Commentary For reprint orders, please contact: [email protected]
Personalized medicine: its implications and its impact on patents “...right now nobody can tell whether personalized medicine will lower or increase the cost of the public health system... But the huge advantage of personalized medicine for the patients is beyond any doubt.” Keywords: better efficacy • companion diagnostic • law of nature • patents • personalized medicine • second and further medical use • side effects • targeted drug development
Despite all advances in modern medicine the need for better methods of treatment and more efficient drugs is undeniable. Personalized medicine promises relief, and therefore the emergence of personalized medicine is accompanied with great hopes and expectations. An overview of this new development is given herein and some examples are considered more closely together with a discussion of the possibilities of patenting in the field of personalized medicine. In a certain way medicine has always been personalized medicine because any responsible physician took (or takes) into account the patient as an individual. But even nowadays the main approach in therapy consists of ‘trial and error’ coupled as far as possible with intuition and experience – simply because of the absence of alternatives. There was a huge, an almost complete lack of information about the diseases and their causes on a molecular and cellular basis on one hand and about the patient’s individual physiology on the other – all this together is the basis of a medicine grounded on scientific facts, the modern type of personalized medicine. Although such ideas were vivid for a long time it was mainly with the event of the sequencing of the human genome that those ideas started to be transformed into reality. But after all trastuzumab (Herceptin®) was found a little bit earlier and trastuzumab was the first example of a drug for a molecularly targeted cancer therapy which was officially approved already in 1998 (vide infra). Hence ‘personalized medicine’ as described in this article is a new concept in the pharma-
10.4155/ppa.15.32 © 2015 Future Science Ltd
ceutical and medical world which probably will become the medicine of the future. The modern concept of personalized medicine is based on the fast growing knowledge of natural sciences, particularly on the knowledge from molecular medicine. Personalized medicine is high-tech medicine where the most advanced knowledge of biochemistry, cell biology and physiology is used to develop and to recognize new drugs or new applications of known drugs. The use of modern biomarkers is indispensable for any kind of personalized medicine [1] . The American Medical Association defined personalized medicine in a more general way at its Annual Meeting in 2010 [2] as follows: “‘Personalized medicine’ refers to healthcare that is informed by a person’s unique clinical, genetic and environmental information”. General remarks Other denominations of personalized medicine are ‘individualized’, ‘targeted’ or ‘stratified’ medicine. The word ‘stratified’ indicates that a group of patients with a certain disease is divided – in other words, stratified – into several subgroups (cohorts) on the basis of observable and significant differences in the genome, the metabolome or the proteome of the patients. Up to now it seems that – with a given disease – quite often only one cohort of patients will react adequately to a drug while members of other cohorts do not respond well. The word ‘targeted’ emphasizes the design of modern drugs based on a profound knowledge of the site where a drug should act; this means that the biochemical target
Pharm. Pat. Anal. (2015) 4(6), 415–420
Dieter Schneider* Senior Consultant, Former Head of Patent Department, German Patent & Trademark Office, Galileiplatz 1, 81675 Munich, Germany *Author for correspondence: [email protected]
Wolfgang Bublak European Patent Attorney, Patentanwalt, Galileiplatz 1, 81675 Munich, Germany
part of
ISSN 2046-8954
415
Commentary Schneider & Bublak of a drug has to be well known. Very often the analysis of the genome forms the basis of personalized medicine. The study of variation of DNA and RNA characteristics as related to drug response is called pharmacogenomics [3] . Almost in every case a new drug is developed together with a diagnostic method to guide its application – we mostly find a tandem of drug and companion diagnostic. [4] It should be understood that in this article the somewhat purest form of a personalized medicine is not dealt with – the production of tissue from cells of a patient; for further details of the situation in Europe see Regulation (EC) No 1394/2007. Another pure form of personalized medicine, not being dealt with here, is the development of medical devices for individuals. And it should be clear already that personalized medicine is certainly not a kind of medicine where the physician spends a lot of time with the patients giving much personal care and attention to them. Personalized medicine in its practical application What means ‘personalized medicine’ in practice? Taking Germany as an example, 42 drugs are presently on the market [5] ; they stand in the forefront of personalized medicine. Two main issues are pertinent to personalized medicine – one is the better efficacy of drugs whereas the second issue is the safer application of drugs. Dosage recommendations are a further issue but of minor importance. Better efficacy of drugs 36 of the 42 drugs on the German market provide much better efficacy of a drug for a distinct subgroup of patients. The subgroup in question is identified by measuring and evaluating the relevant biomarkers. Patients suffering from the same disease but not being part of this subgroup will not respond markedly to the respective drug. Administration of the drug regardless of the subgroups as it was routinely done hitherto, often brought results which looked like treatment failures. For statistical reasons a small, positively reacting subgroup is hardly identifiable and the negative results with the main groups(s) prevail. Table 1 shows, in alphabetic order, the diseases which can be treated more efficiently in case of specific cohorts of patients, together with the respective drugs used. It is obvious that cancer and particularly leukemia are strongly over-represented. But this is not so much surprising: these diseases are the ones with the highest percentage of ineffective drugs (75%) [6] so that any progress in efficiency is looked after intensively and is more than welcome.
