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Drug discovery in renal disease—towards a more efficient framework

Nature Reviews Nephrology volume 10, pages 290–296 (2014)Cite this article

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Abstract

The time and cost involved in bringing new drugs to the market hamper their approval. This problem is especially apparent in the case of renal diseases. Efficient drug research requires an a priori understanding of disease pathophysiology, target validation, rational and efficient drug discovery strategies and early testing of the physiological and pharmacological effects of the new agent in humans. Drug development initiated by academia benefits from international research networks and relies on internationally acceptable high-quality nonclinical data packages and bulk investigational drugs. Academics should, therefore, better understand pharmaceutical practice regulations and novel, efficient drug-development strategies. Many researchers remain unfamiliar with these areas and should collaborate with regulatory authorities to discover and validate surrogate markers for use in drug development, and to efficiently and effectively maximize the benefits and minimize the adverse effects of new drugs. The Japanese government and regulatory authorities have implemented a framework to encourage such collaborations; extension of this framework beyond its current reach is envisaged.

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Figure 1: Procedures for drug discovery and clinical development.
Figure 2: The PMDA Pharmaceutical Affairs Consultation on Research and Development Strategy.
Figure 3: The role of the Science Board in the regulation of drug discovery in Japan.

References

  1. US Department of Health and Human Services. Innovation or stagnation—challenge and opportunity on the critical path to new medical products. US Food and Drug Administration [online], (2004).

  2. Ashburn, T. T. & Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673–683 (2004).

    Article  CAS  Google Scholar 

  3. US Department of Health and Human Services. CDER approval times for priority and standard NDAs and BLAs calendar years 1993–2008. US Food and Drug Administration [online], (2008).

  4. Levey, A. S. et al. Chronic kidney disease as a global public health problem: approaches and initiatives: a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 72, 247–259 (2007).

    Article  CAS  Google Scholar 

  5. US National Library of Medicine. Clinicaltrials.gov [online], (2014).

  6. Shelton, L. M., Park, B. K. & Copple, I. M. Role of Nrf2 in protection against acute kidney injury. Kidney Int. 84, 1090–1095 (2013).

    Article  CAS  Google Scholar 

  7. de Zeeuw, D. et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492–2503 (2013).

    Article  CAS  Google Scholar 

  8. Zoja, C. et al. Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. Am. J. Physiol. Renal Physiol. 304, F808–8819 (2013).

    Article  CAS  Google Scholar 

  9. Rossing, P. Diabetic nephropathy: could problems with bardoxolone methyl have been predicted? Nat. Rev. Nephrol. 9, 128–130 (2013).

    Article  CAS  Google Scholar 

  10. Reichert, J. M. Trends in development and approval times for new therapeutics in the United States. Nat. Rev. Drug Discov. 2, 695–702 (2003).

    Article  CAS  Google Scholar 

  11. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3, 711–715 (2004).

    Article  CAS  Google Scholar 

  12. Boyd, R. A. & Lalonde, R. L. Nontraditional approaches to first-in-human studies to increase efficiency of drug development: will microdose studies make a significant impact? Clin. Pharmacol. Ther. 81, 24–26 (2007).

    Article  CAS  Google Scholar 

  13. US Department of Health and Human Services. Guidance for industry, investigators, and reviewers: exploratory IND studies. US Food and Drug Administration [online], (2006).

  14. European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Concept paper on the development of a CHMP guideline on the non-clinical requirements to support early Phase I clinical trials with pharmaceutical compounds. European Medicines Agency [online], (2006).

  15. US Department of Health and Human Services. Guidance for industry: M3 (R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. US Food and Drug Administration [online], (2010).

  16. Structural Genomics Consortium (SGC). SGC Oxford. SGC [online], (2014).

  17. Ha, H., Oh, E. Y. & Lee, H. B. The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases. Nat. Rev. Nephrol. 5, 203–211 (2009).

    Article  CAS  Google Scholar 

  18. Izuhara, Y. et al. Inhibition of plasminogen activator inhibitor-1: its mechanism and effectiveness on coagulation and fibrosis. Arterioscler. Thromb. Vasc. Biol. 28, 672–677 (2008).

    Article  CAS  Google Scholar 

  19. Izuhara, Y. et al. A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. J. Cereb. Blood Flow Metab. 30, 904–912 (2010).

    Article  CAS  Google Scholar 

  20. Ibrahim, A. A. et al. Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration. Stem Cells http://dx.doi.org/10.1002/stem.1577.

