Precision medicine and monoclonal antibodies: breach of promise?

Precision medicine (PM) is an emerging approach for disease treatment and prevention that, beyond environment and lifestyle, mainly takes into account individual gene variability ( 1 ). PM best incorporates all the expectations raised by the most advanced pharmacological therapies in development ( 2 ). Unlike competing definitions (eg, personalized medicine) ( 3 ), PM aims to stratify (rather than individualize) pharmacological therapies to subgroups of patients who have the genetic variant of interest ( 4 ), overcoming the traditional “one size fits all” drug paradigm. Pharmacogenomics − the study of the influence of genetic variability on drug responses ( 5 ) − should help identify “the right drug at the right dose for the right patient” ( 2 ). By influencing or predicting the response to treatment ( 1 ), PM should optimize the efficacy and safety of drugs administered according to the patient’s genomic profile ( 6 ), ideally maximizing pharmacological responses and minimizing the side effects ( 7 ). Since tumors tend to arise from genetic variants ( 1 ), cancer treatment has so far been the most investigated area of PM. However, longer-term expectations of PM are pharmaceutical therapies for all diseases ( 2 ).

Monoclonal antibodies (mABs) are the latest generation of drugs that fit the PM paradigm most ( 8 ). Approved in record numbers (at twice the rate of small molecules) ( 9 ) and having sky-high prices, mABs are indicated for many tumors (their main field of application) and chronic illnesses. The pharmaceutical industry expects biological markers – molecules found in the human body that are signs of normal or abnormal processes ( 10 ) − to play a major role in using mABs for optimal treatment in clinical practice ( 11 ). The first paradigmatic example of targeted therapy in oncology was trastuzumab (with HER2 as a biomarker in breast cancer) ( 12 ), followed by cetuximab (with EGFR and KRAS in colorectal cancer) ( 3 ).

To assess the general trend of mABs and their relationship with PM, we analyzed the main characteristics of the 68 mABs approved in the European Union (EU) in the last two decades (1998-2018).

Monoclonal antibodies survey

After a slow take-off, the number of mABs approved by the European Medicines Agency has dramatically increased in the last five years ( Figure 1 ). The majority of mABs approved in the second decade are human or humanized ones ( Figure 2 ), a trend which might reduce allergic reactions and boost clinical effects. The proportion of mABs indicated for cancer is still highest, although it has slightly decreased in the second decade ( Figure 3 ).

The European public assessment reports for half of the 26 approved anti-cancer mABs do not list a biomarker ( 13 ) ( Table 1 ). Biomarkers are reported more frequently for the mABs approved for solid tumors ( 14 ), which are slightly more numerous than those for blood cancers ( 12 ) – the latter being more curable than the former for a long time with small molecules. Of the nine biomarkers reported, all but one (Philadelphia chromosome) are proteins, and the only companion tests explicitly written in all the European reports are still those for detecting the biomarkers of the two “pioneer” targeted mABs ( 3 ).

Many of the more recent non-anti-cancer mABs have overlapping indications ( Table 2 ). However, none of the 42 approved so far have a specific biomarker (and thus a companion test) indicated in the European reports.

From theory to practice

Precision medicine

Focused on biology rather than on other variables, such as lifestyle or environment, PM presents itself as the ultimate science, and its full promise goes even beyond targeting therapies for patients ( 14 ) and includes the ability to identify healthy individuals at high risk and take preventive measures for them ( 15 ). The PM’s basic assumption is that genetics is the underlying factor in most health conditions, so diseases are mainly affected by the human genetic make-up ( 16 ). Progress in characterizing individual differences in genomic sequences should extend the application range of PM from rare monogenic diseases to more common and genetically complex pathologies ( 17 ). Although diseases such as cancer and diabetes are largely a consequence of lifestyles, inherited genetic variations are considered their crucial cause ( 2 ).

Politically exploited by the former president of the USA to successfully baptize a major research initiative ( 2 ), PM has aroused great expectations as a “weapon” that will defeat most human diseases in the next decades and fully transform medicine from art to science ( 16 , 18 ). However, clinical results so far have not been as encouraging as promised. There is still a chasm between identifying a genetic susceptibility and developing safe and effective medicines. If no therapies are available, the value of diagnosis or risk stratification is very limited ( 5 ). Even more, combining various risk markers not necessarily implies providing clinically meaningful information, and much variability in therapeutic efficacy is not genetically driven ( 16 ). So, regardless of PM progress, complete success is still unlikely.

Especially for cancer, the major field of PM application, genetic mutations are numerous and evolve so heterogeneously in the majority of patients that it is almost impossible to find two identical tumors ( 19 ). This is why surgical interventions are still vital as they are the only way to immediately remove this cellular diversity from patients. There are persuasive scientific reasons why cancer has no miracle cure ( 20 ). When considered objectively, the potential of PM in oncology is sobering ( 21 ), with at best short-lived responses (and unavoidable toxicity) in a small proportion of patients, at high cost. Many of the recent successes against cancer still stem from traditional public health measures (eg, screening and early detection) ( 22 ). Although targeted therapies have so far offered limited benefit for overall survival − probably due to the adaptive nature of cancer ( 19 , 22 ) − PM still promises to pair patients with drugs based on genetic testing irrespective of the tissue of tumor origin ( 21 ).