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Pharm. Pat. Anal. (2015) 4(6)
The progress which is found can be quite impressive. The following four examples show such progress and explain some characteristics of personalized medicine at its best. Non-small-cell lung cancer (NSCLC) is a disease with few effective treatment options. However, about 5% of the patients show a genetic defect, a rearrangement of the ALK gene. In this subgroup of NSCLC patients, crizotinib (Xalkori®) [7] , an oral small-molecule tyrosine kinase inhibitor [8] targeting, in other words, ALK, shows striking activity [9] , making it the drug of choice for this small subgroup of patients. The response rates of 65% and the median progression-free survival of 7.7 months are significantly higher as compared with therapies with standard single-agent chemotherapies (pemetrexed or docetaxel), namely 20% and 3.0 months. An improvement in overall survival has been reported as well [10] . About 20% of the breast cancers (and some stomach cancers) present a gene change which causes the cancer cells to produce abnormally large amounts of the regular HER2. The HER family of receptors comprises membrane-bound proteins which communicate signals from outside the cell to inside the cell. HER2 when present in abnormally high amounts stimulates cell proliferation and thus makes the cancer cells grow and divide. A monoclonal antibody called trastuzumab [11] (Herceptin) attaches to HER2 and eliminates its proliferative effects. However, if the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm instead); this holds true for about 80% of all patients. Metastatic colorectal cancer can effectively be treated with another monoclonal antibody, called panitumumab (Vectibix®) [12] . In this case the KRAS gene is of vital importance. This gene encodes for a protein which is essential in normal tissue signaling, acting as a GTPase and thus being important in many signal transduction pathways. The mutation of the KRAS gene is very often the starting point of cancer development. The only requirement for a successful application of panitumumab is that the KRAS gene is still present as the wild-type KRAS. In about 60% of the patients this is the case; in the remaining 40% of the patients the KRAS gene is already mutated and the antibody is not useful [13] . Cystic fibrosis (CF) is called a monogenetic disease caused by a mutation in the CFTR gene.; in reality there are around 2000 mutations known, leading to CF. Therefore, CF should better be looked upon as an aggregation of many monogenetic diseases. All of these diseases have in common that they show an impaired transport protein for chloride and thus a disturbed fluid flow within cells on a molecular level. The trans-
future science group
Personalized medicine: : its implications & its impact on patents
Commentary
Table 1. Higher efficacy in subgroups of patients. Disease
Drug
Cystic fibrosis with certain mutations
Ivacaftor
Duchenne muscular dystrophy
Ataluren
Gaucher disease (lipid storage disease)
Eliglustat
HIV (AIDS)
Maraviroc
Increased cholesterol or fat value levels
Lomitapid
Cancer Breast cancer
Anastrozole, everolimus, exemestane, fulvestrant, lapatinib, letrozole, pertuzumab, tamoxifen, toremifene, trastuzumab emtansine
Breast and stomach cancer
Trastuzumab
Bowel cancer
Cetuximab, panitumumab
Lung cancer
Afatinib, ceritinib, crizotinib, erlotinib, gefitinib
Medullary thyroid cancer
Vandetanib
Melanoma
Dabrafenib, trametinib, vemurafenib
Ovarian cancer
Olaparib
Leukemia and lymphoma Acute lymphoblastic leukemia
Dasatinib, ponatinib
Acute lymphoblastic and chronic myelogenous leukemia
Imatinib
Acute promyelocytic leukemia
Arsenic trioxide
Chronic lymphatic leukemia
Ibrutinib
Chronic myelogenous leukemia
Bosutinib, nilotinib
Hodgkin lymphoma and anaplastic large cell lymphoma
Brentuximab vedotin
port protein is called cystic fibrosis transmembrane conductance regulator. Clinically all the patients have a disturbed composition of mucus, sweat and digestive fluids; frequently CF patients are afflicted with concomitant (potentially life threatening) diseases of the lung and the digestive tract. One of the CF variants shows a mutation called G551D [14] and only about 4% of the CF patients carry this mutation. For this small group of patients a particular drug was developed and found approval by regulatory authorities worldwide – ivacaftor (Kalydeco®) [15] . Ivacaftor directly influences the ion channel and induces improved ion transport through the cell membrane. Fortunately, however, (according to the Prescribing Information [16]) some more, but rather rare, mutations are known where ivacaftor can successfully be applied: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R. This is a very clear example of a drug development which was only possible on the basis of a profound knowledge of molecular and cellular properties of the disease in question. Thus, ivacaftor (like crizotinib or dabrafenib) exemplifies what is meant with ‘targeted medicine,’ an expression mentioned above. It should be noted that the genetic analysis of the oncological cases described (NSCLC, breast cancer
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and colorectal cancer) is carried out with tumor tissue and this analysis leads to the identification of subgroups within a given disease. Side effects The use of biomarkers in personalized medicine is not limited to the issue of efficacy but it is also very important in order to save the patients from intolerable side effects. Six from the 42 drugs on the German market shall not be used with patients suffering from certain diseases constituting a subgroup within the respective disease as identified by the measurement of specific biomarkers. In Table 2 the six diseases are summarized where severe side effects can be prevented by simply not using those drugs for certain cohorts of patients. Again here an example: abacavir (Ziagen®) [17] is a nucleoside analog reverse transcriptase inhibitor and slows down the progression of AIDS. It should always be used together with another antiretroviral agent. In 6% of the cases (6% being the mean, the values ranging from 1.2 to 13.6% in different populations [18,19]) however, severe and sometimes fatal side effects occur which are associated with the presence of the HLAB*5701 allele [20,21] . A screening to prevent the occurrence of hypersensitivity to abacavir is mandatory.
