Spring Intro 2023

03/03/2023

Small molecules – Nonclinical safety

Initial Safety Batch Development Batch Using Clinical Synthesis

First Dose in Man

Development

Initial Safety

Development Track

Safety Assessment Lead

Total 19 (21) Months

3 Months

4 Months

3 Months 7 Months (9 months for 13 wk) 2 Months

Toxicology for IND/CTA

Initial Safety Assessment

IND/CTA Regulatory Submission/ Approval

Acute Rodent (2, 4, or 13 Week) Non-Rodent (2, 4 or 13 Week) Non-Rodent CV Safety Pharm Rodent CNS, Resp. Safety Pharm In Vivo Mouse Micronucleus

Rodent RF 5-14 Day (+Histo) Screening Ames

Non-Rodent RF 5-14 Days (+Histo)

In vitro Ames, Chromo Ab

9

To proceed - appropriate safety profile and ideally: ● Target organs identified ● Methods identified for monitoring toxicity and blood drug levels in clinic ● Type of toxicity observed in animals is predictive of toxicity in human ● There are adequate exposure and dose safety margins for patient population and for indication involved – No observed adverse effect level (NOAEL) – Minimum anticipated biological effect level (MABEL) – Target engagement and receptor occupancy Nonclinical safety evaluations

10

5