have any effect on me,” or “I find this particular antibiotic better than that one.” Even without knowing what exactly causes this, we know that we are special.
Over recent decades medical science has gradually come round to the idea of tailor-made medicine, while medical rules of thumb (of the type that rules headache = paracetamol) have become more flexible. There were several reasons for this, among them the deciphering of the genome, that will in future enable the precise mapping of the differences between people; the development of computers that can now store a mass of information about an individual or community; the development of the Internet and the provision of access to medical information to patients, who often know more about their conditions than their doctors; surveys that have shown that every year two million people suffer irreversible damage due to the use of unsuitable drugs; and the introduction in the West of Chinese medicine, whose basic approach is to treat the whole patient, rather than just the disease.
Whatever the reasons, tailor-made medicine is almost upon us. The most far-reaching vision is that in the not too distant future, Mrs. Cohen of Hadera (or to be more specific, Mrs. Rosa Cohen of 53 Herzl St, appt 4, Hadera) will be able to visit her doctor and ask him or her to design a precise customized drug for the genetic damage to her unique body, or a treatment for the one-time mutation of the virus with which she has been infected. Drug dosage, frequency of use, timing of use and complementary nutritional habits will also be tailored according to personal characteristics.
We’re still some way from this scenario, but we can already see the seeds of the impending revolution and can try to assess its impact on life sciences. A considerable number of Israeli companies are joining the party.
A virtual patient
Israeli start-up Optimata Ltd. has an extremely ambitious approach to tailor-made medicine. The company’s founder, chairman, and CSO Pro. Zvia Agur would like to build a computerized model of every one of us, and use it to test drugs, methods of administration, dosages and frequencies, thereby enabling the choice of the optimal course of treatment.
Recent years have seen the development of a calculation capacity that enables the simultaneous assessment of the interaction between tens and hundreds of factors, something which happens inside the body. But do we, as humans, know enough about our bodies to build an exact model of them? At Optimata they believe this is indeed possible and declare that a preliminary model of a “virtual patient” suited for cancer, will be introduced at oncology clinics in two years time.
Globes: Zvia Agur, how was the Virtual Patient developed and how does it work?
Agur: “I began to develop the model as a researcher in biomathematics at the Weizmann Institute of Science back in 1980. Biomathematics tries to build models of biological processes that take place inside the body. One process I was participated in the modeling of was the production of blood. We took all the existing research information on the subject, and tried to define the process of blood production using certain key words. After the process is explained verbally, we represent the verbal links in mathematical equations, and once this has been done, it’s easy to translate them into computer language.”
Do we know enough about the human body to be able to model it? After all, everything inside the body is interconnected, and perhaps we may miss the most important factor?
“We have to create a model that takes into account all the important variables, and disregards the less important ones, to reach a result that enables a prediction that has practical significance. What counts are results.
“Today, doctors are already using their knowledge about the links between processes inside the body to decide which medicine to prescribe, but their decisions are based on only a few variables, so their predictions may be successful statistically, that is to say they are correct for ‘most people’ but we are interested in reaching prediction that is more than just statistical.
“The human brain cannot simultaneously calculate the entire range of effects that a drug has on the human body. For this we need the calculating strength of a mathematical processor. We believe that we have now managed, after investing 100 man hours in the project, to model some of the processes in a manner that will enable correct predictions.”
This model is based on the average patient. How does it tailor specific drugs for patients?
“The equation itself describes the links between processes, links which are universal. Each patient’s unique characteristics feature in the equation’s coefficients. Hypertension, for example, can lead to arteriosclerosis in anyone. This is the equation. But it will have an effect in to a degree of x in one person, and 2x in another - this is the coefficient. Naturally, real equations are much more complex. One can adjust coefficients according to the condition of a specific patient, by taking into account age, gender, and genetic characteristics, and also by conducting preliminary tests.
“The figures that are input into the equation are the treatment protocol frequency, dosage, type of drug. The result of the equation is the patient’s state of health at the end of the treatment. One can use various treatment protocols in an equation and see which of them produces better results, even though our limited brain can’t understand exactly why”
And how we will know if we really have received the right result?
“You have to try out the model at the beginning, and see whether it produces correct predictions. The first model that we built was one for the tailoring of treatment for solid cancer. We conducted a trial on a patient who had been given a certain form of chemotherapy. We asked the computer, ‘what state will this person’s white blood cells be in after 45 days of treatment.’ The results we received were very similar to the actual ones. Through this system, we will be able to tell doctors what is the highest dosage of the drug that can be given before the number of white blood cells drops to a critical level, whether complementary treatment should be given, and so on. The prediction applies to a specific patient with a specific type and size of growth.”
