Precision Medicine

PRECISIO N MEDICI NE DRUG Spleon asm or r eality?

The complexity and uniqueness of human metabolism and physiology in the past decade has been highlighted and dissected. Arguments have been made to suggest that our lack of understanding about human individuality has led to the limited efficacy and safety of many marketed therapeutic drugs. The Drug Discovery and Development (DDD) process continues to slowly evolve to address this perpetual problem. More recently with the advent of personalised and precision medicine, there have been efforts made to address individual complexity. An understanding of personalised versus precision medicine is necessary in order to understand such endeavours. This has led to the development of what have been labelled ‘Targeted’ or ‘Personalised Medicine Drugs’. Based on the differences between the N-of-1 model (personalised medicine) and the 1-in-N model (precision medicine), we propose that a more appropriate name is ‘Precision Medicine Drugs’. Such issues are discussed herein.

here appears to be a considerable discon - (Phase II) and 30% (Phase III) 3. The average time By Dr Urban A. nect between the expectation of stakehold - required from drug discovery to product launch Kiernan and T ers and the pragmatic demands of bringing remains at an eye-watering 12-15 years 4. Finally, Dr Stephen Naylor a therapeutic drug to market 1. The Drug Discovery the total capitalised cost of bringing a new drug to and Development (DDD) process was conceived in market was recently estimated at a staggering the early 1960s and has remained relatively $2.87 billion 5. unchanged over the past 50-plus years. It continues The metrics associated with the DDD process to be risk-laden, slow, costly and inefficient, as well are clearly problematic. There is also a concern as delivering products of questionable value in about the value proposition of current, marketed terms of safety and efficacy 1. For example, cumu - therapeutic drug products produced by the DDD lative risk is associated with any effort to bring a process. These issues include: drug to market. The initial screening of compound libraries (104-106) leads to a single lead compound i. Drug safety that has only an ~8% chance of successfully Not all approved drugs stand the test of market traversing the clinical trials gauntlet 2. In addition, pressures due to the scrutiny of pharmacovigiliance the failure rate of a drug candidate at each stage of and post-market surveillance. In some cases clinical trials is reported to be, 46% (Phase I), 66% approved drugs can be removed from the market

Drug Discovery World Summer 2018 9 Precision Medicine

because they manifest safety, effectiveness or eco - differentiation, market need, patient acceptance, nomic problems. For example from 1994-2015, sales and marketing strategy and IP position as the USA Food and Drug Administration (FDA) well as individual R&D costs 10 . In many cases, issued 215 ‘Withdrawal of Application’ notices 6. pharmaceutical companies have used rampant During that same time period the FDA actually R&D costs to maximise prices charged to the recalled 26 drugs from the US market predicated patient/consumer. Unfortunately, even in such a primarily on safety concerns 7. favourable economic climate, only 3-in-10 approved drugs generate revenues that are at least ii. Drug effectiveness equal to or greater than average R&D costs 11 . There is now a significant body of evidence that indicates individual patients diagnosed with the We have argued in the past that the same disease indication respond differently to the ‘Blockbuster Model ’ has inadvertently led to the same therapeutic drug 8. For example Spears and ‘wagon-of-woe ’ for the DDD process 12 . This co-workers analysed the effectiveness of a number model focused on a ‘one drug-one target’ mecha - of different drug classes against major disease indi - nism that was potentially safe and effective in a cations 9. They found that most drugs were 50- large, but heterogeneous population. We have 75% effective as determined by patient responses. suggested the use of more efficient technology The lowest patient responders occurred with con - usage 13 , decision-making tools 13 , systems biolo - ventional cancer chemotherapy (25%) whereas the gy 14,15 , and personalised/precision medicine 16 in highest percentage of patient responders was treat - order to overcome the limitations of such a ed with Cox-2-inhibitors (80%). Therapeutic model. More recently, we presented the concept drugs were reported to be ineffective for of a combined systems biology-personalised/pre - Alzheimer’s (70%), arthritis (50%), diabetes cision medicine approach to the development of (43%), and asthma (40%) patients 9. more effective and safe therapeutic drugs 17 , par - ticularly in the treatment of Alzheimer’s iii. Pricing Disease 18 . In this manuscript we introduce the Approved drug price points are determined by concept of ‘Targeted ’ or ‘Precision Medicine market forces that include drug safety and efficacy Drugs’ which is a logical outflow from a combi -