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417
Commentary Schneider & Bublak
Table 2. Avoidance of severe side effects in subgroups of patients. Disease
Drug
Acute lymphoblastic leukemia
Mercaptopurine
Epilepsy
Carbamazepine
Epilepsy
Oxcarbazepine
HIV (AIDS)
Abacavir
Immunosuppressant
Azathioprine
Multiple sclerosis
Natalizumab
Dosage regimen The dosage regimen is the aspect of personalized medicine which is the least advanced. Taking body weight or body surface as marker to decide on the dose rate is an established practice since long time. Warfarin (Coumadin) is a blood thinning drug. In the case of warfarin the dose rate is routinely controlled by measuring the prothrombin time as defined by the international normalized ratio, there is no major difference to the conventional methods, except that the biomarker is more modern. However, in the case of warfarin, genetic differences also influence the dose rates and, thus, here we are back again to real personalized medicine [22] . The tandem of therapeutic & diagnostic agent: economic aspects To sum up, typical and essential for personalized medicine is the tandem of therapeutic and diagnostic agents as already mentioned in the introduction. The diagnostic agents to test the respective biomarker are called ‘companion diagnostics.’ Of course this implies that there is a dual business segment opening. Different regulations for the market authorization of therapeutic agents and the (companion) diagnostics cause sometimes problems for the manufacturer. Reimbursement rules differ from country to country and may present additional challenges but additional chances as well. It is obvious that personalized medicine represents a complete turnover form the emphasis on blockbusters – designed for widespread diseases with large numbers of patients thus guarantying high sales volume in the order of 1 billion Euros or US dollars or more per year – to niche buster, where only small entities of patients can be treated [23] . Two facts have to be considered in order to understand why such a turnover can be economically interesting. First, by stratification the number of patients concerned becomes small and very often so small that an orphan disease is created [24] . An orphan disease is defined in the EU as a disease with less than five patients
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Pharm. Pat. Anal. (2015) 4(6)
per 100,000 inhabitants. In the case of the corresponding orphan drugs the market authorization is strongly facilitated which in turn cuts down the cost of drug development. Second, extremely high prices for those drugs are charged, sometimes exceeding US$300,000 per year and patient (insofar representing a questionable pricing policy) [25] . Thus even a niche buster will yield a sales volume of 1 billion Euros or US dollars and more. Personalized medicine & patents The patent situation in Europe is much in favor of personalized medicine where a new subgroup of patients is identified for treatment with a known substance. The subgroup has to present a new clinical situation and has to be distinguishable from the former group by its physiological or pathological status. The European Patent Convention (EPC) allows patents in such cases. The legal basis for these patents is found in EPC 2000, Art. 54 paragraph 5 EPC (second and further medical use). Stratification and second medical use patents correspond perfectly. For claim drafting, Art. 53(c) EPC has to be kept in mind: the European Patent Office (EPO) accepts claims in the form ‘Substance X for use in the treatment of disease Y when a biomarker Z is positive ….’ The words ‘for use’ are mandatory in order to closely adhere to Art. 54 paragraph 5 EPC. A little bit tricky is to patent the avoidance of side effects – here the subgroup without side effects would have to be addressed. Tests based on biomarkers are eligible for patents anyway at the EPO. This approach has also been confirmed by the case law of the Boards of Appeal of the EPO, see G 5/83, T 19/86, T 893/90, T 836/01, T 1399/04, T 1642/06 and T 734/12. There is only one more restrictive decision, T 233/96, according to which two conditions have to be met in order to acknowledge novelty – the patient group must be nonoverlapping and there has to be a functional relationship between the biomarker and the therapy. The case law of the EPO did not follow these arguments. In the USA, the patentability of diagnostics or diagnostic methods is thrown in uncertainty since the Supreme Court’s decision in Mayo v Prometheus [26] in 2012. The Supreme Court invalidated claims with a relationship between a metabolite and an optimized dosage; according to the Supreme Court this claim presented only a patent-ineligible ‘law of nature’. The situation is complicated since then and somehow a combination of the elements of such a law of nature with other, strictly technical elements has to be found in order to escape from the verdict of the Supreme Court. The selection of subgroups renders the effects of a new drug application much more impressive. Crizotinib (see above) works only in 5% of all cases and its application for the whole group of NSCLC patients
