How my Yale PhD prepared me for a career in the pharmaceutical industry

1. Novartis Institutes of Biomedical Research How my Yale PhD prepared me for a career in the pharmaceutical industry Amy C.S. White, PhD CardiovascularandMetabolicDisease August 7, 2019

2. Graduate school research Business Use Only

3. Post-doctoral research Business Use Only

4. The challenge of drug research and development • Time consuming - 10 to 15 years • Expensive ~ $2.6 billion USD per New Molecular Entity • Risky - less than 5% success rate Business Use Only

5. How do we reach the patient? Proof of Concept (PoC) Clinical Study Clinical Trials Phases I - IIa Clinical Development & Registration Clinical TrialsPhases IIb & III Target Discovery & Validation Safety & Drug Metabolism Drug Discovery Business Use Only

6. Finding a good drug candidate Every drug needs certain properties • Be able to make a dosage form (e.g., pill, injection etc.) • Getintothebody • Modulatethetarget • Modulatethedisease • Get out ofthebody • Not causeunwantedsideaffects The balanceofthesepropertiesis different foreveryproject Business Use Only

7. Step 1 Proof of Concept (PoC) Clinical Study Clinical Trials Phases I - IIa Clinical Development & Registration Clinical TrialsPhases IIb & III Target Discovery & Validation Safety & Drug Metabolism Drug Discovery Business Use Only

8. Target discovery and validation phase Modality Cell or gene therapy • Target/disease biology • Reproduce published work suggesting connection between target and disease • Provide evidence that pathway/target modulation could impact disease • Expand basic biology knowledge of target/pathway • Evaluate disease markers for target validation • Identify early safety (on target/off-target, pathway), other concerns and issues Small molecule Biologic • Establish design criteria • Define best LMW or biologics approach i.e. antibody, fragment, proteins, new scaffold, etc. Translational Medicine • Identify indication(s) that might be affected by modulating target/pathway Business Use Only

9. Step 2 Proof of Concept (PoC) Clinical Study Clinical Trials Phases I - IIa Clinical Development & Registration Clinical TrialsPhases IIb & III Target Discovery & Validation Safety & Drug Metabolism Drug Discovery Business Use Only

10. Drug discovery phase Lead Strategy Target/Disease Biology • LMW: Fragment based drug development; biochemical or phenotypic screening; structural biology, in silico design and others • Biologics: Define best biologics approach (antibody, fragment, proteins, new scaffold, etc.) • Develop relevant assaysystemsandreagents (celllines,proteins, etc.) • Develop predictive toxicology assays Chemistry • Generatetoolcompounds for flowchartvalidation (internal orexternal) • Initiate hit to lead chemistry for chemical series or single hits Biophysics • Biophysical and structural understanding of hits where applicable Business Use Only

11. Step 3 Proof of Concept (PoC) Clinical Study Clinical Trials Phases I - IIa Clinical Development & Registration Clinical TrialsPhases IIb & III Target Discovery & Validation Safety & Drug Metabolism Drug Discovery Business Use Only

12. Safety and metabolism Team Actions Target/Disease Biology • Establish criteria for differentiating compounds based on indication • Establish plan for characterization and beyond • Continue assessment of target and candidate potential • Continue to validate target and develop biomarkers PK/ADME Chemistry • Optimize lead candidates to address desirable properties and liabilities based on indication and strategy • Drug metabolism and pharmacokinetics (in vitro and in vivo) • Pharmacodynamics / efficacy Pre-formulation Toxicology • Measure physicochemical properties / pre-formulation • Early in vitro toxicology (Off target panels) • in vivo, only when clear rationale Business Use Only

13. How do we reach the patient? Proof of Concept (PoC) Clinical Study Clinical Trials Phases I - IIa Clinical Development & Registration Clinical TrialsPhases IIb & III Target Discovery & Validation Safety & Drug Metabolism Drug Discovery Business Use Only

14. How is a PhD helpful? A PhD teaches you: • How to think strategically about a problem • How to set goals to progress a project • Organize to get what you need to do done. • Writing skills: How to be direct and get the point across. • Presentation skills: How to tell your story and influence others. Business Use Only

15. How do you get into this? • Early phase drug discovery is the closest to what you do now. Easy to move from PhD/Post-doc into research in industry. If you have expertise it's a plus and makes the move easier, but it's not necessary. • Networking. Hands down the best way to learn about different jobs! • Doing a post-doc in industry allows you to see how it works, but an academic post-doc is very useful to have before you make the transition. • Collaborations with industry from your academic position. • Long term thinking about your career: many researchers start off at the bench and then move into management and then to a different arm of the organization (Clinical, business development, program management, etc.). Business Use Only

17. Backup

18. Approaches for identifying small molecule hits? 15N Biophysics High throughput & Focused Screens In silico 1H Data Annotation & Integration Knowledge-Based Drug Discovery Disease-relevant Target or Pathway Knowledge Creation X-Ray & Structure based drug discovery Chemistry Functional Assays Lead Molecule Business Use Only

19. Triaging hits:Enabled by a series of scientific questions Primary HTS 105~106 cmpds Does the compound affect the assay? Hit confirmation & counterscreen 103~104 cmpds Does the compound reproducibly affect the assay in the desired way? Hit Validation, SAR, secondary screen(s) 101~103 cmpds Confirm the compound specifically interacts with the target Confirmed hits Business Use Only

20. Typical profile of a tractable hit series Business Use Only

21. + ATP RAF Kinase MEK MEK -P ? Assays for modulating the target/phenotype Biochemical • Can take molecular approach (mutations, specific molecular locations, binding) • Simplified biology • Need to establish functional activity, both at pathway and disease level • Limitations: • Translatability/relevance • Need purified proteins Cellular • Can take holistic approach (classical pharmacology) • Evaluating potential drug candidates against phenotype or readout • Limitations: • Compound properties play a bigger role • May need to identify target after screen Business Use Only

22. Is my candidate safe for humans? ≠ Safety studiesin animals + Safe starting dose PK/PD studiesin animals Business Use Only