The victory of personalized medicine is inevitable

The pill recognized you
Personalized medicine is becoming one of the leading trends
in healthcare and the global pharmaceutical industryGalina Kostina, "Expert" No. 5-2013

"An employee worked in my company who suddenly had a strange speech disorder: he started talking, then fell silent, unable to finish a sentence. He started talking again only after a few minutes," says Thomas Grogan, one of the founders of the diagnostic company Ventana, part of the Roche group. – A colleague turned to a doctor, a standard examination revealed nothing, he sent him for a computer diagnosis, as a result of which a brain tumor was detected. Surgeons removed it, but a biopsy showed that this kind of tumor is incurable and will develop again. We found out that his tumor growth is caused by a certain mutation. The result is disappointing: patients with such a diagnosis literally get a black mark.

Whether it was any other patient, and not an employee of the famous company that develops diagnostic systems for oncology, he probably would only have to say goodbye to his family, settle his affairs and wait for the inevitable end. But Grogan knew that Duke University had developed an immunotherapy program to treat patients with just such a mutation variant. Together with the patient, Grogan went to the university, where he underwent an examination, after which he was included in a clinical study. More than three years have passed since then. Before that, a man's life was counted in days. "This is an important lesson," says Grogan, "modern and accessible information about new technologies has played a huge role in human life. And we have to do this not only for our friends, but for every patient."

Thomas Grogan told this story at a conference on personalized medicine. Yes, they commented from the audience, this is a truly personal approach – to apply all the latest knowledge and achievements, take a person under your arm, fly with him to another state and agree to participate in the testing of a new technology; this is cool even for the average American or Swiss patient. Grogan himself admitted that so far this is the exception rather than the rule. However, in recent years, personalized medicine has become one of the most important areas of development of healthcare and pharmaceutical industry.

Treat a person, not a diseaseIn the XXI century, people finally decided to put in the spotlight.

History says that at the dawn of medicine it was so. Hippocrates also remarked: it is more important to know which person is sick than what he is sick with. Not being a therapist, the great Alexander the Great used a personalized approach to testing his recruits: he scared them and watched them blush or turn pale. I chose the crimson ones: their nervous system is stronger.

In the XX century, the place of man was increasingly occupied by pharmaceutical companies, pharmacy chains, clinics, insurers, ministries. The focus has turned to diseases, especially those that cover large populations. For them, it was possible to produce so–called blockbusters - drugs with sales of more than $ 1 billion. Lipitor, a cholesterol–lowering drug, has become the most popular. Its sales in 2008 reached $ 13 billion.

However, clinicians have accumulated more and more information that universal drugs may not work on a third, or even half of patients – for example, the same lipitor. According to WHO, at the beginning of the XXI century, standard pharmacotherapy did not give effective results in the treatment of depression (20-40% of patients), ulcers (20-70%), bronchial asthma (40-75%), diabetes mellitus (5-75%), oncology (70-100%), migraine (30-60%), hypertension (10-75%), schizophrenia (25-75%). And this despite the fact that such ineffective treatment has constantly become more expensive.

Since scientists have penetrated deeper into the molecular level, it has become clear what actually happens in a diseased cell, what mechanisms work in it and what can be a target, as well as a biomarker of the disease. Depending on these features, the diseases began to be divided into sub-diseases: in particular, breast cancer can have at least six variants. Therefore, it needs to be treated in different ways. The goal of modern personalized medicine is an integrated approach that includes all kinds of testing for predisposition to diseases, recommendations for prevention, selection of personalized drugs and treatment regimens based on individual characteristics of the patient, monitoring of treatment.

In the eyes of pharmacists, the personalized approach received a powerful incentive already in the XXI century, after genome sequencing. Actually, they knew about the genes and mutations in them before. "For example, since 1954 it has been known that a mutation in one gene responsible for the enzyme that digests the drug leads to the patient taking the medicine in a normal dose, and the biochemical effect is as if he ate the whole package," says Vitaly Prutsky, head of the Center for Bioinformatics and Prognostic medicine of AstraZeneca- Now more than a hundred thousand people a year die from drug overdoses in the United States. Knowledge about molecular mechanisms and mutations in different genes accumulated, but in practice nothing happened – there were no technologies for effective clinical testing and understanding what in a practical sense this could lead to."

One of the most famous analysts of the world pharma, Stephen Burell, devoted his speech at the Open Innovation forum to preventive and personalized medicine. "The era of personalized medicine began only ten years ago, but the region itself is growing like a snowball. In the last few years, companies focused on personalized medicine – developers of both tests and medicines - have been growing at a faster pace. We get the opportunity to use huge amounts of genome data, we begin to understand how one patient differs from another, and this allows us to prescribe treatment individually and takes medicine to a higher level."

Chasing molecular targetsRoche was one of the first companies in bigfarm to engage in personalized therapy.

