Personalised Medicine
tion7, increase in soluble CSF level from gamma secretase inhibition8, or mitotic cells fol- lowing Aurora A kinase inhibition9. A significant difficulty with mechanistic biomarkers, however, is that the required degree of change in these markers is often derived from animal models of disease and as such lack the translatability to the human condition.
Disease relevance Figure 1 Conceptualising the
multimechanistic contributions to disease. There are multiple mechanistic pathways that can result in disease classified by clinical phenotype (eg, tumour type, atherosclerosis, diabetes, etc). Reconfiguring how we think about disease and
developing new treatments is crucial to achieving meaningful breakthroughs in patient
health. Consider that different mechanistic wedges represent Mrs S and Mrs T. Treating them with a mismatched drug that does not influence the
dominant, respective causal mechanism of their diabetes mellitus will likely result in a negative clinical result. These ‘apparent’ failures will also
force the selection of more regulatory (biological)
mechanisms that may be less relevant to the disease. As a result, the clinical
manifestation of their disease, but not its cause, is treated
In consideration of the major factors required for Phase II success with novel mechanisms of action, several possibilities warrant discussion. These include: 1. The investigational agent did not yield the required pharmacology; 2. The biological target or mechanism is not relevant to the disease; and 3. The biological target is correct, but only for a subset of patients.
Inadequate pharmacology
The first and most obvious reason that an investi- gational drug may fail to yield an efficacious response in Phase II is that the agent did not exert the desired pharmacology. That could be due to several causes, including suboptimal drug levels from high clearance, low bioavailability, high pro- tein binding, or safety issues that restrict dosing. Some of these issues have been obviated by modern drug metabolism, pharmacokinetic and safety test- ing methods undertaken in the preclinical phase of drug development.
Despite achieving predicted drug exposure, however, the in vivo human pharmacology still may not reflect the preclinical testing regimens, including cell lines or animal pharmacology. To address this, many clinical studies strive to incor- porate mechanistic (pharmacodynamic) biomark- ers, to ensure that the biological target is being manipulated. These biomarkers are distinct from efficacy biomarkers. Examples include: increase in circulating GLP-1 level with DPP-IV inhibition6, an increase in HDL level following CETP inhibi-
48
The second consideration for the lack of demon- strable Phase II efficacy is that the biological tar- get or mechanism is not relevant to the disease under study. If the target is not relevant in humans, then how was it selected? In general, the rationale for selecting that target for prosecution is multifaceted, including input from human genetics, observational clinical studies (eg, a measure related to the target is abnormal), and animal experiments. In most therapeutic areas, however, concrete decisions regarding the pursuit of a specific programme often hinge on animal models of disease. Examples of animal models of disease include: Apo E knockout mouse for ather- osclerosis; the rat conditioned avoidance behav- iour model of schizophrenia; the mouse tumour transplant model, or the ob/ob mouse model of diabetes10-13. From these models, partial correc- tion of the abnormality may be achieved by knocking out or overexpressing a specific gene (biological target) or through the use of a phar- macological tool. A positive outcome, signalling potential human efficacy with a pharmacological agent is a ‘go forward’ result, ie, the project team is armed with evidence that the exerted pharma- cology will yield a salutary outcome in people. Yet the problem with animal models of disease is that they very often do not reflect the human cir- cumstance (eg, avastimibe in animal models of atherosclerosis, among others)14-18. If they did, then one would expect that success rates in Phase II would be significantly higher than 20%. Intuitively, this is not surprising, as the physiolo- gy and associated pharmacology of the test species is likely to be very different from that of the human despite similar and apparent clinical manifestations (eg, elevated glucose). Thus, a pos- itive animal model result might be due to a target that is relevant to the animals per se, and much less so to humans.
It is important to acknowledge the potential value of animal models of disease to identify a promising target for future exploration in humans. That is, animal models of disease can lead to new ideas that can be explored in humans.
Drug Discovery World Summer 2011
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