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A post-apocalyptic world: The need to move beyond the current approaches Although presented in very simplistic terms, the apocalyptic horsemen of the pharma industry are areas that contribute individually and in aggregate to the current low success rates across pharma R&D. For the present discussion, the current phar- maceutical R&D and clinical disease management processes can be roughly grouped together as the ‘current paradigms’. While they represent the cur- rent way(s) of working, these paradigms are fraught with limitations:
Current paradigms that attempt to produce sys- tem-wide changes beyond ‘biological tolerance limits’ or on time scales that ‘overwhelm’ the system will be more strongly resisted and possi- bly limited by biological adaptations designed to keep the system ‘as was’.
Current paradigms that attempt to reverse irre- versible processes will not likely work, as ‘resetting the system’ to initial states (ie predis- ease) is impossible.
Current paradigms that are based on simple lin- ear readouts will likely not adequately predict systems-wide and alinear outcomes. Moreover, current paradigms that attempt to ‘change too much, too quickly’ will nearly always produce additional and unwanted effects (toxicities or other secondary pharmacological effects).
Current paradigms that presume intra-patient variability is small enough to generalise and those that assume simple and linear dosage adjustments (ie varying treatment doses two- to 10-fold) are all that are needed to treat large enough segments of the intended disease popula- tion will likely fail to address the significant uniqueness of the individual patient. Moreover, these will fail to address how the individual’s physiology and disease-load, and thus therapy- requirements, change over time.
Current paradigms that are perceived by patients or trial subjects to operate, or that actually do operate, in an ‘industrial/professional’ manner, or those that do not espouse narrative medicine approaches, will not successfully engage subjects at all levels and will ultimately compromise drug development and post-approval utility.
Because the primary areas of focus in this paper will not be impacted by any extrinsic means and
Drug Discovery World Winter 2011/12
are likely to be rather resistant to fluctuations in other development environments (eg regulatory, political, payer, etc), a radically different approach away from the current paradigms is required.
On towards an ‘evolutionary disease management’ future? Current paradigms predominantly consist of one or a handful of highly-selective and potent pharmaco- logical agents with relatively long pharmacological half lives. The push of the industry during at least the last half-century has been to identify the most potent, longest-lasting selective agents possible, with a very prescriptive set of criterion desired (eg Lipinski’s ‘rule of five’)34,35. Although this has been challenged by some36, in general ‘dirty’ (ie nonse- lective) and low potency agents requiring multiple daily dosing usually do not progress further than early drug discovery5. High potency, selective and long-duration attributes have certainly contributed to increased convenience and dosing frequency- related compliance, and have helped mitigate the risks inherent to agents with diverse sets of actions and higher dose-related limitations (manufacturing, doses required, etc). They may have, however, con- currently brought on significant limitations. For example, although there are correlations there are distinct differences between ligand affinity, potency and efficacy37-39. In addition, barring some excep- tions, for many systems higher-efficacy ligands are associated with a more rapid and extensive devel- opment of tolerance and desensitisation (including receptor internalisation and degradation)40, thus leading to higher subsequent dosing requirements and the manifestation of withdrawal reactions after ligand administration ceases. Historically, the pharmaceutical industry has depended primarily on selective manipulation of critical nodal point targets that were thought to singly ‘reset’ a diseased system back to normal or to prevent further development of disease, ie, low- hanging, but critical, ‘fruit’ (targets). This interpre- tation is now believed to be based on overly sim- plistic hypotheses that have needed extensive revi- sions in order to reconcile the hypotheses with experimental data. For example:
● -adrenergic blockade in the long-term mainte- nance of hypertension may result less in the direct
prevention of G-protein coupled receptor (GPCR) activation by endogenous ligands than it does receptor internalisation, sequestration and interac- tions with other proteins like RGS and GIRK fam- ily members and subsequent heterologous/het- erogenous/pleiotropic effects41,42.
References 1 Cuatrecasas, P. J. Clin. Invest. 2006; 116:2837-42. 2 Johnstone, C, Pairaudeau, G, Pettersson, JA. Drug Discov. Today 2010;
doi:10.1016/j.drudis. 2010.11.005. 3 Paul, SM et al. Nat. Rev. Drug Discov. 2010; 9:203-14. 4Wehling, M. Nat. Rev. Drug Discov. 2009; 8:541-546. 5 Hopkins, AL. Nat. Chem. Biol. 2008; 4:682-690. 6 Mullard, A. Nat. Rev. Drug Discov 2011; 10:82-85. 7 Campbell, J.
http://www.jcf.org/new/ index.php. 8 Four Apocalyptic Horsemen.
http://en.wikipedia.org/wiki/Fo ur_Horsemen_of_the_ Apocalypse 9 Elliott, DE, Urban Jr, JF, Argo, CK, Weinstock, JV. FASEB J. 2000; 14:1848-1855. 10 Grant, B. The Scientist 2011; 25:42-47. 11 Citri, A, Malenka, RC. Neuropsychopharm. 2008; 33:18-41. 12 Füllgrabe, J, Hajji, N, Joseph, B. Cell Death and Diff. 2010; 17:1238-1243. 13 Aron, L, Klein, R. Trends NeuroSci. 2011; 34:88-100. 14 Cai, L, Friedman, N, Xie, XS. Nature 2006; 440:358-362. 15 Houle, D, Govindaraju, DR, Omholt, S. Nat. Rev. Gen. 2010; 11:855-866. 16 Kar, G, Keskin, O, Gursoy, A, Nussinov, R. Curr. Opin. Pharmacol. 2010; 10:715-722. 17 Raj, A, van Oudenaarden, A. Cell 2008; 135:216-226. 18 Renart, A et al. Science 2010; 327:587-590. 19 Silver, RA. Nat. Rev. Neurosci. 2010; 11:474-489. 20 Snijder, B, Pelkmans, L. Nat. Rev. Mol. Cell Biol. 2011; 12:119-125. 21 Thurmond, RL, Gelfand, EW, Dunford, PJ. Nat. Rev. Drug Discov. 2008; 7:41-53. 22 Dodge, ME, Lum, L. Ann. Rev. Pharmacol. Toxicol. 2011; 51:289-310. 23 Rateitschak, K, Wolkenhauer, O. J. Theor. Bio. 2010; 264:334-346. 24 Bruder, CEG et al. Amer. J. Human Genet. 2008; 82:1-9.
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