  21. Tashiro, N. et al. Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice. Blood 119, 6382–6393 (2012).

    Article  CAS  Google Scholar 

  22. Boe, A. E. et al. Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence. Circulation 128, 2318–2324 (2013).

    Article  CAS  Google Scholar 

  23. Huang, W. T. et al. Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor-1 for lung fibrosis. Am. J. Respir. Cell Mol. Biol. 46, 87–95 (2012).

    Article  CAS  Google Scholar 

  24. Ichimura, A. et al. A small molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration. Arterioscler. Thromb. Vasc. Biol. 33, 935–942 (2013).

    Article  CAS  Google Scholar 

  25. University Hospital Medical Information Network (UMIN). UMIN000010686. UMIN Clinical Trials Registry [online], (2013).

  26. International Society of Nephrology (ISN). ISN Nexus Symposium: New era of drug discovery and clinical trials in kidney disease. ISN Nexus [online], (2014).

  27. Robinson, H. M. & Hort, K. Non-communicable diseases and health systems reform in low-and-middle-income countries. Pac. Health Dialog. 18, 179–190 (2012).

    PubMed  Google Scholar 

  28. Braun, M. M. et al. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nat. Rev. Drug Discov. 9, 519–522 (2010).

    Article  CAS  Google Scholar 

  29. US Department of Health and Human Services. Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. US Food and Drug Administration [online], (2013).

  30. IMS Institute for Healthcare Informatics. The global use of medicines: outlook through 2016. Essential Medicines and Health Products Information Portal [online], (2012).

  31. Chakma, J. & Chakma, H. Developing countries can contribute to global health innovation. Nat. Med. 19, 129 (2013).

    Article  CAS  Google Scholar 

  32. Lameire, N. & van Biesen, W. Epidemiology of peritoneal dialysis: a story of believers and nonbelievers. Nat. Rev. Nephrol. 6, 75–82 (2010).

    Article  Google Scholar 

  33. Li, P. K. et al. Increased utilization of peritoneal dialysis to cope with mounting demand for renal replacement therapy–perspectives from Asian countries. Perit. Dial. Int. 27 (Suppl. 2), S59–S61 (2007).

    PubMed  Google Scholar 

  34. Prentice, R. L. Surrogate endpoints in clinical trials: definition and operational criteria. Stat. Med. 8, 431–440 (1989).

    Article  CAS  Google Scholar 

  35. Lambers Heersprink, H. J. et al. Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan Diabetic Nephropathy Trial (IDNT). Am. J. Kidney Dis. 63, 244–250 (2014).

    Article  Google Scholar 

  36. Burris, H. A. 3rd et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).

    Article  CAS  Google Scholar 

  37. Ministry of Justice, Japan. Pharmaceutical Affairs Act. Japanese Law Translation [online], [Japanese] (2009).

  38. PMDA Pharmaceuticals and Medical Devices Agency, Japan. PMDA Updates: August 2011. pmda.go.jp[online], (2011).

  39. PMDA Pharmaceuticals and Medical Devices Agency, Japan. PMDA's efforts in medicinal area. pmda.go.jp[online], (2013).

  40. PMDA Pharmaceuticals and Medical Devices Agency, Japan. Press release: the Pharmaceuticals and Medical Devices Agency (PMDA) convenes the inaugural Science Board meeting. pmda.go.jp[online], (2012).

  41. PMDA Pharmaceuticals and Medical Devices Agency, Japan. The Science Board. pmda.go.jp[online], (2014).

  42. PMDA Pharmaceuticals and Medical Devices Agency, Japan. Press release: human resource exchange with universities and research institutions. pmda.go.jp[online], (2012).

  43. Asahina, Y., Tanaka, A., Uyama, Y., Kuramochi, K. & Maruyama, H. The roles of regulatory science research in drug development at the Pharmaceuticals and Medical Devices Agency of Japan. Therapeutic Innovation & Regulation Science 47, 19–22 (2013).

    Article  Google Scholar 

  44. Fuchs, T. C. & Hewitt, P. Biomarkers for drug-induced renal damage and nephrotoxicity—an overview for applied toxicology. AAPS J. 13, 615–631 (2011).

    Article  CAS  Google Scholar 

  45. Vaidya, V. S., Ramirez, V., Ichimura, T., Bobadilla, N. A. & Bonventre, J. V. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am. J. Physiol. Renal Physiol. 290, F517–F529 (2006).

    Article  CAS  Google Scholar 

  46. Donovan, K. L., Coles, G. A. & Williams, J. D. An ELISA for the detection of type IV collagen in human urine—application to patients with glomerulonephritis. Kidney Int. 46, 1431–1437 (1994).

