The Pitfalls of Personalized Medicine

Personalized medicine – the possibility of selecting therapies depending on the individual genetic characteristics of the patient – has been the "holy grail" of the biomedical industry for a long time. Work in this direction has led to a number of successful innovations, including the introduction into clinical practice of several drugs intended for the treatment of patients with certain genetic profiles, and the official approval in Europe of the world's first method of gene therapy. An innovative method of treating leukemia, first tested at the Philadelphia Children's Clinic, based on the use of modified immune cells of the patient himself to fight tumor cells, is also widely discussed. While these achievements undoubtedly inspire patients, they simultaneously raise a number of ethical, legal and financial problems that specialists working in this industry will have to solve before personalized medicine begins its rapid development.

According to Professor Ezekiel J. Emanuel, a specialist in medical ethics and health policy at the University of Pennsylvania, these problems are so serious that claims of a "renaissance" in medicine due to the emergence of personalized approaches often look exaggerated. He cautions that before believing this, it is necessary to pay attention to the fact that almost every attempt to find out the reasons for the increase in medical care costs points to new technologies. "We should be skeptics. Before people believe in the idea that personalized medicine will reduce costs and benefit the system, we need to see real data."

Despite skepticism, recent advances have given supporters of personalized medicine a reason to rejoice. On December 7, the Children's Clinic of Philadelphia announced that the staff of its oncology department had brought a girl with acute lymphoblastic leukemia into complete remission by injecting her own T-lymphocytes, genetically reprogrammed to destroy malignant cells. This therapeutic approach, called CART-19, was developed by them together with researchers at the University of Pennsylvania and licensed last August by Novartis, which is currently adapting it for wider use in clinical practice.

On November 2, the Dutch company UniQure B.V. received approval for the use in Europe of the gene therapy drug Glybera, intended for the treatment of a rare hereditary disease known as lipoprotein lipase deficiency. This disease is caused by a defect in a gene encoding an enzyme necessary for the breakdown of fats coming from food, which leads to a life-threatening accumulation of fats in the body. The active component of a single-use gliber is a carrier virus that provides delivery to the patient's cells of a full-fledged gene necessary for the production of this vital enzyme.

Another indicator of progress in the field of personalized medicine is the fact that the US Food and Drug Administration has approved 23 drugs, mainly intended for the treatment of cancer, offered on the market complete with tests to identify biomarkers or genetic variants to identify patients who are most likely to respond to treatment.

However, according to Emanuel, everything is not as simple as it looks at first glance. The use of genetics is just one of the methods of dividing patients into groups. It does not provide "personalization" in the literal sense of the word, since there is still a group of patients who will receive standard treatment that can help only a part of them. He also adds that the financial barriers to personalized medicine can be insurmountable.

This contradicts the opinion of many experts who believe that dividing patients into subgroups based on their expected response to therapy is more economically effective than randomly selecting treatment methods until a solution to the problem is found.

Moreover, Emanuel notes that the financial issue is complicated by the motivation of profit-oriented enterprises. The fact is that personalized drugs are designed to treat a limited number of patients, whereas companies want not only to compensate for the costs of drug development, but also to make a profit. The idea of the cheapness of personalized medicine is just a myth. In fact, the use of such approaches requires huge costs.

Even companies that have introduced personalized therapy drugs to the market for the first time are having a hard time getting a stable income from them. The chief executive Officer of UniQure, Jorn Aldag, admits that it is very difficult to even assume that a single-use gene therapy drug for lipoprotein lipase deficiency, from which only about 3,000 people suffer worldwide, can provide the company with stable profits. For this reason, the company is currently consulting with specialists about possible solutions to the problem, including approving a plan for annual payments for therapy instead of a one-time payment of the entire amount. This is very difficult, since patients will have to pay for therapy that supposedly has a long-term effect, while there are no guarantees of its effectiveness.

Who owns the genetic information?According to Jay Mohr, CEO of the advisory company Locust Walk Partners, there are prerequisites indicating that stakeholders in the field of personalized medicine are already approaching the creation of viable business models.

Mohr was one of the pioneers in this industry. Ten years ago, he served as Chief executive Officer of Variagenics, a company that developed a method for sequencing tumor DNA and using the data obtained to predict the response of patients to certain therapeutic approaches. As a result of several subsequent mergers, Variagenics became part of ARCA Biopharma, which refused to develop methods for sequencing the DNA of malignant tumors.

One of the difficulties that Variagenics had to face is the development of an optimal compensation scheme for all parties involved in the selection of optimal treatment methods for specific patients. This problem still remains relevant for personalized medicine. At the dawn of Variagenics, Mor entered into an agreement with Novartis for the possibility of studying the feasibility of using its glivec drug, effective for the treatment of prostate cancer in the presence of certain genetic markers on tumor cells. He notes that one of the most difficult tasks in concluding this transaction was to determine the scheme for paying Variagenics part of the profit brought by sales of glivec for the treatment of prostate cancer.

