Rational for the 5R Philosophy

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)

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

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.

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

TEMPLATES & INSTRUCTIONS

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

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

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)

The Right Target (continued)

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

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

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

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

Program Nomination Form

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)

The Right Target

The Right Target (continued)

The Right Tissue

The Right Tissue (continued)

The Right Safety

The Right Safety (continued)

The Right Patients

The Right Patients (continued)

The Right Commercial Potential

The Right Commercial Potential (continued)