Precision Medicine

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21 Hood, L and Flores, M. A Personal View on Systems Medicine and the Emergence of Proactive P4 Medicine: Predictive, Preventive, Personalized and Participatory. New Biotechnol. 29, 613-624 (2012). 22 Redekop, WK and Madsi, D. The Faces of Personalized Medicine: A Framework for Understanding its Meaning and Scope. Value in Health. 16, S4- S9 (2013). 23 Christensen, CM, Grossman, MD and Hwang, J. The Innovator’s Prescription: A Disruptive Solution for Health Care. McGraw-Hill, New York, NY, USA. (2009). 24 US National Research Council. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. US National Academies Press, Washington DC USA (2011). 284/toward-precision- medicine-building-a- knowledge-network-for- biomedical-research. 25 Institute for Precision Medicine. 2015. ut/definition. 26 An, G and Vodovotz, Y. What is ‘Precision Medicine’ – And Can it Work? Elsevier Connect March 9th (2015). onal/2013/02/04/whats-in-a- name-a-lot-when-it-comes-to- precision-medicine/. 27 Zhang, XD. Precision Medicine, Personalized Medicine, Omics and Big Data: Concepts and Relationships. Pharmacogenomics & Pharmacoproteomics. 6, (2015). e14 doi: 10,4172/2153- 0645. 1000e144. 28Yensen, J and Naylor, S. The Complementary Iceberg Tips of Diabetes and Precision Medicine. J. Precision Med. 3; 39-57 (2016). 29 Millner, LW and Strotman, LN. The Future of Precision Medicine in Oncology. Clin. Lab. Med. 36, 557-573 (2016).

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The drug was developed and is now sold by Novartis. The FDA and EMA approved the drug in both the US and Europe respectively in 2001, for the treatment of chronic myeloid leukaemia (CML). However, the drug was approved and thus prescribed only for patients with Philadelphia chromosome BCR-ABL-positive CML38. The jour- ney of Gleevec began with the observation by Nowell and Hungerford in the early 1960s that a number of patients diagnosed with CML had an abnormally short chromosome. This characteristic chromosome was named the ‘Philadelphia chro- mosome’ after their home city. Additional research revealed that 95% of patients with CML had this unique chromosomal marker. Subsequently, Heisterkamp demonstrated that when the Philadelphia chromosome is formed the result pro- duces a fusion gene labelled BCR-ABL. This ‘new’ gene produces a fusion protein, abl with bcr (breakpoint cluster region), termed bcr-abl which was recognised as a potential disease specific, drug- gable target38. Dr Druker (Oregon Health and Science

University) and Dr Lydon (then Ciba-Geigy Pharmaceuticals which merged with Sandoz to cre- ate independent entity Novartis in 1996) investi- gated the druggability of the fusion protein bcr-abl. The rationale was that patients with CML would have the BCR-ABL gene and hence the fusion pro- tein bcr-abl, conferring highly specific efficacy. One such drug candidate, known then as STI-571, later renamed Imatinib, inhibited bcr-abl by binding proximal to the ATP binding site. This caused a conformational change in the enzyme resulting in a ‘self-inhibited conformation’, and thus curtailment of activity. In the first Phase I clinical trial of the drug, the majority of patients went into remission, and even five years later >98% were still in remi- sion38. This mechanism-based approach led to yet another successful Targeted/Precision Medicine Drug to enter the market.

Current perspectives of Precision Medicine Drugs Last year (2017) the Center for Drug Evaluation and Research (CDER) at the FDA approved 46 NMEs. However, 16 of them were classified as Precision Medicine Drugs by the PMC, representing an annual high of ~35% of total NMEs approved39. These are all listed in Table 1, and it is noteworthy that almost 50% of these drugs (seven out of 16) were for disease indications other than oncology. This was the highest percentage yet reported of Precision Medicine Drugs approved by the FDA in any one year. In 2005 only 5% of approved drugs were classified as Precision Medicine Drugs, but

there has been a steady and consistent increase over the past decade as highlighted in Figure 1. Note that the data was obtained from the annual reports pro- vided by the PMC and summarised in its latest pub- lications34,39. In addition, three gene therapies were approved for the first time ever, in the treatment of acute lymphoblastic leukaemia (Kymriah), large B- cell lymphoma (Yescarta) and retinal dystrophy (Luxturna). Finally and of note, the first Precision Medicine Drug biosimilar was approved in 2017. Herceptin (see above) was approved by the FDA in 1998, and now in 2017 Ogivri (trastuzumab) was approved as a biosimilar for HER-2 (+) breast can- cer39. Last year was also pivotal for the number of

marketed Precision Medicine Drugs that were approved for new indications. They included Revlimid (lenalidomide), Ibrance (palbociclib), Tecentriq (atezolizumab), Kalydeco (ivacaftor), Zykadia (ceritinib), Opdivo (nivolumab), Zelboraf (vemurafenib), Alecensa (alectinib), Adcetris (bren- tuximab vedotin), Sprycel (dasatinib), Sovaldi (sofosbuvir), Bosulif (bosutinib), Perjeta (per- tuzumab) and Tasigna (nilotinib) for “new molec- ularly defined subsets of patients”39. Dr Janet Woodcock, the Director of CDER, stated that: “[These expanded] approvals point to an encour- aging future for ‘precision medicine’ – an approach for disease treatment that tailors medical therapies, including medications, to the needs of individual patients39.” In another watershed moment, the FDA

approved the Precision Medicine Drug Keytruda (pembrolizumab) for the expanded indications of patient treatment with unresectable or metastatic microsatellite instability-high (MSI-H) or mis- match-repair deficient (dMMR) solid tumours40. The groundbreaking approval was predicted on the fact that only the presence of a specific biomarker was required, and not a conventionally defined disease indication. This clinical trials data that afforded such an outcome consisted of 15 dif- ferent conventional oncological indications! This is in stark contrast to traditional oncology drugs that have been approved for treatment of specific can- cers located in specific organs and/or tissues in the body. This is an exciting harbinger for the future of Precision Medicine Drugs and the impact they will have on the quality of therapies offered patients.

Conclusions In the early 2000s one of us (Dr Stephen Naylor) formed a personalised medicine company, Predictive Physiology and Medicine Inc. The com- pany provided a patient’s predictive molecular

Drug Discovery World Summer 2018

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