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Personalized medicine: : its implications & its impact on patents
would be evaluated as a therapy failure but its real potential would rest undetected. The question of the proper basis for the comparison of such effects – subgroup versus subgroup or versus whole group – is more of academic interest although it is an important question in relation to the assessment of inventiveness. Conclusion The turnover from blockbusters to niche buster is of fundamental importance for the pharmaceutical industry. However, it is too early to judge the possible extent of personalized medicine and how far this concept will reach. Likewise, currently the question of the costs cannot be answered in a definite way; right now nobody can tell whether personalized medicine will lower or increase the cost of the public health system. References 1
Hamburg MA, Collins FS. The pathway to personalized medicine. N. Engl. J. Med. 363, 301–304 (2010).
2
American Medical Association. AMA Adopts New Policies During Final Day of Annual Meeting. www.ama-assn.org/ ama/pub/news/news/2010-new-policies.page
3
Paving the Way for Personalized medicine: FDA’s Role in a New Era of Medical Product Development, page 8 (2013). www.fda.gov/downloads/ScienceResearch/SpecialTopics/ PersonalizedMedicine/UCM372421.pdf
4
Thiermann A. Rechtliche Fragen beim Einsatz von Tandems aus personalisierten Fertigarzneimitteln und Biomarkertests. Pharm. Ind. 75, 87–92 (2013).
5
German Association of Research-Based Pharmaceutical Companies. In Deutschland zugelassene Arzneimittel für die personalisierte Medizin. http://www.vfa.de/de/arzneimittelforschung/datenbanken-zu-arzneimitteln/individualisiertemedizin.html
6
Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol. Med. 7(5), 201–204 (2001).
7
US 2006 0275305 A1. WO 2013/181251 A1.
8
The UPAC name of Crizotinib is 3-[(1R)-1-(2,6-Dichlor-3fluorphenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin2-amin.
9
Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl. J. Med. 368, 2385–2394 (2013).
10
Kramer HK. Vom Verständnis molekularer Mechanismen der Krankheitsentstehung zu maßgeschneiderten Therapien. Pharm. Ind. 73, 1570–1574 (2011).
11
US 20060275305 A1; US 5,677,171; Lewis GD, Figari I, Fendly B et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol. Immunother. 37, 255–263 (1993).
12
US 6,235,883; US 7,807,798; WO 2012/138997 A1.
13
US 2008 0293055 A1; US 2014 0199405 A1.
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Commentary
But the huge advantage of personalized medicine for the patients is beyond any doubt. The patients enjoy only effective therapies or they are saved from severe side effects. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
14
Bobadilla JL, Macek M Jr, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations – correlation with incidence data and application to screening. Hum. Mutat. 19(6), 575–606 (2002).
15
The UPAC name of Ivacaftor is N-(2,4-Di-tert-butyl-5hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.
16
Prescribing Information. http://pi.vrtx.com/files/uspi_ ivacaftor.pdf
17
The IUPAC name of Abacavir is (1S,4R)-4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-yl} methanol.
18
Heatherington S, Hughes AR, Mosteller M et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359, 1121–1122 (2002).
19
Mallal S, Nolan D, Witt C et al. Association between presence of HLA*B5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359, 727–732 (2002).
20
Mallal S, Phillips E, Carosi G et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568–579 (2008).
21
Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin. Infect. Dis. 43, 99–102 (2006).
22
Coumadin, package insert. http://packageinserts.bms.com/pi/ pi_coumadin.pdf
23
Dingermann T, Zündorf I. Vom Blockbuster zum Nichebuster. Pharm. Ind. 75, 576–580 (2013).
24
Thiermann A. Rechtliche Fragen beim Einsatz von Tandems aus personalisierten Fertigarzneimitteln und Biomarkertests. Pharm. Ind. 75, 87–92 (2013).
25
O’Sullivan BP, Orenstein DM, Milla CE. Pricing for orphan drugs: will the market bear what society cannot? JAMA 310(13), 1343–1344 (2013).