In 2006, she made personalized medicine the center of her strategy. To do this, she had a solid base: the group has the strongest division engaged in the development of diagnostic technologies (they have 20% of the global diagnostic market), and there are drug development units that also cooperate with a large pool of large and small companies, various laboratories. And diagnosticians have been cooperating with the developers of new drugs since the first stages of creating a promising drug.

The company considers the herceptin drug for the treatment of a certain type of breast cancer and a test to identify patients with an excessive amount of the HER2 receptor on the cell surface to be the gold standard of a personalized approach. Herceptin entered the world market back in 1998. The stimulus for the creation of the drug was the discovery of a gene encoding the HER2 receptor. It turned out that a breakdown in this gene repeatedly increases the number of receptors and allows them, like a jammed plate, to continuously send a signal to the cell to divide. And it causes one of the most aggressive forms of breast cancer. Such mutations were detected in about 25% of cases. And it was for these patients that herceptin, an antibody designed to block this signal, was created. The first clinical studies showed that the use of herceptin for a group of patients with HER2-positive breast cancer has a significant effect, increasing survival without signs of the disease and without side effects characteristic of traditional therapy. Later it turned out that a certain stomach cancer, where the development of the tumor is mainly controlled by the same receptor, also responds well to herceptin treatment.

At the end of 2011, a new Roche drug, zelboraf, entered the market. This is the world's first remedy for the treatment of a type of malignant melanoma – the deadliest form of skin cancer, which is called black melanoma. "Our research has allowed us to obtain fundamental information about the disease at the molecular level. We found out that inside the cell there is such a protein B-raf, which, due to a mutation of the gene, causes it to send signals to the nucleus for division and growth all the time. This constant internal signaling leads to the development of a very aggressive tumor," says Roche CEO Severin Schwann. – And we began to look for an inhibitor of this protein, while simultaneously developing a test for mutation of the B-raf protein. Already the first tests showed that as a result of the use of zelboraf in some patients, tumors literally evaporated." Before zelboraf, patients with such a diagnosis, which occurs in 50% of cases of malignant melanoma, had six months to a year to live. Zelboraf significantly increases this period.

How to catch up with a tricky tumorThe development and approval of the drug by the FDA (Food and Drug Administration, Food and Drug Administration) took only five years, while the average time to create a drug is 12-15 years.

"This is the result of our strategy – the joint work of the diagnostic and pharmaceutical divisions," says Daniel O'Day, CEO of the Roche Farma division. In particular, it significantly reduces the time of clinical trials. Diagnostic tests make it possible to identify for clinical studies those groups of patients who have a breakdown of the B-raf protein. Therapy with zelboraf acting specifically on this protein has shown high efficacy compared to standard therapy for several weeks already, and these obvious results allowed the relevant authorities to register the new drug fairly quickly.

But in oncology, it often happens that the tumor is looking for and finds a workaround. The researchers saw that after a while she began to slip away from zelboraf therapy. "And we went in pursuit of her," continues Severin Schwann. – We learned that the tumor begins to act not only through B-raf, but also through another protein – MEK. Naturally, our next step was to develop a connection blocking MEK. We believe that combination therapy will significantly increase the life expectancy of patients and preserve its quality."

Today, in Roche's portfolio of 40 candidates under development, about half are drugs for personalized medicine.

A promising nicheAccording to Peter Keeling, head of the department of the analytical company Diaceutics, the leading positions in the field of personalized medicine are occupied by Roche and Novartis.

The prospects for the development of personalized medicine for each of them are very wide. AstraZeneca, Johnson & Johnson, Abbot, Eli Lilly & Co., Bristol-Myers Squibb and others are also developing this direction. According to estimates by the Tufts University Medical Research Center, from 12 to 50% of current research by pharmaceutical companies falls on personalized medicine. According to PricewaterhouseCoopers, the volume of the market of medicines for personalized medicine in the United States from 2010 to 2015 should almost double and reach $ 425 billion. With a projected global market volume of $1.2 trillion by 2016, the share of personalized products will account for a third of all drugs.

This trend forces companies to work closely with laboratories developing diagnostic tests and systems. According to PwC, 16 partnership agreements were concluded in 2010 (for comparison: in 2008 – seven). Three of them came from GlaxoSmithKline, two each from Pfizer and Merck. The diagnostic division of Siemens (Siemens Healthcare Diagnostics) became partners of ViiV Healthcare and Tocagen pharmaceutical companies.

In 2011, Novartis, which has its own fairly powerful diagnostic division, bought Genoptix, specializing in personal diagnostics. Enters into Novartis and partnership agreements. In particular, in 2011, she joined forces with the world market leader in the field of personalized molecular medicine – Invivoscribe Technologies Inc. to develop and implement a joint diagnostic test. The test should identify patients with acute myeloid leukemia (AML) with FLT3 mutations. This mutation, which is associated with a very unfavorable prognosis, occurs in about 30% of adults with AML. Novartis is developing the drug midostaurin, which will help patients with this mutation.

