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25 Eichler, EE et al. Nat. Rev. Gen. 2010; 11:446-450. 26 Nadeau, JH, Lee, C. Nature 2006; 439:798-799. 27 Stranger, BE et al. Science 2007; 315:848-853. 28 Cohn, LD, Becker, BJ. Psychol. Meth. 2003; 8:243-253. 29 Barrett, JC et al. Nat. Gen. 2008; 40:955-962. 30 Myers, KR, Green, MJ. Ann. Int. Med. 2011; 154:129-130. 31 Moerman, DE, Jonas, WB. Ann. Intern. Med. 2002; 136:471-476. 32 Silberman, S. PLoS BLOGS December 22, 2010:
http://blogs.plos.org/neurotribe s/2010/12/22/meet-the-ethical- placebo-a-story-that-heals/. 33Tracey, I. Nat. Med. 2010; 16:1277-1283. 34 Hill, AP, Young, RJ. Drug Discov. Today 2010; 15:648-655. 35 Lipinski, CA, Lombardo, F, Dominy, BW, Feeney, PJ. Adv. Drug Deliv. Rev. 2001; 46: 3-26. 36 Zhang, M-Q. Drug Discov. Today: Technologies 2010; 7:e95-96. 37 Broadley, KJl, Sykes, SC, Davies, RH. Biochem. Pharmacol. 2010; 80: 1537-1545. 38 Colquhoun, D. Br. J. Pharmacol. 1988; 125:923-947. 39 Kenakin, T, Onaran, O. Trends Pharmacol. Scil 2002; 23:275-280. 40 Lopez-Gimenez, JF, Milligan, G. CNS & Neurol. Disorders – Drug Targets 2010; 9:616-626. 41 Whalen, EJ, Rajagopal, S, Lefkowitz, RJ. Trends in Mol. Med. 2010;
doi:10.1016/
j.molmed. 2010.11.004. 42 Wieland, T, Lutz, S, Chidiac, P. Curr. Opin. Pharmacol. 2007; 7:201-207. 43 Heinrich, R, Neel, BG, Rapoport, TA. Mol. Cell 2002; 9:957-970. 44 Rovira, X, Pin, J-P, Giraldo, J. Trends Pharmacol. Sci. 2009; 31:15-21. 45Vaidehi, N, Kenakin, T. Curr. Opin. Pharmacol. 2010; 10:775-781. 46 van Wageningen, S et al. Cell 2010; 143:991-1004.
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(endogenous metabolite) chemical backbones may have more ‘natural’ physicochemical and pharma- cological actions and are metabolised locally (intracellularly) at rates and by systems more sim- ilar to endogenous ligands50,51. The more tradi- tional developmental pursuit, therefore, of ligands with extremely long half-lives and/or activation/deactivation/metabolism/excretion kinetics that allow for single daily or less frequent dosing requirements may serve a ‘dosing conven- ience’ purpose but at the expense of inappropriate physiological actions. Finally, the cognitive-behavioural and somato- physiological changes that are necessary for long- term health/disease mitigation might best be thought of in more extended timeframes than pre- viously. For example, significant caloric restriction diets can prompt overt conditions (hyperammone- mia) leading to chronic changes (chronic inflam- matory disorders and epimutations), sequelae that are not mirrored when more gradual, but even more extensive, restrictions are established52,53. Likewise and extremely important, abrupt initia- tion or withdrawal of therapeutic agents from nearly every disease area studied, can produce pro- found physical and psychiatric sequalae, while more gradual onset and withdrawal paradigms of the same agents are not necessarily observed. Based on these lines of evidence, pharmacologi- cal manipulations with more subtle and directed pressures, primarily ones that offer full inclusion of the patient and their wider ‘world,’ might be expected to better guide diseased biological sys- tems toward healthy or disease-managed states: a process that could be described as ‘evolutionary disease management’. Similar to traditional evolu- tionary changes (Darwinian evolution), subtle pressures over more extended periods of time allow biological systems to not just adapt to new environments, but to eventually become quite rad- ically changed. Moreover, if more salutatory (ie, step-jump) evolution is needed, subtle (but suba- cute) changes in a person could occur that en masse set up the person for a ‘jump change’ (from, say, disease to health). Changes brought on too strongly or too quickly tend to overwhelm the sys- tem and result in either systems-wide collapse or a concerted ‘counter attack’ by the system to keep it unchanged. Occasionally, strongly concerted efforts are precisely what are required to prevent a damaged part of the system from shutting down the entire system (eg systemic infection or outright ablation of aggressive cancer cells). More often, though, the biological system has been exposed to small but progressive changes over the course of
years to decades and strong manoeuvres might be able to force the system out of its ‘current state’ (disease or pre-disease) but at great cost. This approach would represent a dramatic shift in nearly every established part of drug discovery, development, marketing and business approach, as well as disease treatment paradigms, payer systems and regulatory best practices. All of which could be seen as threats to be fought.
Heading into paradise – or at least a more paradisiacal place – may require multiple battles?
The complete harmonisation of the areas (ie, the five horsemen) discussed, the evolutionary disease management paradigm and the current state and approach of the pharmaceutical industry seems to be quite difficult, if not outright impossible. For sure there are significant differences on both philo- sophical and practical levels among them. Any attempt to address them without an open and hon- est dialogue about their impact on the current par- adigms would be ill-founded and would certainly be a recipe for failure. In fact, their impacts across the entire value chain would need to be evaluated and a deep understanding about how they are interconnected would be a required early step. These differences should not prevent us from con- fronting them head-on, battle-ready and prepared to struggle through a hard slog.
“So many of our dreams at first seem impossible, then they seem improbable, and then when we summon the will, they soon become inevitable.” Christopher Reeve
A preparatory (pre-battle) first step to be con- ducted may be to solidify the tenet that what was defined as impossible in the past may be now defined as only improbable or even commonplace in the future. The evolution from our past to our present may have been methodically carried out, or may have been due to a ‘random’ series of events. The cause is less important than the outcome for those factors leading us to our current state. The influencing of the future, however, should neither be left to providence nor chance, but as a conse- quence of conscious action based on experience and ingenuity.
As is true for numerous issues in life, simply starting is more important than the actual starting point. The five horsemen highlight that nearly every aspect of drug discovery, development and business process is open to challenge, but is there a better first battle to be waged? There may, indeed,
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