What stage have you reached?
“Our product for the treatment of solid cancer is now at the clinical trials stage. We believe that we will see it in clinics in a few years.”
Already saving excessive chemotherapy
One of the companies that has decided to make the vision a reality is Oncotest-Teva, which was founded by Dr. Lior Soussan-Gutman and which was acquired by Teva Pharmaceutical Industries Ltd. (Nasdaq: TEVA; TASE: TEVA) in 2002. Oncotest offers the Israeli public biological and genetic methods for tailoring treatment to the unique characteristics of patients’ cancers.
Many cancerous growths can withstand some types of chemotherapy but are sensitive to others. How is the right treatment found for a certain patient today? No problem: trial and error. The result, of course, is a lot of unnecessary pain and suffering for patients, as well as the wasting of time on excessive treatment. The use of this method does not stem from any evil intent or sloppiness on the part of the attending medical staff. Until recently there was simply no other alternative.
Scientists across the globe have begun to develop tests designed to determine how many receptors to a certain chemotherapy drug exist in the patient’s growth. Oncotest markets these tests, most of which are actually conducted in the US, in Israel. A biopsy is taken from the growth and sent to the laboratory, which then returns it with a recommendation to use, or not use, a specific drug.
One of the more familiar types of test for tailoring cancer drugs for patients is the “Fluorescence In Situ Hybridization” (FISH) test which assesses the sensitivity of a breast cancer tumor to the drug Herceptin. In 25% of female patients with breast cancer, the growth is characterized by an increased expression of the HER 2 receptor, which makes it especially sensitive to this drug. Herceptin was, in fact, developed specifically to reach the HER 2 receptor, making it the first drug to be developed with the aim of personally tailoring it for specific patients. This is a small step for mankind, but a great leap for breast cancer patients.
Cancer and chemotherapy will apparently be the leading field for the pioneering work on tailor-made drugs, since the process of “trying and seeing what happens” exacts such a high price. Oncostest currently markets dozens of tests which assess the likely efficacy of chemotherapy or genetic treatment and predict the chances of success and the likely side effects. The breakthrough in this field will come once it becomes possible to ascertain the optimal chemotherapy treatment (if at all) with one single test.
Not a big hit with the drug companies
The tailoring of drugs is likely to have a significant impact financially - no more blockbuster drugs. Today, drug companies invest tens of millions of dollars in the development of each drug, and the price just keeps rising (especially following the tightening by the US Food and Drug Administration of its clinical trial regulations). Consequently, drug companies are gradually losing interest in the development of drugs that are likely to have sales of less than $1 billion a year. Many diseases don’t appear on the drug companies’ radar because there aren’t enough patients who suffer from them. The situation became so grave, that the US enacted the Orphan Drugs Law, which provides extended exclusivity on drugs targeted at small groups with rare conditions.
Drug tailoring will, in effect, make all diseases rare and all drugs orphans. Once we know how to tailor specialized drugs for patients, sales of most blockbuster drugs will fall substantially. Although the total volume of drug consumption is not likely to fall, companies will have to work much harder and develop a larger and more diverse range of drugs to reach the same profit margins.
If the big drug companies don’t have an interest in developing tailored drugs, who will do it instead? One alternative is development by medium-sized or new companies such as Genzyme Corp. (Nasdaq: GENZ), which specializes in the development of orphan drugs. “The world is moving towards the integration of diagnosis and treatment,” says Genzyme Israel business development manager Oved Amitay. “In our company we have a research department which also tries to find unique rather than commonly found expressions of diseases, and to develop drugs on the basis of this research. Actually, the first step toward tailored drugs is to divide each disease into lots of subcategories. These subcategories need orphan drugs, and that’s our field of expertise.”
Amitay believes that the big drug companies will eventually adopt the trend. “When a drug company brings a blockbuster product onto the market, and someone who is not suited to the drug gets hurt by it, the drug company gets hurt too. Tailored drugs for small groups will prevent unnecessary harm and will also create a new market - of patients who did not use a drug that suited ‘everyone’. The response rate among the Asian population, for example, to drugs developed in the West is low. Giving up the ‘one single drug for everyone’ approach will also throw this market open to the big drug companies.”
Published by Globes [online], Israel business news - www.globes.co.il - on October 19, 2006
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