Monoclonal antibodies

Our survey on the mABs approved in the EU confirmed that in practice target prioritization is still a major issue, since in most cases there is a lack of biomarkers and the biomarkers are always the same in the few mABs that report them. After two decades, the industry’s mantra “no biomarker no drug” ( 11 ) has been mainly (for anti-cancer mABs) and fully (for the remaining ones) neglected in practice. Targeted therapies are still the major PM bottleneck, and “one size fits all” medicines continue to be employed ( 21 ). In oncology there are currently 343 mABs (60% of the total) under clinical trial ( 9 ), and the tendency is to treat tumors with different sites of origin with combination therapies ( 11 , 23 ) rather than to stratify therapies for the same cancer. This tendency should help further raise the already high returns generated by anticancer mABs through their sky-high prices ( 24 ), probably distorting further investment in this field at the expense of promising research in other disease areas.

Comment

Critics argue that PM is continuously fueling unrealistic expectations, distracting funds from tackling widespread risk factors such as smoking, alcoholism, and obesity ( 5 ). Although it is well known that many diseases stem from unhealthy lifestyles and socio-economic conditions ( 22 ), researchers’ ambitions and media channels relentlessly foster the arguable PM promises, and keep attracting big funding ( 14 ). However, PM advocates would do better to temper their narrative of radical change and communicate a more realistic set of expectations through the media to the public ( 5 ), in line with the incremental nature of science.

While we are waiting for the gap between the exorbitant expectations raised by PM and the discouraging results achieved so far to be filled, there is widespread evidence in this period of never-ending economic crisis that pharmaceutical expenditure has become increasingly unsustainable for health authorities even in most high-income countries ( 25 ), and Europe is no exception.

Pharmaceutical expenditure, like anything else, is determined by prices and volumes, and the former are increasingly out of control. This was easy to predict in a typically “market failure” situation ( 26 ), where prices cannot competitively match demand with supply. Since all pharmaceutical prices are necessarily set through arbitrary decisions, the unavoidable results are a distortion of relative prices and irrational allocation of financial resources in pharmaceuticals ( 27 ), from upstream research investments to downstream health expenditures.

The pharmaceutical industry is mainly private, and negotiating sky-high prices for new drugs like mABs is a crucial factor of success when it comes to generating high returns on research and development investments and maximizing profits in all countries ( 28 ). In this landscape, PM helps create an ideal setting for price discrimination for new similar drugs ( 29 ), and anti-cancer mABs can be considered an emblematic example of less and less sustainable prices ( 30 ). Because of the emotive nature of cancer, health authorities find it hard to resist “pleas” for reimbursement of new drugs, even when their efficacy is marginal ( 31 ). So, pharmaceutical companies have a clear incentive to invest in new anti-cancer therapies, regardless of their real impact on patients’ survival and quality of life ( 32 ).

We contend here that the time has come to stop setting arbitrary prices for new, very expensive drugs, so as to limit the distortion of allocation of financial resources in pharmaceuticals ( 33 ). Prices can hardly − if ever − be competitive in a “market failure” context, so their effect should be minimized. Leveling out prices for a very limited number of therapeutic classes and capping expenses to respect yearly budgets should become the “recipe” to master pharmaceutical expenses in the future ( 33 ). It is hard enough – probably impossible − to rank therapies on the basis of the importance of their related pathologies, so the benefits of effective medicines are even harder to differentiate through pricing.

If we strive to restore a balance between public objectives of health services and the private incentives of the pharmaceutical industry, and improve the long-term sustainability of pharmaceutical expenditure in all European countries, rational budgeting should be given priority over irrational pricing. Realistic expectations to improve patients’ health thanks to PM as a concept and mABs as therapies might then be pursued in the long run with much less suspicion in the literature.

References

1 Psaty BM Dekkers OM Cooper RS Comparison of 2 treatment models: precision medicine and preventive medicine. JAMA 2018 320 751 2 10.1001/jama.2018.8377 30054607

2 Collins FS Varmus H A new initiative on precision medicine. N Engl J Med 2015 372 793 5 10.1056/NEJMp1500523 25635347 PMC5101938

3 Garattini L Curto A Freemantle N Personalized medicine and economic evaluation in oncology: all theory and no practice? Expert Rev Pharmacoecon Outcomes Res 2015 15 733 8 10.1586/14737167.2015.1078239 26289733

4 Tutton R Personalizing medicine: futures present and past. Soc Sci Med 2012 75 1721 8 10.1016/j.socscimed.2012.07.031 22906526

5 Evans JP Meslin EM Marteau TM Caulfield T Genomics. Deflating the genomic bubble. Science 2011 331 861 2 10.1126/science.1198039 21330519