26
Mayo Collaborative Services v. Prometheus Laboratories, Inc., 132 S. Ct. 1289 (2012).
www.future-science.com
419
Personalized medicine: its implications and its impact on patents “...right now nobody can tell whether personalized medicine will lower or increase the cost of the public health system... But the huge advantage of personalized medicine for the patients is beyond any doubt.” Keywords: better efficacy • companion diagnostic • law of nature • patents • personalized medicine • second and further medical use • side effects • targeted drug development
Despite all advances in modern medicine the need for better methods of treatment and more efficient drugs is undeniable. Personalized medicine promises relief, and therefore the emergence of personalized medicine is accompanied with great hopes and expectations. An overview of this new development is given herein and some examples are considered more closely together with a discussion of the possibilities of patenting in the field of personalized medicine. In a certain way medicine has always been personalized medicine because any responsible physician took (or takes) into account the patient as an individual. But even nowadays the main approach in therapy consists of ‘trial and error’ coupled as far as possible with intuition and experience – simply because of the absence of alternatives. There was a huge, an almost complete lack of information about the diseases and their causes on a molecular and cellular basis on one hand and about the patient’s individual physiology on the other – all this together is the basis of a medicine grounded on scientific facts, the modern type of personalized medicine. Although such ideas were vivid for a long time it was mainly with the event of the sequencing of the human genome that those ideas started to be transformed into reality. But after all trastuzumab (Herceptin®) was found a little bit earlier and trastuzumab was the first example of a drug for a molecularly targeted cancer therapy which was officially approved already in 1998 (vide infra). Hence ‘personalized medicine’ as described in this article is a new concept in the pharma-
10.4155/ppa.15.32 © 2015 Future Science Ltd
ceutical and medical world which probably will become the medicine of the future. The modern concept of personalized medicine is based on the fast growing knowledge of natural sciences, particularly on the knowledge from molecular medicine. Personalized medicine is high-tech medicine where the most advanced knowledge of biochemistry, cell biology and physiology is used to develop and to recognize new drugs or new applications of known drugs. The use of modern biomarkers is indispensable for any kind of personalized medicine [1] . The American Medical Association defined personalized medicine in a more general way at its Annual Meeting in 2010 [2] as follows: “‘Personalized medicine’ refers to healthcare that is informed by a person’s unique clinical, genetic and environmental information”. General remarks Other denominations of personalized medicine are ‘individualized’, ‘targeted’ or ‘stratified’ medicine. The word ‘stratified’ indicates that a group of patients with a certain disease is divided – in other words, stratified – into several subgroups (cohorts) on the basis of observable and significant differences in the genome, the metabolome or the proteome of the patients. Up to now it seems that – with a given disease – quite often only one cohort of patients will react adequately to a drug while members of other cohorts do not respond well. The word ‘targeted’ emphasizes the design of modern drugs based on a profound knowledge of the site where a drug should act; this means that the biochemical target
Pharm. Pat. Anal. (2015) 4(6), 415–420
Dieter Schneider* Senior Consultant, Former Head of Patent Department, German Patent & Trademark Office, Galileiplatz 1, 81675 Munich, Germany *Author for correspondence: [email protected]
Wolfgang Bublak European Patent Attorney, Patentanwalt, Galileiplatz 1, 81675 Munich, Germany
part of
ISSN 2046-8954
415
Commentary Schneider & Bublak of a drug has to be well known. Very often the analysis of the genome forms the basis of personalized medicine. The study of variation of DNA and RNA characteristics as related to drug response is called pharmacogenomics [3] . Almost in every case a new drug is developed together with a diagnostic method to guide its application – we mostly find a tandem of drug and companion diagnostic. [4] It should be understood that in this article the somewhat purest form of a personalized medicine is not dealt with – the production of tissue from cells of a patient; for further details of the situation in Europe see Regulation (EC) No 1394/2007. Another pure form of personalized medicine, not being dealt with here, is the development of medical devices for individuals. And it should be clear already that personalized medicine is certainly not a kind of medicine where the physician spends a lot of time with the patients giving much personal care and attention to them. Personalized medicine in its practical application What means ‘personalized medicine’ in practice? Taking Germany as an example, 42 drugs are presently on the market [5] ; they stand in the forefront of personalized medicine. Two main issues are pertinent to personalized medicine – one is the better efficacy of drugs whereas the second issue is the safer application of drugs. Dosage recommendations are a further issue but of minor importance. Better efficacy of drugs 36 of the 42 drugs on the German market provide much better efficacy of a drug for a distinct subgroup of patients. The subgroup in question is identified by measuring and evaluating the relevant biomarkers. Patients suffering from the same disease but not being part of this subgroup will not respond markedly to the respective drug. Administration of the drug regardless of the subgroups as it was routinely done hitherto, often brought results which looked like treatment failures. For statistical reasons a small, positively reacting subgroup is hardly identifiable and the negative results with the main groups(s) prevail. Table 1 shows, in alphabetic order, the diseases which can be treated more efficiently in case of specific cohorts of patients, together with the respective drugs used. It is obvious that cancer and particularly leukemia are strongly over-represented. But this is not so much surprising: these diseases are the ones with the highest percentage of ineffective drugs (75%) [6] so that any progress in efficiency is looked after intensively and is more than welcome.
