Darren Warren

1. Essential Considerations for Your IND Submission: Objectives and Pitfall Avoidance in Your Preclinical Program  Darren Warren

2. Overview • Focus on objectives for preclinical arm of the IND package, highlighting concerns and potential pitfalls • Will assume some familiarity with IND requirements • Chemistry considerations - high level concerns • Assumptions for IND structure, mindfulness of: • Clinical indication / Clinical plan • Chemical production plans • Strategies for satisfying applicable regulations, guidances, and agency expectations • Local / regional concerns • IND orientation is drug development, not drug discovery

3. Case Study – Concordia Pharmaceuticals Clinical entry with a well characterized molecule Outcome, Timelines, Resources: Safety assessment supporting FIH Phase I trials Commercially-viable prototype API process developed and demonstrated IND filed 10 - 12 months after lead selection, barring any technical or safety issues. Requires parallel activities including IND preparation and clinical plan determination(15-18 months for biologics) Total project cost = $ 2.5 – 4.0 million (biologics can be more) A Successful IND Program

4. Pitfall #1: Rush to the first dose Chemistry precedes Biology. Allow adequate Chemistry / Production timelines. First dose may occur 40% of the way into the full development timeline. There is significant interconnection between CMC and Toxicology activities prior to first dose. The Quote: “I want to file my IND by next July. When can we start dosing?” Credit: XKCD.com

5. Understanding of the Desired Target (Primary Pharmacology) and Off-Target Activity Understanding candidate MOA and biology of the target Confirmation of desired pharmacology in animal model(s) of human disease. In vivo pharmacology assessment in relevant animal model(s). Key for Biologics Characterized dose & exposure responses, identify MED. Define PK/PD relationships Model dose response and dose schedules Prediction of clinically efficacious exposure as well as dose and exposure multiples Pitfall #2: Inadequate modeling of clinical use schedules and exposures. These information are critical for an efficient IND program. Research / Lead Optimization Yields

6. DMPK & Early Development • In Vitro Metabolism • Ex. Plasma & microsomal stability, Metabolism profiling, Protein binding, Species comparisons • Drug-Drug Interaction (DDI) • Ex. CYP Assays (induction, inhibition, etc.), UGT enzyme inhibition • Cell Transport Assays • Ex. Permeability / MDR (P-gp), Drug or Uptake transporters • Pharmacokinetics (PK) & Toxicokinetics (TK) • Active drug profiles (AUC, Cmax/Cmin, Tmax, T1/2, Vd, & Cl) • Characterized over range of dosages, including expected clinical and toxicology dosages (1x-10x efficacious dosages) • Single & Repeat-dose PK profiling (3-7 days) • Metabolite kinetics if needed

7. DMPK & Early Development • Critical endpoints / models: • Non-clinical species selection / justification • Formulation selection • Bioavilability • Models for saturation of absorption, metabolism, clearance/excretion, accumulation, gender and species differences (rodent / non-rodent). • Defined metabolic pathway and major metabolites; metabolite structure elucidation • Prediction of human DMPK responses • Alerts for Drug-Drug Interactions of clinical concern Pitfall #3: Proceeding to pivotal GLP studies without a solid DMPK foundation. Risks errant dose selection and inadequacy of IND to support clinical usage plan.

8. A Question on Species Selection “My efficacy model / MED information was developed in mice. Is it prudent to continue with mice for my preclinical rodent species?” • No, not always. Consideration for Rat vs. Mouse: • DMPK considerations for relevance to humans • Selection typically based on in vitro metabolism and PK data • Major metabolites must be expressed in tox species (small), or pharmacology must be expressed (large) • Mice are small • Potential Pitfall: Ill-advised consistency in species usage. Utility of MED and IND information is for extrapolation to humans

9. DrugSafety ToxicologyStudies • Pilot Toxicology Studies • Initial toxicity readouts (single and multiple dose) • Required in each species, non-GLP • Tolerability - define the Maximum Tolerated Dose (MTD): single dose; morbidity/mortality, GI distress, severe CNS effects, respiratory distress, immune reactions • Repeat Dose Range-Finding Toxicity: repeat dose 5-14 days; identify dose & exposure responses, target organ toxicity; major organ system pathology; dose-limiting toxicities; repeat-dose TK • A go/no-go decision often follows: Toxicity profile? PK profile? Dose limitations? Off target tox? Pitfall #4: not considering your formulations carefully Pitfall #5: not conducting complete / robust pilot tox studies

10. DrugSafety Toxicology& SafetyPharmacologyStudies • Dose Administration & Schedule • Should be the same as intended clinical route & schedule • Dose schedule: daily (or multiple daily) vs. cycle dosing • Characterize dose-response relationship • Minimum of 3 dosages • Good separation between dosages to avoid exposure overlap • Dose to toxic effect or maximum feasible limit • GLP vs non-GLP • Any study can be conducted in accordance with GLP • GLP incurs increased cost and timelines • GLP (only) required for extrapolation to humans Pitfall #6: Insufficient Test Article characterization and demonstration of stability for GLP studies

11. Pivotal DrugSafety • Safety Pharmacology • Required: Respiratory, CNS, Cardiac (in vivo), hERG • Determine potential for untoward pharmacology • Single dose pharmacology study, top dose near MTD • Small molecule – commonly stand alone studies • Biological – incorporate endpoints into non-rodent tox study • Oncology (end stage) – waived • Genetic Toxicology • Hazard Identification for DNA damage (mutation or chromosomal) • Pre-IND requires 2 in vitro assays (AMES & Mammalian chromosomal aberration) • Registration requires additional in vivo ChromAb assay (Micronucleus Test) • Prudence in conducting all 3 assays pre-IND

12. Pivotal DrugSafety • IND-enabling (pivotal tox studies, 2 species) • Typically 14-28 day repeat dose studies specifically designed to support SAD & MAD Phase I clinical studies • Intended as survey studies. Expected to include endpoints relevant to molecular class, anticipated toxicity, PD identification • Augment with specific assessments Ex. Local tolerance (dose site), Biomarkers, Immunogenicity • Blood volume limitations for large animals • TA preferred same batch as Phase I

13. Pivotal tox study goals: Identify target organ toxicity/pathology, translational predictive safety biomarkers, assess reversibility or progression, assess local tolerance, determine adverse effects with NOAEL & exposure ratios. Provide a basis for selecting initial clinical doses & escalations Pivotal DrugSafety • Recommendation: Maintain purity of purpose = IND enabling • Pitfall #7: Over reaching for data or over designing studies. Avoid discovery investigations and addition of unneeded endpoints.

14. Summary • Pitfall hit list (common sources of disappointment): • Rush to the first dose • Inadequate modeling of clinical use schedules and exposures • Proceeding to pivotal GLP studies without a solid DMPK foundation • Not adequately considering formulations used in tox studies • Not conducting complete / robust pilot toxstudies • Insufficient Test Article characterization and demonstration of stability for GLP studies • Over designing pivotal studies

15. Questions