    Article  CAS  Google Scholar 

  47. Dieterle, F. et al. Renal biomarker qualification submission: a dialog between the FDA–EMEA and Predictive Safety Testing Consortium. Nat. Biotechnol. 28, 455–462 (2010).

    Article  CAS  Google Scholar 

  48. Hoffman, J. M., Gambhir, S. S. & Kelloff, G. J. Regulatory and reimbursement challenges for molecular imaging. Radiology 245, 645–660 (2007).

    Article  Google Scholar 

  49. Prasad, P. V., Edelman, R. R. & Epstein, F. H. Noninvasive evaluation of intrarenal oxygenation with BOLD MRI. Circulation 94, 3271–3275 (1996).

    Article  CAS  Google Scholar 

  50. Takasawa, M. et al. Imaging of brain hypoxia in permanent and temporary middle cerebral artery occlusion in the rat using 18F-fluoromisonidazole and positron emission tomography: a pilot study. J. Cereb. Blood Flow Metab. 27, 679–689 (2007).

    Article  Google Scholar 

  51. Kaneta, T. et al. Initial evaluation of dynamic human imaging using 18F-FRP170 as a new PET tracer for imaging hypoxia. Ann. Nucl. Med. 21, 101–107 (2007).

    Article  CAS  Google Scholar 

  52. Kaneta, T. et al. Imaging of ischemic but viable myocardium using a new 18F-labeled 2-nitroimidazole analog, 18F-FRP170. J. Nucl. Med. 43, 109–116 (2002).

    CAS  PubMed  Google Scholar 

  53. Rosenberger, C. et al. Adaptation to hypoxia in the diabetic rat kidney. Kidney Int. 73, 34–42 (2008).

    Article  CAS  Google Scholar 

  54. Izuhara, Y. et al. Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. J. Am. Soc. Nephrol. 16, 3631–3641 (2005).

    Article  CAS  Google Scholar 

  55. Hajduk, P. J. & Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discov. 6, 211–219 (2007).

    Article  CAS  Google Scholar 

  56. Meagher, K. L. & Carlson, H. A. Incorporating protein flexibility in structure-based drug discovery: using HIV-1 protease as a test case. J. Am. Chem. Soc. 126, 13276–13281 (2004).

    Article  CAS  Google Scholar 

  57. Chessari, G. & Woodhead, A. J. From fragment to clinical candidate—a historical perspective. Drug Discov. Today 14, 668–675 (2009).

    Article  CAS  Google Scholar 

  58. Nangaku, M. et al. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia. Arterioscler. Thromb. Vasc. Biol. 27, 2548–2554 (2007).

    Article  CAS  Google Scholar 

  59. Ekins, S., Mestres, J. & Testa, B. In silico pharmacology for drug discovery: applications to targets and beyond. Br. J. Pharmcol. 152, 21–37 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

T. Dan, N. Hirasawa, K. Akahori and K. Miyata contributed to helpful discussions. The authors' work is supported in part by grants from the Ministry of Health, Labour and Welfare of Japan (Initiative to facilitate development of innovative drug, medical devices, and cellular and tissue-based products), from the Japan Science and Technology Agency (Adaptable & Seamless Technology Transfer Program through Target-driven Research and Development) and from the National Institute of Biomedical Innovation (Advanced Research for Medical Products Mininng Programme).

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Authors and Affiliations

  1. United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Toshio Miyata

  2. Pharmaceuticals and Medical Devices Agency, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan

    Tsuyoshi Ando, Hisami Hiragi, Kanako Watanabe & Fumi Yamamoto

  3. Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Galter Pavilion, Suite 3-150, 251 East Huron Street, Chicago, 60611-2908, IL, USA

    Douglas E. Vaughan

  4. Division of Drug Development and Regulatory Science, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan

    Tatsuo Kurokawa

  5. Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan

    Yoshiteru Oshima

  6. Service de Nephrologie, Cliniques Universitaires Saint Luc, Avenue Hippocrate 10, Brussels, 1200, Belgium

    Charles van Ypersele de Strihou

  7. Research Center for Clinical Pharmacology, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Masahiro Takeuchi

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Contributions

All authors wrote the article. T.M., T.A., H.H., K.W., F.Y. and M.T. researched the data and made substantial contributions to discussions of the content. D.E.V., T.K., Y.O. and C.v.Y.d.S. reviewed and/or edited the manuscript before submission.

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Correspondence to Toshio Miyata.

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Miyata, T., Ando, T., Hiragi, H. et al. Drug discovery in renal disease—towards a more efficient framework. Nat Rev Nephrol 10, 290–296 (2014). https://doi.org/10.1038/nrneph.2014.36

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