An academic talk ...

1. Neurotoxicity & Neurodegeneration
in Drug Development & its Life Cycle
Obaid Ali, R.Ph., Ph.D.
Chief Scientific Officer, CQS
International Brain Research Organization, Associate School of Neuroscience
IBRO – APRC Conference - Malir University, Karachi - 11th August 2023

2. Key Reference of talk
Drug Discovery & Development: Biomarkers of
Neurotoxicity & Neurodegeneration
Abigail L Walker, Ruth A Roberts & Syed Z Imam
University of Glasgow, University of Birmingham, UK & Division of Neuro-toxicology, US-FDA.

3. Safety/toxicity … most prevalent reasons
Cardiovascular & CNS toxicity
Failure

4. Safety/toxicity … most prevalent reasons
Cardiovascular & CNS toxicity
Failure
Non-invasive biomarker of
neurotoxicity
Earlier prediction of likely
neurotoxicity in pre-clinical
studies

5. Safety/toxicity … most prevalent reasons
Cardiovascular & CNS toxicity
Failure
Non-invasive biomarker of
neurotoxicity
Earlier prediction of likely
neurotoxicity in pre-clinical
studies
Facilitating clinical trial of new therapies particularly for
neurodegenerative conditions (PD & MS)

6. Neurodegeneration
Neurotoxicity

7. Functional
Neurotoxicity
Structural
Neurotoxicity
Associated with tissue damage Associated with electrical activity
From small molecule to complex biologics

8. Attrition remains a major challenge
Reason of attrition with focus on neurotoxicity

9. Attrition remains a major challenge
Reason of attrition with focus on neurotoxicity
Enhanced and improved success
• Development of
imaging
• Development of fluidic
biomarker

10. • Parkinson’s disease (PD)
• Traumatic brain injury
• Multiple sclerosis (MS)
Models of CNS damage
& degeneration

11. • Parkinson’s disease (PD)
• Traumatic brain injury
• Multiple sclerosis (MS)
Models of CNS damage
& degeneration
Opportunity to improve tools for non-clinical
toxicologist in the early detection of potential
neurotoxicity

12. • Parkinson’s disease (PD)
• Traumatic brain injury
• Multiple sclerosis (MS)
Models of CNS damage
& degeneration
Opportunity to improve tools for non-clinical
toxicologist in the early detection of potential
neurotoxicity
Learning
from studies
of animal
neurotoxicity

13. Selection of target based on
linkage of the target with
disease & target expression
across the tissues
Target

14. Characterize the potential
unwanted side effects of
target inhibition or
activation
Target Safety
Assessment
(TSA)

15. Impact of chemical
modification
• Potency
• Selectivity
• Solubility
• Partitioning
High -
Thoroughput
Screening (HTS)
Right time to run early safety screening … e.g. genetic toxicity
& potential to form reactive metabolites

16. Inhibition of potassium current
through this ion channel linked
to a potentially fatal cardiac
arrhythmia called torsade de
pointes
hERG
human Ether-a-go-go-
Related Gene
All are done before entering the clinical trial that may
recognize FTIH (First Time In Human)

17. TS
Target Selection
LG
Lead
Generation
LO
Lead
Optimization
CD
Candidate Drugs
GLP FTIH

18. • Tolerance
• Kinetics
• Pharmacology
• Signals for potential safety
• Signals for potential efficacy
Human Trial
Aimed at Establishing

19. • Tolerance
• Kinetics
• Pharmacology
• Signals for potential safety
• Signals for potential efficacy
Human Trial
Aimed at Establishing
From small dose

20. • Tolerance
• Kinetics
• Pharmacology
• Signals for potential safety
• Signals for potential efficacy
Human Trial
Aimed at Establishing
From small dose
Usually initial phase of human trial is conducted on healthy volunteers.
Can Phase I trial for anti-cancer CD be conducted in initial stage of cancer
patients?

21. • of mechanism (pharmacology)
• of concept (efficacy)
Proof

22. Confidence on
• Tolerance
• Kinetics
• Pharmacology
• Efficacy
• Dose range
• Drug interactions
• Double blind, randomized, placebo
controlled, multi-center ….
Phase II & III

23. • DRF (Dose Range Findings)
• EFD (Embryo Fatal Development)
• MOLY (Mouse Lymphoma)
• MTD (Maximum Tolerance Dose)
• P&P (Pre and Post Natal)
• SAR (Structural Activity Relationship)
✓ ICH M3 (R2)
✓ ICH S9
✓ ICH S4
✓ ICH S7
✓ ICH S2 (R2)
✓ ICH S1
✓ ICH S5 (R2)
Regulatory
Frames

24. • DRF (Dose Range Findings)
• EFD (Embryo Fatal Development)
• MOLY (Mouse Lymphoma)
• MTD (Maximum Tolerance Dose)
• P&P (Pre and Post Natal)
• SAR (Structural Activity Relationship)
✓ ICH M3 (R2)
✓ ICH S9
✓ ICH S4
✓ ICH S7
✓ ICH S2 (R2)
✓ ICH S1
✓ ICH S5 (R2)
Regulatory
Frames

