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New era for drug discovery and development in renal disease

Nature Reviews Nephrology volume 7, pages 469–477 (2011)Cite this article

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Abstract

Drug discovery and development is a lengthy and expensive process. Testing new agents in humans at an early stage could reduce the time and costs involved in identifying drugs that are likely to succeed in clinical studies. New guidance has outlined the concept of exploratory clinical trials, which provide important information on a drug's distribution as well as its physiological and pharmacological effects in humans. This strategy reduces the need for preclinical testing by limiting the dose and duration of exposure to a new drug in humans to below those required by the traditional testing of investigational new drugs. Exploratory, first-in-man studies should provide insights into human physiology and pharmacology, identify therapeutic targets relevant to disease and increase our knowledge of a drug's characteristics. Implementation of a new drug also requires the development of useful biomarkers of disease and of the drug's efficacy, as well as sensitive molecular imaging techniques. In this Review, we outline the benefits of exploratory clinical trials, especially in academia, and provide an overview of the experimental tools necessary for rational drug discovery and development.

Key Points

  • New drug approvals are decreasing and very few drugs are developed for the treatment of kidney disease despite the large number of patients who might benefit from these drugs

  • Understanding the pathophysiology of disease and assessing a drug's effects in humans at an early stage of drug development is important to reduce the time and costs involved in research

  • New guidance has defined the concept of exploratory clinical trials, which involve the administration of a small dose of compound to humans for a limited time

  • Exploratory clinical trials should provide insights into human physiology and pharmacology, identify therapeutic targets relevant to disease and expand our knowledge of a drug's distribution in the kidney

  • The implementation of a new drug requires the identification of biomarkers of the disease and of the drug's effectiveness, as well as development of sensitive molecular imaging techniques

  • Collaboration between regulators and researchers is essential to find more efficient strategies for preclinical and clinical development of a drug

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Figure 1: Traditional process of drug discovery and clinical development.
Figure 2: New framework for drug discovery and development based on exploratory clinical trials.
Figure 3: Relationship between drug dose and response.
Figure 4: Predicted binding modes obtained by docking simulations.
Figure 5: Utility of BOLD-MRI.
Figure 6: Tools for exploratory clinical trials.

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References

  1. US Food and Drug Administration. Challenge and opportunity on the critical path to new medical products [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 Food and Drug Administration. CDER approval times for priority and standard NDAs and new BLAs. Calendar Years 1993–2008 [online], (2009).

  4. 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 

  5. 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 

  6. 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 

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

    Article  CAS  Google Scholar 

  8. US Food and Drug Administration. Guidance for industry, investigators, and reviewers: exploratory IND studies [online], (2006).

  9. European Medicines Agency. Concept paper on the development of a CHMP guideline on the non-clinical requirements to support early phase I clinical trials with pharmaceutical compounds [online], (2006).

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

  11. Karara, A. H., Edeki, T., McLeod, J., Tonelli, A. P. & Wagner, J. A. PhRMA survey on the conduct of first-in-human clinical trials under exploratory investigational new drug applications. J. Clin. Pharmacol. 50, 380–391 (2010).

    Article  Google Scholar 

  12. European Medicines Agency. Position paper on non-clinical safety studies to support clinical trials with a single microdose [online], (2004).

  13. Sugiyama, Y. & Yamashita, S. Impact of microdosing clinical study. Why necessary and how useful? Adv. Drug Deliv. Rev. 63, 494–502 (2011).

    Article  CAS  Google Scholar 

  14. Lappin, G. et al. Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Clin. Pharmacol. Ther. 80, 203–215 (2006).

    Article  CAS  Google Scholar 

  15. European Union Microdose AMS Partnership Programme. Outcomes from EUMAPP—a study comparing in vitro, in silico, microdose and pharmacological dose pharmacokinetics [online], (2008).

  16. 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 

  17. 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 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. 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 

  21. Rondeau, E. et al. Plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies. Clin. Nephrol. 33, 55–60 (1990).

    CAS  PubMed  Google Scholar 

  22. Nakamura, T. et al. The localization of plasminogen activator inhibitor 1 in glomerular subepithelial deposits in membranous nephropathy. J. Am. Soc. Nephrol. 7, 2434–2444 (1996).

    CAS  PubMed  Google Scholar 

  23. Hamano, K. et al. Expression of glomerular plasminogen activator inhibitor type 1 in glomerulonephritis. Am. J. Kidney Dis. 39, 695–705 (2002).

    Article  CAS  Google Scholar 

  24. Matsuo, S. et al. Multifunctionality of PAI-1 in fibrogenesis: evidence from obstructive nephropathy in PAI-1-overexpressing mice. Kidney Int. 67, 2221–2238 (2005).

    Article  CAS  Google Scholar 

  25. Kitching, A. R. et al. Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic glomerulonephritis. J. Am. Soc. Nephrol. 14, 1487–1495 (2003).

    Article  Google Scholar 

  26. Nicholas, S. B. et al. Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Kidney Int. 67, 1297–1307 (2005).

    Article  CAS  Google Scholar 

  27. Huang, Y. et al. A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis. J. Clin. Invest. 112, 379–388 (2003).

    Article  CAS  Google Scholar 

  28. 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 

  29. Goto, J., Kataoka, R. & Hirayama, N. Ph4Dock: pharmacophore-based protein-ligand docking. J. Med. Chem. 47, 6804–6811 (2004).

    Article  CAS  Google Scholar 

  30. 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 

  31. Miyata, T. & de Strihou, C. Y. Diabetic nephropathy: a disorder of oxygen metabolism? Nat. Rev. Nephrol. 6, 83–95 (2010).

    Article  CAS  Google Scholar 

  32. Fine, L. G., Orphanides, C. & Norman, J. T. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int. Suppl. 65, S74–S78 (1998).