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nation of systems biology and personalised/preci - National Research Council (NRC) in 2011 24 . The References sion medicine approach to DDD. report laid out a series of recommendations for dis - 1 Kauppi, DM and Naylor, S. ease ontology predicated on molecular information Therapeutic Drug Repurposing, Repositioning Personalised and Precision Medicine content in the form of causal genetic variants or and Rescue: Part IV – Financial In order to understand the concept and nomencla - genomic information rather than a symptom-based Model and Analysis. Drug ture of a ‘Precision Medicine Drug’ it is important classification system. This prompted a firestorm of Discov. World Winter Edition. to first appreciate the subtle but real differences activity, and the initial focus of Precision Medicine 54-63 (2016). between the terms Personalised versus Precision was on genetic and genomic underpinnings of dis - 2 Cook, D et al. Lessons Learned from the Fate of Medicine. As with any new and emerging field of ease. For example, the Institute of Precision Astra-Zeneca’s Drug Pipeline: endeavour, clear definitions are often a work in Medicine provided an early definition that stated: A Five Dimensional Network. progress as terminology evolves and/or disappears. “Precision medicine is targeted, individualised care Nature Reviews: Drug In the case of Personalised and Precision Medicine that is tailored to each patient based on his or her Discovery. 13, 419-431 (2014). it is complicated by the fact that these terms are specific genetic profile and medical history. Unlike 3 Paul, SM et al. How to Improve R&D Productivity: the often mistakenly used interchangeably as umbrella traditional medicine where one-size-fits-all, practi - Pharmaceutical Industry’s descriptors. Hence, the terms Personalised and/or tioners of precision medicine use genomic sequenc - Grand Challenge. Nature Precision Medicine and how they are practised ing tools to interrogate a patient’s entire genome to Reviews: Drug Discovery, 9, have broad and confusing interpretations 19 . locate the specific genetic alterations that have 203-214 (2010). given rise to and are driving his or her tumour” 25 . 4 Deloitte Centre for Health solutions. Measuring the Personalised Medicine This type of approach garnered significant atten - Return from Pharmaceutical Historically, Personalised Medicine emerged in the tion, but it was difficult to discern the fundamental Innovation 2014. Turning a early 2000s. The Personalised Medicine Coalition differences practiced by the Precision Medicine ver - Corner? http://www2.deloitte. (PMC), founded in 2004 to represent the interests sus Personalised Medicine communities 19 . com/content/dam/Deloitte/uk/ of the then fledgling Personalised Medicine com - Documents/life-sciences- health-care/measuring-the- munity, defined Personalised Medicine as “…an Differences between Personalised return-from-pharmaceutical- evolving field in which physicians use diagnostic versus Precision Medicine innovation-2014.pdf. tests to determine which medical treatments will The NRC Council Report in 2011 attempted to 5 DiMasi, JA, Grabowski, HG work best for each patient. By combining the data define and differentiate Precision Medicine from and Hansen, RW. Innovations in from those tests with an individual’s medical histo - Personalised Medicine. The report stated: the Pharmaceutical Industry: New Estimates of R&D Costs. J. ry, healthcare providers can develop targeted treat - “Precision Medicine is the tailoring of medical Health Econ. 47, 20-33, (2016). 20 ment and prevention plans” . Other pioneers of treatment to the individual characteristics of each 6 Gaffney, A. How Often Does Personalised Medicine continued to stress the patient. It does not literally mean the creation of FDA Withdraw Drugs Using importance of the individual. The belief was that drugs or medical devices that are unique to a Discontinuation Petitions? Very “actionable understanding of disease and wellness patient, but rather the ability to classify individuals Rarely. Regulatory Affairs Professional Society. June 15th, as a continuum of [molecular] network states into subpopulations that differ in their susceptibil - (2015). http://www.raps.org/ unique in time and space to each individual human ity to a particular disease, in the biology and/or Regulatory-Focus/News/2015/ being” is possible 21 . Redekop and Madsi have sur - prognosis of those diseases they may develop, or in 06/15/22690/How-Often- veyed that literature and the plethora of competing their response to a specific treatment. Preventive or Does-FDA-Withdraw-Drugs- definitions of Personalised Medicine. They con - therapeutic interventions can then be concentrated Using-Discontinuation- Petitions-Very-Rarely/. cluded that the most appropriate definition for on those who will benefit, sparing expense and 7 ProCon.Org Thirty-Five Personalised Medicine is “the use of the combined side-effects for those who will not. Although the FDA-approved Prescription knowledge (genetic or otherwise) about a person to term ‘personalised medicine’ is also used to convey Drugs Later Pulled from the predict disease susceptibility, disease prognosis or this meaning, that term is sometimes misinterpret - Market. http://prescription treatment response and thereby improve that per - ed as implying that unique treatments can be drugs.procon.org/view.resourc e.php?resourceID=005528. son’s health 22 . They reinforced the idea of specific designed for each individual” 24 . 8 Vizirianakis, IS (Ed). analyses for treatment of the individual patient. It should be noted that the word ‘precision’ in Handbook of Personalized Precision Medicine is used colloquially to include Medicine: Advances in Precision Medicine both accurate and precise scientific measure - Nanotechnology, Drug The term ‘Precision Medicine’ was first coined by ment 24,26 . However, based on the NCR definition, Delivery and Therapy. CRC Press/Taylor Francis Group. Clayton Christensen in his book the Innovator’s it is clear that the Precision Medicine approach Boca Raton, FL, USA. (2013). 23 Prescription published in 2009 . However, the utilises individuals and defined (sub)-population- 9 Spear, BB, Heath-Chiazzi, M descriptor ‘Precision Medicine’ did not gain wide based cohorts that have a common network of dis - and Huff, JJ. Clinical acceptance and usage until a report entitled ease (or health) taxonomy. In addition, it requires Applications of Toward Precision Medicine: Building a Knowledge an integrated molecular and clinical profile of both Pharmacogenetics. Trends Mol. Medicine 7, 201-204 (2001). Network for Biomedical Research and a New the individual as well as the subpopulation-based Taxonomy of Disease was published by the US cohort. Zhang has described Precision Medicine, Continued on page 12

