project progression monitoring and compound ......data driven decisions about 90 to 95 % of front...

Bruno Filoche-Rommé, Ph.D

Sr. Research ScientistSanofi Research CenterVitry sur Seine, FranceF-94403

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Project progression monitoring and compound multiparametric scoring: the key to unbiased data

driven decisions?

TibcoSpotfire user group meeting, Basel, nov. 2016

Data Driven Decisions

● Experiment to decision● Experiment● Primary data● Information● Knowledge● Wisdom (?)

● Decision● Definitely after some information has been

derived from data• data alone is not enough to take

decision• Bringing context to data yield decisions

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The data to wisdom pyramid

Borrowed from wikipedia



● Questions: Day to day life in projects● Which chemical series do we select?● Is the phenyle optimum or do we need pyridin?● Which compound to choose for 7 days rat tox?● Is potency preferable over properties?● To wich extent a 15% increase in solubility can help to achieve enough exposure, ensuring

suitable pharmacological effect with required safety margin?

● Some answers● Series1; stop S2 but keep exploring S4● Neither, we need pyrimidin● Among CPD_D; G and Y; they are all well in the criteria● No; we can even relax criteria down to 100nM if we maintain the property profile● no need for 15% increase, we know 5 is enough.

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Typical Q and A from real life projects



● Daily monitoring of data and derive as much information as possible ● Anticipate questions● Prepare and structure the data

• support question formalism• Provide visual that answer the question(s)

• If the question is about Chem Series, have a mean to put the series in context…● Set up the right tools

• Project dynamic dashboard ? yes• Static colored excel speeadsheet ? no

● Think about the questions that may come in the way and have data prepared and structured to answer them.

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How to answer these?



● About 90 to 95 % of front screen data are captured (primary)● Project specifics : Target related

• Potency• Specificity,

• Target isoform,• metabolism enzymes, safety enzymes

• MOAs• Functional assays

● Compound Specifics• Structre based properties

• Solubility, crystalline state• eADME

● Some exceptions (no primary, only meta data)● In life experiments

• Pk screens, pharmacology experiments

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Foreword : Small molecules project data

Image of dashboard



● Materialisation of the objective: The blue print● A set of predefined ranges or values describing the overall

profile of the targeted compound• Optimal desirable value, sub optimal yet acceptable

values, off range ● Scope

• Target related properties• Compound related properties• Functional• Safety• Therapeutic Index, as a combo of the above

• Ex. trying to compensate low solubility by higherdosing may result in toxicity induced by saturation of the efflux mechanism, regardless of the potency…

• Property• Functional efficiency

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The Blue Print

Image of blue print

Time Travelling DeLorean Blue PrintPr. Emmett L. Brown1640, riverside St.Hill Valley, CA, USACa 1984



● Why?● Keep an exhaustive eye on the project assets● Identify strenght and weakness

• Show how the former stay strong• Highlight how the later disapear or evolve

● Document the SAR• How the team controls it (not the other way around)• Differentiates outliers from the trends• Confirm when the ouliers becomes a trend

● Anticipate the SAR• Linearity domain• SAR cliffs

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Monitoring Progression to (or away from) BP

As time goes, target potency increasewhile offtarget potency decreases. Is this truly the right optimisation direction?



● Why? (again)● To convince and negociate !!

● To convince● That decisions are being taken

• Killing a reccurrent sub optimaml series is aways profitable● By showing relevant progression in

• agreed upon domains on • agreed upon time frame

● To negociate● Optimization time

• Sr management dont give time away to project teams, they invest it• However, like every other businessman, they are likely to invest if the ROI is likely• A well controlled and documented project progression is key in this matter.

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Monitoring Progression to (or away from) BP



● Remove the appropriation/identification enabling features● Get rid of structure● Get rid of ids● Focus on compound profile

• Display random ids to support argumentation• Disclose true IDS and Structure when agreement on profile is obtained.

• Enough compounds meeting the criteria ?• Adjust?• Select?• Dicscuss?• Decide?

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Removing the bias



● Sanofi Standard SAR tool are used● Origin: Cloud and/or on premise

• Ad hoc addition of data is mandatory (knime)● Daily refresh off assets

• Chemistry is still run outside Spotfire (sorry guys!)• Series, sub series, key param.• MMP, SAR cliffs etc…(will not shown today)

● Data table(s) are unpivoted, annotated and fed to Spotfire• Also possible from oracle as you know…

● Spotfire hosts• Blue print definition

• 100% interactive for 20 properties to select • hard coded for now, but will improve

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Data reshaping and exploitation: the key to success



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The gears behind the screen



● Hopefully the demo syndrom will not strike!

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Demo



● Thanks to the organizing comitee for inviting me here. Apologies for being late in submitting infos.

● Thanks to my fellow Researchh Scientist and Data Science mate Y.Foricher (at Vitry as well) for usefull and enlighting discussions about al this; thx to my boss for allowing me comming here to speak.

● Thanks to you, dear audience for your attention

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Acknowledgement

project progression monitoring and compound ......data driven decisions about 90 to 95 % of front...

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