In Russia, while, alas, it is not leading in the development of any innovative drugs, nevertheless there are companies that are actively developing a new direction. In particular, "NewVak", the "daughter" of the High–Tech Center "HimRar", has set personalized medicine as one of its goals – see "Double blow to cancer" ("Expert" No. 14 for 2012). In its portfolio is a pioneering method of combined therapy of renal cell cancer using a therapeutic personalized vaccine oncophagus (for its manufacture, cancer cells of a particular patient are taken) and so-called coadjuvants, molecules that will reduce the protection of the tumor from attacks by the immune system. Preclinical trials of the method are already coming to an end. There are plans to test this therapy in other areas – in the treatment of melanoma and lung cancer. "In addition, the NewVak company and the N. N. Petrov Research Institute of Oncology are jointly developing another unique technology of immunotherapy with bone marrow precursors of dendritic cells using their own cancer cells of patients with metastatic cancer," says Nikolay Savchuk, Chairman of the Board of Directors of the company.

How much does a year of life costThe creation of personalized drugs faced a number of problems that hindered the faster development of this direction.

One of them was related to the traditional format of clinical trials. In the second and third phases, it is usually necessary to recruit many patients, sometimes up to several thousand, in order to conduct comparative studies and obtain reliable statistics. Now it is difficult to even estimate how many potentially effective drugs have flown off the trials due to the fact that the percentage of effectiveness was too low. Some studies show that 50 to 75% of drugs failed. But it was probably not the drugs that were to blame, but the selection of patients. At the same time, development companies lost a lot of money: it is known that clinical research is the most expensive part of creating a drug, they can devour up to $ 1 billion.

Regulatory authorities should also adapt to the new trend. The main such US body in the field of medicines, the FDA, has taken a number of steps in recent years to develop personalized medicine. The Agency is preparing regulatory documents that encourage the joint development of medicines and diagnostic tools, which reduces the time and cost of clinical trials. When testing new personalized oncological products, the FDA took into account the fact that preliminary diagnostic testing made it possible to show the maximum effectiveness of the drug in a very short time. Thus, Pfizer's drug xalkori for the treatment of metastatic non-small cell lung cancer was tested on 255 patients, and only four years have passed since the scientific discovery that allows the isolation of groups of patients with the ALK gene mutation before the approval of the drug by the FDA. For Roche's zelboraf, this period was five years.

The economics of personalized drugs raises many questions. Their development takes about the same amount of money as the development of a blockbuster, despite the fact that the company can save some time and money during clinical trials. However, since the drug is not intended for hundreds of millions of people, but sometimes for several thousand, its cost for one patient increases significantly. In addition, the cost of treatment increases due to the use of tests. Whether it is cost–effective, who will pay - these issues require discussion by government agencies, insurance companies, patient communities. There are already a number of studies concerning the economics of personalized medicine. In particular, Thomas Stsuks, head of the Helsana research laboratory and professor at the University of Zurich, argues that personalized medicine is a real value not only for patients, but also for society. Analysis of the real value of investments in personalized therapy using specific diagnostic tests for patients with breast cancer, colon cancer, hepatitis C shows that this direction can be cost-effective. For example, if a woman with breast cancer is diagnosed with HER2-positive cancer by the FISH method, then herceptin is prescribed to her. With standard therapy, without such testing, the patient could have died within a couple of years. A cynic would say: there is no person – there are no costs. The cost of testing and therapy with herceptin may amount to approximately 25 thousand euros. At the same time, Stsuks claims that a woman's life saved with a targeted drug treatment every year (and there may be 10 or 20 of them) brings 12 thousand euros to the state: after all, she works, pays taxes, buys goods and services. This is the benefit of the state. Not to mention the personal benefit of a woman – she continues to live a full life.

Daniel O'Day says that the development of personalized medicine will require a change in the healthcare system: "We have the right to raise the question of a more correct allocation of funds in the healthcare system. Diagnostic costs can account for 2 percent of total healthcare costs, pharmaceuticals account for 10 percent, and the remaining almost 90 percent are all other healthcare costs. The better we identify the groups of patients for whom a particular treatment is effective, the better we will allocate healthcare budgets."

Another important problem: personalized medicine requires high-quality diagnostics. Roche and Ventana, which is part of this group, create unique systems. For example, it is enough to insert a glass with a sample into the Ventana Ultra system – and you can see genes and proteins that are biomarkers of a particular disease with certain mutations. These systems are certified. Clinics often use their own equipment and reagents, which do not have to be certified, however, according to various researchers, they can often give erroneous results. And these are erroneous diagnoses. And someone's life. Ventana specialists, for example, believe that clinics do not necessarily have to buy expensive diagnostic systems. The solution can be found in a centralized approach to diagnostics, in the creation of specialized centers where trained professionals will work. By the way, the training center will open in Moscow this year.

Portal "Eternal youth" http://vechnayamolodost.ru04.02.2013