Drug Discovery World Summer 2018 11 Precision Medicine

Continued from page 11 predicated on the individual patient/subpopulation a genetic marker in oncology trials, and a mode of 10 Persidis, A. The Benefits of model, as “one-step-up” from the individual action for the candidate drug against a number of Drug Repositioning. Drug patient focus of Personalised Medicine 27 . Implicit related disease indications. In contrast, an ‘umbrel - Discov. World Spring Edition: in his statement is that Personalised Medicine is la’ trial tests the effectiveness of a myriad of drug 9-12 (2011). 31 11 Kaitin, KI. Deconstructing based on a single individual ‘N-of-1’ model where - candidates against a single disease indication . the Drug Development as Precision Medicine uses a ‘1-in-N’ model predi - More recently, Schork has suggested an N-of-1 Process: The New Face of cated on widely-used biostatistical data analysis clinical trial, in which a systems-level analysis of Innovation. Clin. Pharmacol. and “big data” analytical tools. Precision Medicine data is collected on an individual patient who is Ther. 87, 356-361 (2010). can best be described as an amalgam of being treated with a therapeutic agent 31 . In all 12 Naylor, S. NostraPharmus Revisited: Splendid Isolation or Personalised Medicine and modern conventional cases the intertwining of appropriate biomarkers, Multifactorial Participation for medicine. companion diagnostics and mechanistic under - the Pharmaceutical Industry? It is clear that Precision Medicine has attracted standing of the drug mode of action are driving Drug Discov. World. Summer huge attention and is in the ascendancy compared such efforts. Supplement. 10-12 (2010). with Personalised Medicine. The attributes of the 13 Naylor, S. Technology: Bane or Bonanza for the 1-in-N model of Precision Medicine have been Definition of a Precision Medicine Drug Pharmaceutical Industry. Drug more fully accepted and rendered into practice The oncology research and clinical communities Discov. World. Fall Edition. 51- compared to the challenging N-of-1 model of have pioneered the development of ‘Targeted 57 (2007). Personalised Medicine. A number of disease area Therapies’. It was long recognised that in a patient 14 Davidov, EJ, Holland, J, specialties have started to query or implement ele - population with the same clinical disease state, het - Marple, E and Naylor, S. Advancing Drug Discovery ments of Precision Medicine into everyday practice erogeneity of the molecular etiology and develop - through Systems Biology. Drug and treatment of patients and they include such ment of the tumour led to different therapeutic Discovery Today, 8, 175-181 diverse areas as diabetes 28 and Alzheimer’s responses by individual patients. However, a tar - (2003). Disease 18 . In particular, the oncology community geted therapy may be effective in a sub-population 15 Naylor, S. Systems Biology, has been quick to embrace and reduce Precision of patients who have different underlying molecu - Information, Disease and Drug Discovery. Drug Discov. World. Medicine to practise in the diagnosis and treatment lar similarities. The PMC has extended this con - Winter Edition. 