This document discusses the importance of incorporating safety considerations into drug design from an early stage. It notes that safety issues related to the primary drug target remain a major reason for drug project failure and delay. Considering the target's normal physiological role allows researchers to anticipate and plan for potential toxicities. Early studies, such as in silico modeling, in vitro screening assays, and in vivo validations in animal models, can help identify potential safety hazards to hopefully design them out of drug candidates. Understanding toxicity risks in the context of the intended patient population can help assess the risk-benefit of a given drug target or compound series. Incorporating safety assessments from the beginning of the drug design process can lead to better informed decisions and improved chances of

1. 1
Making Safety Part of Drug Design
Richard Knight, PhD
Director and Co-founder, ApconiX, Alderley Park, UK

2. What does safety in drug discovery mean to you?What does safety in drug discovery mean to you?

4. BIO survey: Clinical Development Success Rates 2006-2015
9,985 clinical and regulatory phase transitions were analyzed from 7,455
development programs, across 1,103 companies

5. An analysis of the attrition of drug candidates from GSK, Pfizer, Lilly Takeda.
Waring et al, Nature Rev Drug Disc, 2015

6. Chemistry Biology DMPK Toxicology
Toxicology should be part of drug design

7. Target
Chemistry

8. • Safety issues related to primary target remain a
major reason for drug project failure and delay
• Early understanding the role of the target in
normal physiology allows you to:
• Anticipate and plan for potential toxicities
• Recognise on- versus off-target toxicity
• Influence dosing schedule/combinations
• Drive selectivity requirements
• Prioritise between targets Drug Discovery Today (2018) 23,
1925-1928.
Target

9. Control
• ALK5 - TGF-β signaling pathway
• Important role in the progression of many tumours
• Target of considerable interest, including AZ and Lilly
• In vivo toxicity studies: degenerative lesions in heart valves
(haemorrhage, inflammation)
• Pathology seen in all four heart valves, with variety of
chemicals scaffolds, in multiple species
• High level of expression of ALK5 in heart valve leaflets
• Purported role in valve homeostasis
Treated
ALK5 as a novel anti-cancer target
Evidence suggests on-target effect. What next?

10. Making the right decision on an early understanding of the risks

11. • Reducing potential risks associated with chemical series
• In silico – SAR databases
• In vitro – screening assays
• Cardiac ion channels
• Secondary pharmacology profiles
• Genetic toxicology
• In vivo studies
• PK studies, efficacy studies, bespoke investigative studies
Chemistry
Identify potential hazards early – potential design out problems

12. Designing out liabilities - osimertinib
• Inhibitor of mEGFR in lung cancer
• EGFR inhibition associated with:
• Wild-type EGFRi - skin rash
• IGF-1R i – increased plasma glucose
• hERG inhibition – cardiac arrhythmia
Specific criteria for clinical candidate selection

14. In vivo validation
Cross et al, Cancer Discov; 4(9); 1046–61. 2014
Rat Glucose & Insulin

15. • Put hazards identified into context of the patient population – hazard v risk
• Indication risk/benefit
• Age, co-morbidities, co-medications
• Healthy volunteers or patients in Phase I
• Competitive landscape
• Anticipated exposure range for efficacy
Wont have all the answers
Patient

16. Asking the right questions
Right data
Better decisions
Understand
the
translation
Design the
right
experiment
Define the
question
X

17. Thank you for listening
richard.knight@apconix.com