416
Pharm. Pat. Anal. (2015) 4(6)
The progress which is found can be quite impressive. The following four examples show such progress and explain some characteristics of personalized medicine at its best. Non-small-cell lung cancer (NSCLC) is a disease with few effective treatment options. However, about 5% of the patients show a genetic defect, a rearrangement of the ALK gene. In this subgroup of NSCLC patients, crizotinib (Xalkori®) [7] , an oral small-molecule tyrosine kinase inhibitor [8] targeting, in other words, ALK, shows striking activity [9] , making it the drug of choice for this small subgroup of patients. The response rates of 65% and the median progression-free survival of 7.7 months are significantly higher as compared with therapies with standard single-agent chemotherapies (pemetrexed or docetaxel), namely 20% and 3.0 months. An improvement in overall survival has been reported as well [10] . About 20% of the breast cancers (and some stomach cancers) present a gene change which causes the cancer cells to produce abnormally large amounts of the regular HER2. The HER family of receptors comprises membrane-bound proteins which communicate signals from outside the cell to inside the cell. HER2 when present in abnormally high amounts stimulates cell proliferation and thus makes the cancer cells grow and divide. A monoclonal antibody called trastuzumab [11] (Herceptin) attaches to HER2 and eliminates its proliferative effects. However, if the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm instead); this holds true for about 80% of all patients. Metastatic colorectal cancer can effectively be treated with another monoclonal antibody, called panitumumab (Vectibix®) [12] . In this case the KRAS gene is of vital importance. This gene encodes for a protein which is essential in normal tissue signaling, acting as a GTPase and thus being important in many signal transduction pathways. The mutation of the KRAS gene is very often the starting point of cancer development. The only requirement for a successful application of panitumumab is that the KRAS gene is still present as the wild-type KRAS. In about 60% of the patients this is the case; in the remaining 40% of the patients the KRAS gene is already mutated and the antibody is not useful [13] . Cystic fibrosis (CF) is called a monogenetic disease caused by a mutation in the CFTR gene.; in reality there are around 2000 mutations known, leading to CF. Therefore, CF should better be looked upon as an aggregation of many monogenetic diseases. All of these diseases have in common that they show an impaired transport protein for chloride and thus a disturbed fluid flow within cells on a molecular level. The trans-
future science group
Personalized medicine: : its implications & its impact on patents
Commentary
Table 1. Higher efficacy in subgroups of patients. Disease
Drug
Cystic fibrosis with certain mutations
Ivacaftor
Duchenne muscular dystrophy
Ataluren
Gaucher disease (lipid storage disease)
Eliglustat
HIV (AIDS)
Maraviroc
Increased cholesterol or fat value levels
Lomitapid
Cancer Breast cancer
Anastrozole, everolimus, exemestane, fulvestrant, lapatinib, letrozole, pertuzumab, tamoxifen, toremifene, trastuzumab emtansine
Breast and stomach cancer
Trastuzumab
Bowel cancer
Cetuximab, panitumumab
Lung cancer
Afatinib, ceritinib, crizotinib, erlotinib, gefitinib
Medullary thyroid cancer
Vandetanib
Melanoma
Dabrafenib, trametinib, vemurafenib
Ovarian cancer
Olaparib
Leukemia and lymphoma Acute lymphoblastic leukemia
Dasatinib, ponatinib
Acute lymphoblastic and chronic myelogenous leukemia
Imatinib
Acute promyelocytic leukemia
Arsenic trioxide
Chronic lymphatic leukemia
Ibrutinib
Chronic myelogenous leukemia
Bosutinib, nilotinib
Hodgkin lymphoma and anaplastic large cell lymphoma
Brentuximab vedotin
port protein is called cystic fibrosis transmembrane conductance regulator. Clinically all the patients have a disturbed composition of mucus, sweat and digestive fluids; frequently CF patients are afflicted with concomitant (potentially life threatening) diseases of the lung and the digestive tract. One of the CF variants shows a mutation called G551D [14] and only about 4% of the CF patients carry this mutation. For this small group of patients a particular drug was developed and found approval by regulatory authorities worldwide – ivacaftor (Kalydeco®) [15] . Ivacaftor directly influences the ion channel and induces improved ion transport through the cell membrane. Fortunately, however, (according to the Prescribing Information [16]) some more, but rather rare, mutations are known where ivacaftor can successfully be applied: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R. This is a very clear example of a drug development which was only possible on the basis of a profound knowledge of molecular and cellular properties of the disease in question. Thus, ivacaftor (like crizotinib or dabrafenib) exemplifies what is meant with ‘targeted medicine,’ an expression mentioned above. It should be noted that the genetic analysis of the oncological cases described (NSCLC, breast cancer
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and colorectal cancer) is carried out with tumor tissue and this analysis leads to the identification of subgroups within a given disease. Side effects The use of biomarkers in personalized medicine is not limited to the issue of efficacy but it is also very important in order to save the patients from intolerable side effects. Six from the 42 drugs on the German market shall not be used with patients suffering from certain diseases constituting a subgroup within the respective disease as identified by the measurement of specific biomarkers. In Table 2 the six diseases are summarized where severe side effects can be prevented by simply not using those drugs for certain cohorts of patients. Again here an example: abacavir (Ziagen®) [17] is a nucleoside analog reverse transcriptase inhibitor and slows down the progression of AIDS. It should always be used together with another antiretroviral agent. In 6% of the cases (6% being the mean, the values ranging from 1.2 to 13.6% in different populations [18,19]) however, severe and sometimes fatal side effects occur which are associated with the presence of the HLAB*5701 allele [20,21] . A screening to prevent the occurrence of hypersensitivity to abacavir is mandatory.