23-31 of a wide variety of cancers 29,30 , and has pio - cept beyond just the oncology sector. When evalu - (2004/2005). neered the development and use of Targeted or ating New Medical Entities (NMEs) approved by 16 Culbertson, AW, Valentine, Precision Medicine Drugs. the FDA, PMC categorised personalised medicines SJ and Naylor, S. Personalized as “those therapeutic products for which the label Medicine: Technological Innovation and Patient Precision Medicine Drugs includes reference to specific biological markers, Empowerment or Exuberant We have discussed above the limited efficacy of identified by diagnostic tools, that help guide deci - Hyperbole? Drug Discov. currently available therapeutic drugs. These effica - sions and/or procedures for their use in individual World. Summer Edition 18-28 cy limitations also apply to blockbuster drugs. For patients” 33,34 . However, we would propose, based (2007). example, the effectiveness of Cymbalta (duloxe - on our discussions above concerning the differ - 17 Naylor, S and Chen, SY. Unraveling Human Complexity tine- treatment for depression) only applies for 1- ences between personalised (N-of-1 model) versus and Disease with Systems in-9 patients, Copaxane (glatiramer acetate – mul - precision (1-in-N model) medicine that it is more Biology and Personalized tiple sclerosis) is 1-in-16 patients and for Nexium appropriate to refer to them as ‘Precision Medicine Medicine. Personal. Med. 7. (esomeprazole – heartburn) it is 1-in-25 patients 31 . Drugs’. 275-287 (2010). Even more stunning is the report that the widely It is important to note that the physician utilises 18 Waring, SC and Naylor, S. The Silent Epidemic of prescribed class of blockbuster statin drugs, used in the biological marker(s) listed on the drug label in Alzheimer’s Disease: Can the management and treatment of elevated choles - prescribing the Precision Medicine Drug. This Precision Medicine Provide terol levels, is only effective at a 21% response should not be confused with Companion Effective Drug Therapies? J. ratio 32 . Such poor efficacy has led to a reassess - Diagnostic biological markers. There appears to be Precision Med. 4. 38-49 (2016). ment of the clinical trial process 31 . Imagine if a widespread agreement that a Companion 19 Naylor, S. What’s in a Name? The Evolution of ‘P- manufacturing and QA/QC process resulted in Diagnostic is a biomarker(s) used in a specific con - Medicine’. J. Precision Med. 2, your smart phone only working 10-20% of the text that provides biological and/or clinical infor - 15-29 (2015). time in an emergency situation! mation that enables better decision-making about 20 Personalized Medicine The classical form of clinical trials requires the the development and use of a potential drug thera - Coalition (PMC). The Case for compilation of a number of specific measurements py 35 . In recent years the use of Companion Personalized Medicine. (2015). http://www.personalizedmedici from thousands of selected patients. This is a cost - Diagnostics has found broad applicability in clini - necoalition.org. ly, time-consuming, risky and inefficient process. In cal trials and are used in the optimised selection of an attempt to enhance clinical trial design and clinical trial patient populations. In particular they potentially account for patient variability, a num - have found use in selection or exclusion of patient Continued on page 14 ber of other approaches have been utilised. A ‘bas - groups for treatment with that particular drug in ket’ clinical trial utilises a specific biomarker, often determining responders and non-responders to the