6 Conti R Veenstra DL Armstrong K Lesko LJ Grosse SD Personalized medicine and genomics: challenges and opportunities in assessing effectiveness, cost-effectiveness, and future research priorities. Med Decis Making 2010 30 328 40 10.1177/0272989X09347014 20086232 PMC4598076

7 Vegter MW Towards precision medicine; a new biomedical cosmology. Med Health Care Philos 2018 21 443 56 10.1007/s11019-018-9828-z 29429062 PMC6267256

8 Yan L Beckman RA Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development. Biotechniques 2005 39 565 8 10.2144/000112043 16235569

9 Kaplon H Reichert JM Antibodies to watch in 2019. MAbs 2019 11 219 38 10.1080/19420862.2018.1556465 30516432 PMC6380461

10 Godman B Finlayson AE Cheema PK Zebedin-Brandl E Gutiérrez-Ibarluzea I Jones J Personalizing health care: feasibility and future implications. BMC Med 2013 11 179 10.1186/1741-7015-11-179 23941275 PMC3750765

11 de Bono JS Ashworth A Translating cancer research into targeted therapeutics. Nature 2010 467 543 9 10.1038/nature09339 20882008

12 Garattini L van de Vooren K Curto A Cost-effectiveness of trastuzumab in metastatic breast cancer: mainly a matter of price in the EU? Health Policy 2015 119 212 6 10.1016/j.healthpol.2014.12.002 25523144

13 European Medicines Agency. European public assessment reports available from: https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_field/Human/ema_group_types/ema_medicine . Accessed: May 10, 2019.

14 Ten Have H Gordijn B Precision in health care. Med Health Care Philos 2018 21 441 2 10.1007/s11019-018-9870-x 30302604

15 Dzau VJ Ginsburg GS Van Nuys K Agus D Goldman D Aligning incentives to fulfil the promise of personalised medicine. Lancet 2015 385 2118 9 10.1016/S0140-6736(15)60722-X 25957453 PMC6481305

16 Wiesing U From art to science: a new epistemological status for medicine? On expectations regarding personalized medicine. Med Health Care Philos 2018 21 457 66 10.1007/s11019-017-9820-z 29264706

17 Ehmann F Caneva L Prasad K Paulmichl M Maliepaard M Llerena A Pharmacogenomic information in drug labels: European Medicines Agency perspective. Pharmacogenomics J 2015 15 201 10 10.1038/tpj.2014.86 25707393

18 Tooke J The science (and art) of medicine. Lancet 2016 387 Suppl 1 S6 7 10.1016/S0140-6736(16)00263-4 26923276

19 Swanton C Cancer therapeutics through an evolutionary lens. J R Soc Med 2018 111 8 14 10.1177/0141076817742096 29338594 PMC5784489

20 Abbasi K The seductive hope of cancer therapies. J R Soc Med 2018 111 343 10.1177/0141076818807039 30319000 PMC6194960

21 Prasad V Perspective: The precision-oncology illusion. Nature 2016 537 S63 10.1038/537S63a 27602743

22 Joyner MJ Paneth N Seven questions for personalized medicine. JAMA 2015 314 999 1000 10.1001/jama.2015.7725 26098474

23 Wise J Genome sequencing of children promises a new era in oncology. BMJ 2019 364 l105 10.1136/bmj.l105 30622102

24 Tay-Teo K Ilbawi A Hill SR Comparison of sales income and research and development costs for fda-approved cancer drugs sold by originator drug companies. JAMA Netw Open 2019 2 e186875 10.1001/jamanetworkopen.2018.6875 30644967 PMC6324319

25 Ploumen L Schippers E Better life through medicine − let’s leave no one behind. Lancet 2017 389 339 41 10.1016/S0140-6736(16)31905-5 27832876

26 Garattini L Padula A Competition in pharmaceuticals: more product- than price-oriented? Eur J Health Econ 2018 19 1 4 10.1007/s10198-017-0932-4 28993950

27 Frakt AB Chernew ME The Importance of relative prices in health care spending. JAMA 2018 319 441 2 10.1001/jama.2017.20047 29302693

28 Garattini L, Padula A. Between pharmaceutical patents and European patients: is a compromise still possible? Expert Opin Ther Pat. 2017; 27(10):1073-6. 10.1080/13543776.2017.1350648 28671001

29 Chandra A Garthwaite C The economics of indication-based drug pricing. N Engl J Med 2017 377 103 6 10.1056/NEJMp1705035 28700848

30 Dolgin E Bringing down the cost of cancer treatment. Nature 2018 555 S26 9 10.1038/d41586-018-02483-3 32095016

31 van de Vooren K Curto A Garattini L Optional copayments on anti-cancer drugs. BMJ 2013 346 f349 10.1136/bmj.f349 23347986

32 Reinhardt U Probing our moral values in health care: the pricing of specialty drugs. JAMA 2015 314 981 2 10.1001/jama.2015.9593 26348738

33 Garattini L Padula A Pharmaceutical pricing conundrum: time to get rid of it? Eur J Health Econ 2018 19 1035 8 10.1007/s10198-018-0995-x 30030646