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Commentary Schneider & Bublak
Table 2. Avoidance of severe side effects in subgroups of patients. Disease
Drug
Acute lymphoblastic leukemia
Mercaptopurine
Epilepsy
Carbamazepine
Epilepsy
Oxcarbazepine
HIV (AIDS)
Abacavir
Immunosuppressant
Azathioprine
Multiple sclerosis
Natalizumab
Dosage regimen The dosage regimen is the aspect of personalized medicine which is the least advanced. Taking body weight or body surface as marker to decide on the dose rate is an established practice since long time. Warfarin (Coumadin) is a blood thinning drug. In the case of warfarin the dose rate is routinely controlled by measuring the prothrombin time as defined by the international normalized ratio, there is no major difference to the conventional methods, except that the biomarker is more modern. However, in the case of warfarin, genetic differences also influence the dose rates and, thus, here we are back again to real personalized medicine [22] . The tandem of therapeutic & diagnostic agent: economic aspects To sum up, typical and essential for personalized medicine is the tandem of therapeutic and diagnostic agents as already mentioned in the introduction. The diagnostic agents to test the respective biomarker are called ‘companion diagnostics.’ Of course this implies that there is a dual business segment opening. Different regulations for the market authorization of therapeutic agents and the (companion) diagnostics cause sometimes problems for the manufacturer. Reimbursement rules differ from country to country and may present additional challenges but additional chances as well. It is obvious that personalized medicine represents a complete turnover form the emphasis on blockbusters – designed for widespread diseases with large numbers of patients thus guarantying high sales volume in the order of 1 billion Euros or US dollars or more per year – to niche buster, where only small entities of patients can be treated [23] . Two facts have to be considered in order to understand why such a turnover can be economically interesting. First, by stratification the number of patients concerned becomes small and very often so small that an orphan disease is created [24] . An orphan disease is defined in the EU as a disease with less than five patients
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per 100,000 inhabitants. In the case of the corresponding orphan drugs the market authorization is strongly facilitated which in turn cuts down the cost of drug development. Second, extremely high prices for those drugs are charged, sometimes exceeding US$300,000 per year and patient (insofar representing a questionable pricing policy) [25] . Thus even a niche buster will yield a sales volume of 1 billion Euros or US dollars and more. Personalized medicine & patents The patent situation in Europe is much in favor of personalized medicine where a new subgroup of patients is identified for treatment with a known substance. The subgroup has to present a new clinical situation and has to be distinguishable from the former group by its physiological or pathological status. The European Patent Convention (EPC) allows patents in such cases. The legal basis for these patents is found in EPC 2000, Art. 54 paragraph 5 EPC (second and further medical use). Stratification and second medical use patents correspond perfectly. For claim drafting, Art. 53(c) EPC has to be kept in mind: the European Patent Office (EPO) accepts claims in the form ‘Substance X for use in the treatment of disease Y when a biomarker Z is positive ….’ The words ‘for use’ are mandatory in order to closely adhere to Art. 54 paragraph 5 EPC. A little bit tricky is to patent the avoidance of side effects – here the subgroup without side effects would have to be addressed. Tests based on biomarkers are eligible for patents anyway at the EPO. This approach has also been confirmed by the case law of the Boards of Appeal of the EPO, see G 5/83, T 19/86, T 893/90, T 836/01, T 1399/04, T 1642/06 and T 734/12. There is only one more restrictive decision, T 233/96, according to which two conditions have to be met in order to acknowledge novelty – the patient group must be nonoverlapping and there has to be a functional relationship between the biomarker and the therapy. The case law of the EPO did not follow these arguments. In the USA, the patentability of diagnostics or diagnostic methods is thrown in uncertainty since the Supreme Court’s decision in Mayo v Prometheus [26] in 2012. The Supreme Court invalidated claims with a relationship between a metabolite and an optimized dosage; according to the Supreme Court this claim presented only a patent-ineligible ‘law of nature’. The situation is complicated since then and somehow a combination of the elements of such a law of nature with other, strictly technical elements has to be found in order to escape from the verdict of the Supreme Court. The selection of subgroups renders the effects of a new drug application much more impressive. Crizotinib (see above) works only in 5% of all cases and its application for the whole group of NSCLC patients
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Personalized medicine: : its implications & its impact on patents
would be evaluated as a therapy failure but its real potential would rest undetected. The question of the proper basis for the comparison of such effects – subgroup versus subgroup or versus whole group – is more of academic interest although it is an important question in relation to the assessment of inventiveness. Conclusion The turnover from blockbusters to niche buster is of fundamental importance for the pharmaceutical industry. However, it is too early to judge the possible extent of personalized medicine and how far this concept will reach. Likewise, currently the question of the costs cannot be answered in a definite way; right now nobody can tell whether personalized medicine will lower or increase the cost of the public health system. References 1
Hamburg MA, Collins FS. The pathway to personalized medicine. N. Engl. J. Med. 363, 301–304 (2010).