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therapy, as well as early indications of adverse tox - London) reported that some human breast cancers icological effects 35,36 . manifested overexpression of the HER2 gene, as well as the protein product her-2, resulting in a Case studies of Precision Medicine Drugs poor prognosis for the patient. Gullick in conjunc - Herceptin: Herceptin (trastuzumab) is a human - tion with Dr Barnes (Imperial Cancer Fund ised monoclonal antibody and targets the HER-2 Research Unit, Guys Hospital) reported that HER- receptor in breast cancer patients. This drug was 2 (+) tumours were much more aggressive than developed and sold by Genentech/Roche. The FDA HER-2 (-) tumours 37 . The fact that her-2 protein and EMA both approved its use in 1998 and 2000 was present at high concentrations indicated it was respectively for the treatment of breast cancer, but a good target for therapeutic intervention to treat only for patients for HER-2 (+) patients. Herceptin HER-2 positive tumours. Dr Sliwkowski and col - became the first Targeted or Precision Medicine leagues (Genentech) developed a monoclonal anti - Drug to be approved, although at that time such body to target her-2 protein, and the antibody was terminology was not in common usage 37 . ultimately named Herceptin. The development history of Herceptin is instruc - tive in the evolution of Targeted and Precision Gleevec: Gleevec (imatinib) is a 2-phenyl amino Medicine Drugs. In the late 1980s, Professor pyrimidine derivative and acts as a specific Slamon (UCLA) and Professor Gullick (ICR- inhibitor of a number of tyrosine kinase enzymes.

Table 1: Precision Medicine Drugs approved by FDA in 2017. Data taken and adapted from PMC Progress Report 39

