“Top-Down” “Middle-Out” “Bottom-Up” - mcisb
“Top-Down” “Middle-Out” “Bottom-Up” - mcisb
“Top-Down” “Middle-Out” “Bottom-Up” - mcisb
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Improvement in Primary Clinical Endpoint<br />
“But “But it it works works in in<br />
rodents…”<br />
Constrained by Human Data Rodent-<br />
Like Human<br />
Adriano M Henney PhD<br />
Rodent<br />
Data<br />
Alternative Hypothesis<br />
• Limited data to support<br />
• Possible and testable<br />
System pushed to limits of human<br />
behavior<br />
• Constrained to the edges of normal<br />
clinical response<br />
• Numerous validation protocols no longer<br />
reproducible<br />
• Unlikely, but testable<br />
Impact<br />
1) Company stopped compound<br />
development >1year before competitor<br />
Observed Phenotypes<br />
Target pathway “retuned” to Rodent<br />
Behavior<br />
•Pathway capacity increased<br />
–Inconsistent with human data<br />
•Pathway feedback regulation altered<br />
–Inconsistent with human data<br />
•Relative contribution of redundant<br />
pathways<br />
–Inconsistent with human data<br />
•Lifestyle/environmental factors<br />
–Not representative of humans
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