2
American Medical Association. AMA Adopts New Policies During Final Day of Annual Meeting. www.ama-assn.org/ ama/pub/news/news/2010-new-policies.page
3
Paving the Way for Personalized medicine: FDA’s Role in a New Era of Medical Product Development, page 8 (2013). www.fda.gov/downloads/ScienceResearch/SpecialTopics/ PersonalizedMedicine/UCM372421.pdf
4
Thiermann A. Rechtliche Fragen beim Einsatz von Tandems aus personalisierten Fertigarzneimitteln und Biomarkertests. Pharm. Ind. 75, 87–92 (2013).
5
German Association of Research-Based Pharmaceutical Companies. In Deutschland zugelassene Arzneimittel für die personalisierte Medizin. http://www.vfa.de/de/arzneimittelforschung/datenbanken-zu-arzneimitteln/individualisiertemedizin.html
6
Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol. Med. 7(5), 201–204 (2001).
7
US 2006 0275305 A1. WO 2013/181251 A1.
8
The UPAC name of Crizotinib is 3-[(1R)-1-(2,6-Dichlor-3fluorphenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin2-amin.
9
Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl. J. Med. 368, 2385–2394 (2013).
10
Kramer HK. Vom Verständnis molekularer Mechanismen der Krankheitsentstehung zu maßgeschneiderten Therapien. Pharm. Ind. 73, 1570–1574 (2011).
11
US 20060275305 A1; US 5,677,171; Lewis GD, Figari I, Fendly B et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol. Immunother. 37, 255–263 (1993).
12
US 6,235,883; US 7,807,798; WO 2012/138997 A1.
13
US 2008 0293055 A1; US 2014 0199405 A1.
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Commentary
But the huge advantage of personalized medicine for the patients is beyond any doubt. The patients enjoy only effective therapies or they are saved from severe side effects. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
14
Bobadilla JL, Macek M Jr, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations – correlation with incidence data and application to screening. Hum. Mutat. 19(6), 575–606 (2002).
15
The UPAC name of Ivacaftor is N-(2,4-Di-tert-butyl-5hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.
16
Prescribing Information. http://pi.vrtx.com/files/uspi_ ivacaftor.pdf
17
The IUPAC name of Abacavir is (1S,4R)-4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-yl} methanol.
18
Heatherington S, Hughes AR, Mosteller M et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359, 1121–1122 (2002).
19
Mallal S, Nolan D, Witt C et al. Association between presence of HLA*B5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359, 727–732 (2002).
20
Mallal S, Phillips E, Carosi G et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568–579 (2008).
21
Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin. Infect. Dis. 43, 99–102 (2006).
22
Coumadin, package insert. http://packageinserts.bms.com/pi/ pi_coumadin.pdf
23
Dingermann T, Zündorf I. Vom Blockbuster zum Nichebuster. Pharm. Ind. 75, 576–580 (2013).
24
Thiermann A. Rechtliche Fragen beim Einsatz von Tandems aus personalisierten Fertigarzneimitteln und Biomarkertests. Pharm. Ind. 75, 87–92 (2013).
25
O’Sullivan BP, Orenstein DM, Milla CE. Pricing for orphan drugs: will the market bear what society cannot? JAMA 310(13), 1343–1344 (2013).
26
Mayo Collaborative Services v. Prometheus Laboratories, Inc., 132 S. Ct. 1289 (2012).
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