BRAND DRUG NAME(S) INDICATION(S) LABEL BIOMARKER

1 Kisqali Ribociclib Advanced breast cancer HR and HER2

2 Bavencio Avelumab Metastatic Merkel cell carcinoma PD-L1 levels

3 Zejula Niraparib Recurrent epithelial ovarian, fallopian BRCA mutation tube or peritoneal cancers

4 Austedo Deutetrabenazine Huntington’s Disease associated CYP2D6 Chorea

5 Ingrezza Valbenazine Tardive dyskinesia CYP2D6

6 Brineura Cerliponase alfa CLN2 type Batten disease TPP1

7 Alunbrig Brigatinib Metastatic non-small cell lung cancer ALK

8 Rydapt Midostaurin Acute myeloid leukaemia FLT3

9 Imfinzi Durvalumab Advanced urothelial carcinoma PD-L1

10 Nerlynx Neratinib maleate Reoccurring breast cancer HER2

11 Vosevi Sofosbuvir, Velpatasvir Hepatitis C HCV genotype Voxilaprevir

12 Idhifa Enasidenib Refractory acute myeloid leukaemia IDH2

13 Mavyret Glecaprevir & Pibrentasvir Hepatitis C HCV genotype

14 Verzenio Abemaciclib Advanced breast cancer HR and HER2

15 Mepsevii Vestronidase Mucopolysaccharidosis type VII MPS VII (Sly syndrome)

16 Hemlibra Emicizumab-kxwh Hemophilia A Factor VIII antibody

Drug Discovery World Summer 2018 13 Precision Medicine

Continued from page 12 The drug was developed and is now sold by there has been a steady and consistent increase over Novartis. The FDA and EMA approved the drug in the past decade as highlighted in Figure 1 . Note that 21 Hood, L and Flores, M. A both the US and Europe respectively in 2001, for the data was obtained from the annual reports pro - Personal View on Systems the treatment of chronic myeloid leukaemia vided by the PMC and summarised in its latest pub - Medicine and the Emergence 34,39 of Proactive P4 Medicine: (CML). However, the drug was approved and thus lications . In addition, three gene therapies were Predictive, Preventive, prescribed only for patients with Philadelphia approved for the first time ever, in the treatment of Personalized and Participatory. chromosome BCR-ABL-positive CML 38 . The jour - acute lymphoblastic leukaemia (Kymriah), large B- New Biotechnol. 29, 613-624 ney of Gleevec began with the observation by cell lymphoma (Yescarta) and retinal dystrophy (2012). Nowell and Hungerford in the early 1960s that a (Luxturna). Finally and of note, the first Precision 22 Redekop, WK and Madsi, D. The Faces of Personalized number of patients diagnosed with CML had an Medicine Drug biosimilar was approved in 2017. Medicine: A Framework for abnormally short chromosome. This characteristic Herceptin (see above) was approved by the FDA in Understanding its Meaning and chromosome was named the ‘Philadelphia chro - 1998, and now in 2017 Ogivri (trastuzumab) was Scope. Value in Health. 16, S4- mosome’ after their home city. Additional research approved as a biosimilar for HER-2 (+) breast can - S9 (2013). revealed that 95% of patients with CML had this cer 39 . 23 Christensen, CM, Grossman, MD and Hwang, J. unique chromosomal marker. Subsequently, Last year was also pivotal for the number of The Innovator’s Prescription: A Heisterkamp demonstrated that when the marketed Precision Medicine Drugs that were Disruptive Solution for Health Philadelphia chromosome is formed the result pro - approved for new indications. They included Care. McGraw-Hill, New York, duces a fusion gene labelled BCR-ABL. This ‘new’ Revlimid (lenalidomide), Ibrance (palbociclib), NY, USA. (2009). gene produces a fusion protein, abl with bcr Tecentriq (atezolizumab), Kalydeco (ivacaftor), 24 US National Research Council. Toward Precision (breakpoint cluster region), termed bcr-abl which Zykadia (ceritinib), Opdivo (nivolumab), Zelboraf Medicine: Building a was recognised as a potential disease specific, drug - (vemurafenib), Alecensa (alectinib), Adcetris (bren - Knowledge Network for gable target 38 . tuximab vedotin), Sprycel (dasatinib), Sovaldi Biomedical Research and a Dr Druker (Oregon Health and Science (sofosbuvir), Bosulif (bosutinib), Perjeta (per - New Taxonomy of Disease. US University) and Dr Lydon (then Ciba-Geigy tuzumab) and Tasigna (nilotinib) for “new molec - National Academies Press, 39 Washington DC USA (2011). Pharmaceuticals which merged with Sandoz to cre - ularly defined subsets of patients” . Dr Janet http://www.nap.edu/catalog/13 ate independent entity Novartis in 1996) investi - Woodcock, the Director of CDER, stated that: 284/toward-precision- gated the druggability of the fusion protein bcr-abl. “[These expanded] approvals point to an encour - medicine-building-a- The rationale was that patients with CML would aging future for ‘precision medicine’ – an approach knowledge-network-for- have the BCR-ABL gene and hence the fusion pro - for disease treatment that tailors medical therapies, biomedical-research. 25 Institute for Precision tein bcr-abl, conferring highly specific efficacy. One including medications, to the needs of individual Medicine. 2015. such drug candidate, known then as STI-571, later patients 39 .” http://ipm.weill.cornell.edu/abo renamed Imatinib, inhibited bcr-abl by binding In another watershed moment, the FDA ut/definition. proximal to the ATP binding site. This caused a approved the Precision Medicine Drug Keytruda 26 An, G and Vodovotz, Y. conformational change in the enzyme resulting in a (pembrolizumab) for the expanded indications of What is ‘Precision Medicine’ – And Can it Work? Elsevier ‘self-inhibited conformation’, and thus curtailment patient treatment with unresectable or metastatic Connect March 9th (2015). of activity. In the first Phase I clinical trial of the microsatellite instability-high (MSI-H) or mis - http://www.xconomy.com/nati drug, the majority of patients went into remission, match-repair deficient (dMMR) solid tumours 40 . onal/2013/02/04/whats-in-a- and even five years later >98% were still in remi - The groundbreaking approval was predicted on name-a-lot-when-it-comes-to- sion 38 . This mechanism-based approach led to yet the fact that only the presence of a specific precision-medicine/. 27 Zhang, XD. Precision another successful Targeted/Precision Medicine biomarker was required, and not a conventionally Medicine, Personalized Drug to enter the market. defined disease indication. This clinical trials data Medicine, Omics and Big Data: that afforded such an outcome consisted of 15 dif - Concepts and Relationships. Current perspectives of Precision Medicine Drugs ferent conventional oncological indications! This is Pharmacogenomics & Last year (2017) the Center for Drug Evaluation in stark contrast to traditional oncology drugs that Pharmacoproteomics. 6, (2015). e14 doi: 10,4172/2153- and Research (CDER) at the FDA approved 46 have been approved for treatment of specific can - 0645. 1000e144. NMEs. However, 16 of them were classified as cers located in specific organs and/or tissues in the 28 Yensen, J and Naylor, S. The Precision Medicine Drugs by the PMC, representing body. This is an exciting harbinger for the future of Complementary Iceberg Tips an annual high of ~35% of total NMEs approved 39 . Precision Medicine Drugs and the impact they will of Diabetes and Precision These are all listed in Table 1 , and it is noteworthy have on the quality of therapies offered patients. Medicine. J. Precision Med. 3; 39-57 (2016). that almost 50% of these drugs (seven out of 16) 29 Millner, LW and Strotman, were for disease indications other than oncology. Conclusions LN. The Future of Precision This was the highest percentage yet reported of In the early 2000s one of us (Dr Stephen Naylor) Medicine in Oncology. Clin. Precision Medicine Drugs approved by the FDA in formed a personalised medicine company, Lab. Med. 36, 557-573 (2016). any one year. In 2005 only 5% of approved drugs Predictive Physiology and Medicine Inc. The com - Continued on page 16 were classified as Precision Medicine Drugs, but pany provided a patient’s predictive molecular