    CAS  PubMed  Google Scholar 

  33. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    Article  CAS  Google Scholar 

  34. Marx, J. Cell biology. How cells endure low oxygen. Science 303, 1454–1456 (2004).

    Article  CAS  Google Scholar 

  35. Epstein, A. C. et al. C. Elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).

    Article  CAS  Google Scholar 

  36. Schofield, C. J. & Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 5, 343–354 (2004).

    Article  CAS  Google Scholar 

  37. 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 

  38. Fong, G. H. & Takeda, K. Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ. 15, 635–641 (2008).

    Article  CAS  Google Scholar 

  39. Takeda, K., Cowan, A. & Fong, G. H. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation 116, 774–781 (2007).

    Article  CAS  Google Scholar 

  40. Takeda, K. et al. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 111, 3229–3235 (2008).

    Article  CAS  Google Scholar 

  41. Aragonés, J. et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat. Genet. 40, 170–180 (2008).

    Article  Google Scholar 

  42. Watanabe, D. et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N. Engl. J. Med. 353, 782–792 (2005).

    Article  CAS  Google Scholar 

  43. Shah, S. V., Baliga, R., Rajapurkar, M. & Fonseca, V. A. Oxidants in chronic kidney disease. J. Am. Soc. Nephrol. 18, 16–28 (2007).

    Article  CAS  Google Scholar 

  44. Forbes, J. M., Coughlan, M. T. & Cooper, M. E. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57, 1446–1454 (2008).

    Article  CAS  Google Scholar 

  45. Shuaib, A. et al. for the SAINT II Trial Investigators. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med. 357, 562–571 (2007).

    Article  CAS  Google Scholar 

  46. Bath, P. M. et al. for the NXY-059 Efficacy Meta-analysis in Individual Animals with Stroke Investigators. Effects of NXY-059 in experimental stroke: an individual animal meta-analysis. Br. J. Pharmacol. 157, 1157–1171 (2009).

    Article  CAS  Google Scholar 

  47. Nguyen, T., Sherratt, P. J. & Pickett, C. B. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu. Rev. Pharmacol. Toxicol. 43, 233–260 (2003).

    Article  CAS  Google Scholar 

  48. Kobayashi, M. & Yamamoto, M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid. Redox Signal. 7, 385–394 (2005).

    Article  CAS  Google Scholar 

  49. Leonard, M. O. et al. Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury. FASEB J. 20, 2624–2626 (2006).

    Article  CAS  Google Scholar 

  50. Liu, M. et al. Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int. 76, 277–285 (2009).

    Article  CAS  Google Scholar 

  51. Yoh, K. et al. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells 13, 1159–1170 (2008).

    CAS  PubMed  Google Scholar 

  52. Cho, H. Y. et al. Role of NRF2 in protection against hyperoxic lung injury in mice. Am. J. Respir. Cell Mol. Biol. 26, 175–182 (2002).

    Article  CAS  Google Scholar 

  53. Cho, H. Y., Reddy, S. P., Yamamoto, M. & Kleeberger, S. R. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J. 18, 1258–1260 (2004).

    Article  CAS  Google Scholar 

  54. Shih, A. Y., Li, P. & Murphy, T. H. A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J. Neurosci. 25, 10321–10335 (2005).

    Article  CAS  Google Scholar 

  55. Itoh, K. et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76–86 (1999).

    Article  CAS  Google Scholar 

  56. Wakabayashi, N. et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat. Genet. 35, 238–245 (2003).

    Article  CAS  Google Scholar 

  57. Okada, K. et al. Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems. Biochem. Biophys. Res. Commun. 389, 431–436 (2009).

    Article  CAS  Google Scholar 

  58. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  59. Tong, K. I., Kobayashi, A., Katsuoka, F. & Yamamoto, M. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol. Chem. 387, 1311–1320 (2006).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  61. 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 

  62. 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 

  63. 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 

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

    Article  CAS  Google Scholar 

  65. 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 

  66. Dieterle, F. et al. Monitoring kidney safety in drug development: emerging technologies and their implications. Curr. Opin. Drug Discov. Devel. 11, 60–71 (2008).

    CAS  PubMed  Google Scholar 

  67. Goodsaid, F. M. et al. Novel biomarkers of acute kidney toxicity. Clin. Pharmacol. Ther. 86, 490–496 (2009).

    Article  CAS  Google Scholar 

  68. Kimmelman, J. Ethics at phase 0: clarifying the issues. J. Law Med. Ethics 35, 727–733 (2007).

    Article  Google Scholar 

  69. Braun, M. M., Faraq-El-Massah, S., Xu, K. & Coté, T. R. 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 

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Acknowledgements

We thank N. Hirayama for kindly providing representative pictures of docking simulation, S. Takizawa, T. Honma and T. Yano for helpful discussion, T. Mori for representative pictures of blood oxygen level-dependent MRI, and M. Ishikawa for drawing schema.

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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, 980-8575, Japan

    Toshio Miyata & Katsushi Kikuchi

  2. Clinical Research Center of Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, 980-8574, Sendai, Japan

    Hideyasu Kiyomoto

  3. Service de Néphrologie, Université Catholique de Louvain, Avenue Hippocrate 10, Brussels, 1200, Belgium

    Charles van Ypersele de Strihou

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  1. Toshio Miyata
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Contributions

T. Miyata researched data for the article. All the authors contributed to discussion of the content. T. Miyata and C. van Ypersele de Strihou wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Toshio Miyata.

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Miyata, T., Kikuchi, K., Kiyomoto, H. et al. New era for drug discovery and development in renal disease. Nat Rev Nephrol 7, 469–477 (2011). https://doi.org/10.1038/nrneph.2011.84

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