However, not everyone agrees that a company conducting research on the study of genetic variations that allow predicting a patient's reaction to a certain drug should receive financial compensation for this. They argue that investments in the search for biomarkers that allow determining the likelihood of a response to treatment should be considered as a political aspect, and not as an entrepreneurial activity. One of the adherents of such views is Jason Karlawish, professor of medical sciences and senior researcher at the Center for Bioethics and the Leonard Davis Institute of Health Economics, part of the University of Pennsylvania. Professor Karlavish was one of the main actors in the debate caused by a lawsuit filed in 2012 against the Mayo Clinic by Prometheus Laboratories, which patented a method for determining the correct dosage of a drug for the treatment of disorders of the digestive tract by changing the levels of metabolites in the patient's blood. When Mayo Clinic specialists developed a similar method, Prometheus filed a patent infringement lawsuit. According to Karlavish, Prometheus has actually patented a way of thinking that is not an invention. From a fundamental point of view, patenting should pursue completely different goals.

The case was referred to the Supreme Court, whose opinion coincided with that of Karlavish. At a hearing in March, the judge said that allowing companies to patent tests based on natural phenomena for the body is practically the same as allowing Newton to patent the law of gravity. This decision provoked indignation from a group of lobbyists from the Association of the Biotechnology Industry and other stakeholders who were concerned that the restriction of patentability would moderate the ardor of companies engaged in innovative research in the field of personalized medicine.

On the other hand, Karlavish expresses concerns that excessive expansion of the boundaries of patentability in the medical field will lead to the opposite effect. If Prometheus had won the case, the development of Mayo Clinic specialists would never have found a place in clinical practice. Obviously, the opportunity to patent such developments can be useful for business, but from the point of view of science and public health, the situation is not so clear.

A double-edged swordDespite the concern that the patentability-limiting litigation would negatively affect innovation, the desire to develop treatments based on the genetic profiles of patients has caused a rapid development of entrepreneurial activity.

For example, the Swiss company MolecularHealth, which receives financial support from the software giant SAP, is working on a technology platform that will allow oncologists to select treatment methods for patients based on their genetic variants. In September 2012, a new company MyoKardia was founded in San Francisco, whose activities are aimed at developing drugs for the treatment of patients with cardiomyopathy caused by certain genetic mutations.

The head of the Department of Medical Genetics at the Perelman School, Professor Reed Pyeritz, believes that personalized medicine can be especially useful in the treatment of heart diseases, many of which have well-studied genetic causes. He notes that economic studies have demonstrated the potential value of genetic screening in this area. For example, about a third of patients with aortic valve defect are carriers of a certain genetic mutation. Knowing this makes it possible to improve the quality of treatment of patients by timely surgical intervention or prescribing appropriate medication. Screening the relatives of such patients also makes sense, since the absence of a mutation excludes reasons for concern, whereas its detection indicates the need for periodic examinations. The exemption of relatives who do not have a mutation from regular examinations (expensive imaging procedures, etc.) can justify the cost of genetic screening.

Payritz is one of the authors of an article published in June 2012 in the journal Genetics in Medicine. He believes that the results presented in the article prove the feasibility of genetic testing. As part of the work, the researchers selected 100 patients with a genetically determined vascular disease known as hereditary hemorrhagic telangiectasia, and compared the costs of routine screening of at-risk relatives conducted to identify signs and symptoms of the disease with the cost of their genetic testing. It turned out that for a family of 4 people, genetic testing saved more than $22,000. The total savings for the entire group of patients exceeded $9 million.

However, Pieritz notes that genetic testing is a "double-edged sword." Recent advances in genomics make it possible to consider a patient's genetic profile in a closer approximation, which may have unintended consequences. He gives an example of testing using microchips, a new technology that allows for in–depth analysis of chromosomes, including detecting the absence of small fragments of genetic material or their doubling. This tool is very useful for identifying previously unknown syndromes. However, with the help of such methods of analysis, researchers discover a huge number of genetic variations, the significance of which for the body is completely unclear.

There is also the problem of accidental identification when searching for the causes of a patient's existing disease of the risk of developing another disease, which he might not know about until the end of his life. For example, a child with developmental delay has a gene deletion associated with the development of Parkinson's disease in middle age. Further examination leads to the detection of the same deletion in the 30-year-old mother of the child. However, the genetic analysis was carried out for another reason, which puts the specialist in a difficult position, since he must decide whether to inform patients of the information received or not.

According to Jimmy Lin, research director of the Department of Genomic and Pathological Services at the University of Washington School of Medicine, determining the optimal approach to such random findings has become a top priority for specialists working in the field of personalized medicine. Lin is one of the founders of the non-profit Institute of Genomics of Rare Diseases (Rare Genomics Institute), which provides genome analysis and sequencing services to families whose representatives have rare or poorly studied genetic diseases. Lin notes that when analyzing family cases, one should be extremely careful, since possible findings may be important for all family members.

All parents applying to this institute go through a long and carefully planned process of obtaining informed consent. Among other things, they must answer such questions:

• If we find something that indicates a predisposition to malignant diseases, should we inform you about it?
• If we find a gene for a disease that manifests in old age, do you want to know about it?
• If a disease is detected that manifests itself in old age, and there are measures that you can resort to now, do you want to know about it?

Ultimately, the decision is made by the customers.

As a result of all that has been said , we can cite the words of Karlavish: "before personalized medicine becomes a reality, we still have a lot of questions to answer. As a society, we have to start thinking about ethical, legal and social issues. Frankly speaking, the driving force of this machine is money and there are many commercial and private parties interested in receiving this money. In general, personalized medicine is a new model, the introduction of which poses new challenges for us."

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Wharton School of the University of Pennsylvania:
The Promise and Perils of Personalized Medicine.

10.01.2013