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Continued from page 14 profile in areas such as cardiovascular and neuro - he is the Founder, Chairman and CEO of logical health and wellness. At that time there was MaiHealth Inc, a systems/network biology level 30 National Institutes of a great deal of focus on providing individual tools diagnostics company in the health/wellness and Health. Understanding for the prevention, prediction and diagnosis of dis - precision medicine sector. He was also the Founder, Precision Medicine in Cancer Treatment. ease states. However, there was little progress on CEO and Chairman of Predictive Physiology & https://www.cancer.gov/about- the impact of personalised medicine in DDD, but Medicine (PPM) Inc, one of the world’s first per - cancer/treatment/types/precisi significant discussion about how the costly, time- sonalised medicine companies. He serves also as an on-medicine. consuming and risky DDD process could provide Advisory Board Member of CureHunter Inc, a 31 Schork, NJ. Personalized therapeutic drugs for individual patients. The con - computational biology drug discovery company, Medicine: Time for One- Person trials. Nature 520, 609- clusions at the time were that such efforts were and as a business adviser to the not-for-profit 611 (2015). prohibitively expensive and economically unfeasi - Cures Within Reach. In the past he has held pro - 32 Leucht, S, Helfer, B, ble. However the advent of precision medicine and fessorial chairs in Biochemistry & Molecular Gartlehner, G and Davis, JM. its focus on the grouping and identification of sub- Biology; Pharmacology; Clinical Pharmacology How Effective are Common populations (1-in-N model), as well as the tools to and Biomedical Engineering, all at Mayo Clinic in Medications: A Perspective Based on Meta-Analyses of identify such populations led to the concept and Rochester, MN, USA. He holds a PhD from the Major Drugs. BMC Medicine implementation of Precision Medicine Drug dis - University of Cambridge (UK), and undertook a 13, 253-258 (2015). covery and development. In 2005 only 5% of all NIH-funded fellowship at MIT located in the 33 Pritchard, D. Personalized drugs approved by the FDA were Precision ‘other’ Cambridge, USA. Address correspondence Medicine at FDA: 2016 Medicine Drugs. Last year that percentage had to him at [email protected]. Progress Report. J. Precision Med. 8, 74-75 (2017). risen to an all time high of 35% ( Table 1 ), and in 34 PMC. The Personalized 2018 is predicted to go even higher. The pharma - Medicine Report: 2017- ceutical sector has recognised the value of such an Opportunity, Challenges and approach, and it is clear that Precision Medicine the Future. http://www. Drugs are here to stay. They are indeed a reality personalizedmedicinecoalition. org/Userfiles/PMC-Corporate/ and not a pleonasm! file/The-Personalized- Medicine-Report1.pdf (2017). Acknowledgements 35 Naylor, S and Cole, T. We thank Dr Daryl Pritchard, Senior Vice-President Overview of Companion for Science Policy at the Personalized Medicine Diagnostics in Pharmaceutical Industry. Drug Discov. World Coalition, for helpful comments and correspon - Spring Edition. 67-76 (2010). dence during this manuscript preparation. DDW 36 Naylor, S and Cole, T. Companion Diagnostics in Pharmaceutical Industry- Part Dr Urban A. Kiernan is a Co-Founder, CEO and II Business Models. Drug Discov. World Summer Edition. Board Director of iMetabolic Biopharma 61-72 (2010). Corporation, a biopharmaceutical company that is 37 Herceptin developing precision medicine drugs for the treat - http://scienceblog.cancerresear ment of obesity-related diseases. He has almost 20 chuk.org/2013/09/20/counting- years of industrial experience in the biotechnology copies-her2-and-the- development-of-herceptin/. and life sciences fields. In the past he served as a 38 NIH/NCI. How Imatinib Global Business Development Manager within the Transformed Leukemia Laboratory Consumables Division of Thermo Treatment and Cancer Fisher Scientific (Waltham, MA). He previously Research served as the Director of Biomarker Discovery and https://www.cancer.gov/researc h/progress/discovery/gleevec. a Principal Investigator while tenured with Intrinsic 39 PMC. Personalized Bioprobes, Inc (based in Tempe, AZ). He has a PhD Medicine at the FDA: 2017 in Bio-Analytical Chemistry from the Department Progress Report. http://www. of Chemistry at Arizona State University. personalizedmedicinecoalition. org/Userfiles/PMC-Corporate/ file/PM_at_FDA_2017_Progres Dr Stephen Naylor is Co-Founder, COO and s_Report.pdf (2018). Board Chairman of iMetabolic Biopharma 40 Jørgensen, JT. When Corporation. He is also the Co-Founder, CEO and Biomarkers Define a Drug Board Chairman of ReNeuroGen LLC, a virtual Indication. Expert Rev. Mol. pharmaceutical company developing therapies for Diagnostics. 4, 315-317 (2018). the treatment of neurological diseases. In addition,

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