1. Rational for the 5R Philosophy

2. Why do Drugs Fail in the Clinic
Why do Drugs Fail in the Clinic? AstraZeneca Determined Late-Stage Failure Linked to Target Selection
Efficacy- This could be due to:
Insufficient target engagement and/or poor pharmacokinetics
Preclinical models did not translate into human disease modulation
Insufficient target validation data linking target modulation (GOF and LOF) to disease
Safety- This could be due to:
Mechanism based toxicity
Off-target toxicity
Molecule (or metabolite) toxicity
Nature Reviews Drug Discovery 2016, 15, 817
insufficient target engagement and/or poor pharmacokinetics (this could be due to toxicity limiting of dose options leading to insufficient target engagement)

3. AstraZeneca’s 5R Philosophy Focused Resources on Most Validated Targets Which Led to Improved Productivity Metrics
The Right Target
Strong link (human genetics) between target & disease
Strong Target Validation
Available & predictive biomarkers
The Right Tissue
Adequate drug exposure in tissue of interest
Defined PD biomarkers
Clear understanding of PK/PD/functional relationships
The Right Safety
Understanding ALL on-target modulation effects (therapeutic index)
The Right Patients
Know how to identify and stratify patients
The Right Commercial Potential
Differentiated versus standard of care (SOC)
Nature Reviews Drug Discovery 2014, 13, 419

4. Definition of Target
Target: is a molecule in the body, usually a protein, that is intrinsically associated with a particular disease process and that could be addressed by a drug to produce a desired therapeutic effect.

5. Definition of Target Validation
Gain of Function (GOF), Loss of Function (LOF) experiments
Target Validation: the process of physiologically, pathologically, and pharmacologically evaluating a biomolecule. Might be performed at the molecular, cellular, or whole animal level.
Disease association, genetics and expression data
In vitro and in vivo disease models
Target ID & Validation
Transgenic models (knock in or knock out)
Understanding of molecular signaling pathways
Pharmaco-logical modulation with Tool cmpd

6. TEMPLATES & INSTRUCTIONS

7. Message to PI’s: Interact with WARF Therapeutics Early & Often
Pre-submission: PI and WARF Therapeutics can have regular meetings to discuss idea(s)
Review program data, identify gaps and plan next steps
Submission Process to WARF Therapeutics
PI submits IDR & “Program Nomination Form”
Formal presentation made to Scientific Advisory Board
Program Decision & Prioritization
If Program accepted, next steps in collaboration with WARF Therapeutics include
Develop work plan, Go / No Go decisions, and timelines
Discuss and agree on public disclosure/publication plan
Determine model and allocate resources
If Program not accepted
Provide feedback and rationale for the decision
Suggest experiments that if successful could lead to future acceptance

8. Program Nomination Form: Executive Summary
Name/Department of Principal Investigator: insert name here
Target and Therapeutic Indication: insert target & indication here
Date of Submission (Month/day/year): insert date here
The Right
Information Requested and to be filled in from Principal Investigator (PI), WARF Therapeutics , or Consultant
Target
Specify the target
Specify the intended or potential disease(s) and the therapeutic hypothesis
Provide the existing (and/or planned) target validation data: for example target modulation-functional relationships with either CRISPR, siRNA, or small molecule pharmacological modulation (in vitro and/or in vivo), human genetic-disease data
Tissue
Specify which tissues where the target is expressed
Specify which tissue is the intended target
What potential target engagement and/or functional biomarkers and if these assays currently exist, would need to be developed or validated?
Safety
Specify known target related pharmacology that could impact the therapeutic index in patients
Specify proteins with high sequence homology
Patients
Specify what patients would be targeted for this drug
How would patients be identified or stratified?
Commercial Potential
Specify what is the Standard of Care (SOC) for this disease
How will a drug for this target differentiate versus SOC
Specify the competitive landscape for this target or indication?
Molecule (Modality)
Specify the preferred modality (small molecule, PROTAC, anti-sense, siRNA)
This page is for instructional purposes only. View as a template. Use the blank page that follows as your Executive Summary and complete the requested information for each row

9. The Right Target (primary data to the questions below: 3-10 slides as needed)
Insert Tables, figures, images that support the 3 questions for the “Right Target” and target validation.
Annotate with text to articulate key messages
Disease association, genetics and expression data
Gain of Function (GOF), Loss of Function (LOF) experiments
In vitro and in vivo disease models
Transgenic models (knock in or knock out)
Understanding of molecular signaling pathways
Pharmacological modulation with Tool compound
This page is for instructional purposes only for the “Right Target”
View as a template
There is no slide count limitation for each topic: for slide 2 of the “Right Target”, create duplicate slide and make Title “The Right Target (continued)

10. The Right Target (continued)

11. The Right Tissue (primary data to the questions below: 3-10 slides as needed)
Insert Tables, figures, images that support the 3 questions for the “Right Tissue.
Annotate with text to articulate key messages
This page is for instructional purposes only View as a template
There is no slide count limitation for each topic

12. The Right Safety (primary data to the questions below: 3-10 slides as needed)
Insert Tables, figures, images that support the questions for the “Right Safety”
Annotate with text to articulate key messages
This page is for instructional purposes only View as a template
There is no slide count limitation for each topic

13. The Right Patients (primary data to the questions below: 3-10 slides as needed)
Insert Tables, figures, images that support the questions for the “Right Patients”.
Annotate with text to articulate key messages
This page is for instructional purposes only View as a template
There is no slide count limitation for each topic

14. The Right Commercial Potential (primary data to the questions below: 3-10 slides as needed)
Insert Tables, figures, images that support the questions for the “Right Commercial Potential”
Annotate with text to articulate key messages
This page is for instructional purposes only View as a template
There is no slide count limitation for each topic

15. Program Nomination Form

16. Program Nomination Form: Executive Summary
Name/Department of Principal Investigator:
Target and Therapeutic Indication:
Date of Submission (Month/day/year):
The Right
Information Requested and to be filled in from Principal Investigator (PI), WARF Therapeutics , or Consultant
Target
Tissue
Safety
Patients
Commercial Potential
Molecule (Modality)

17. The Right Target

18. The Right Target (continued)

19. The Right Tissue

20. The Right Tissue (continued)

21. The Right Safety

22. The Right Safety (continued)

23. The Right Patients

24. The Right Patients (continued)

25. The Right Commercial Potential

26. The Right Commercial Potential (continued)