25. • M3 (R2) - Non-clinical safety studies for the conduct of human
clinical trials for pharmaceuticals.
• S9 - Non-clinical evaluation for anticancer pharmaceuticals.
• S4 - Duration of chronic toxicity testing in animals (rodent and
non-rodent toxicity testing).
• S7 - Pharmacology Studies.
• S2 (R1) - Genotoxicity testing and data interpretation for
pharmaceuticals intended for human use.
• S1 - Regulatory notice on changes to core guideline on rodent
carcinogenicity testing of pharmaceuticals.
• S5 (R2) - Detection of Reproductive and Developmental Toxicity
for Human Pharmaceuticals.
ICH

26. Development
Discovery
• Target selection
• Lead Generation
• Lead Optimization
• Candidate Drug Nomination
• GLP Toxicology phase
• Phase I CT
• Phase II CT
• Phase III CT

27. Development
Discovery
General Toxicology – Rodent, Non-rodent (MTD/DRF)
One month + recovery, chronic toxicology
M3 (R2) - Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals.
S9 - Non-clinical evaluation for anticancer pharmaceuticals.
S4 - Duration of chronic toxicity testing in animals (rodent and non-rodent toxicity testing).

28. Development
Discovery
Safety & Secondary Pharmacology
CVS, CNS, Respiratory, ++
S7 - Pharmacology studies.
S7A - Safety pharmacology studies for human pharmaceuticals
S7B - Non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval
prolongation) by human pharmaceuticals.

29. Development
Discovery
Genetic Toxicology & Carcinogenicity
SAR, MOLY
S1 - Regulatory notice on changes to core guideline on rodent carcinogenicity testing of
pharmaceuticals.
S2 (R1) - Genotoxicity testing and data interpretation for pharmaceuticals intended for human
use.

30. Development
Discovery
Reproductive Toxicology in Clinical Trials – EFD, Fertility, P&P
S5 (R2) - Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals.

31. Two species toxicology
(7 to 14 days repeat dosing)
Dog & Rat
Maximum Tolerated Dose (MTD)
for 1 month testing
Toxicology

32. Secondary Pharmacology
20 to > 300
Receptors, kinases, ion channels &
others as the compound approaches
FTIH
Unwanted
Targets
Predicted margins to intended targets and
unwanted off target effects

33. Look at …
• CVS (Heart rate, Blood
pressure)
• CNS (Locomotion, Reflexes,
Pain threshold, seizures)
• Respiratory System
Core
Battery

34. Look at …
• Potential to cause cancer … direct
damage to DNA or via non-genotoxic
mechanism
• In silico, in vitro, in vivo tests
• Unless, interaction with DNA is key to
efficacy
• Must be negative in genetic toxicology
to enter Phase I onwards
Genetic
Toxicology &
Carcinogenicity

35. • To support long-term clinical
dosing
• May not go beyond the
duration studied for toxicology
• This is not for oncology product
development
Chronic
Toxicological Study
of > 3 months

36. Target Safety Assessment …
• Unintended consequences of
inhibiting or activating a specific
target
• Understanding of target biology and
disease linkage
• De-risking chemistry … genetic
toxicology, functional interaction
with ion channel, hERG liability
Good Science & Sound
Decision Making

37. • Lead Generation
• Lead Optimization and
• Candidate Selection
Design – Make – Test
Cycle

38. Non-clinical toxicology was found as the
primary cause for failure in drug
discovery and development
(AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer)
Prevalence of
Neurotoxicity

39. • Cardiovascular risk and toxicity
• CNS toxicity about 25% of failure
• CNS toxicity is frequent in CVS &
GIT as well
Frequent
Reason of Failure
GLP is very important ...
… incredible data harms in development

40. • During toxicology
• Safety failure by organ system
• Safety failure both in pre-clinical &
clinical
• In therapy area
CNS is Visible

41. 400 out of 37000 prescription drugs
• Suicidal ideation
• Sedation
• Abuse liability
• Seizure/convulsion
• Depression/Headache
• Retinal/Ocular toxicity
• Ataxia
Black Box Warning of
Neurotoxicity

42. • Differentiate between structural &
functional neurotoxicity.
• Histopathology of functional
endpoint is used.
Challenges for
Detection & Prediction

43. • Seizure may be visible but not suicidal
thoughts
• Sedation may be visible but not abuse
liability
• Tremor or other abnormal movement in
rodent may be used
• Misdiagnosis & misinterpretation is a
challenge … experience is the key
• EEG – Electro Encephalogram for
confirmation of drug induced seizure
Emerging Approaches to
detect Neurotoxicity

44. • 2012 – Health & Environmental Sciences
Institute
• Sensitive & specific biomarkers for
diagnosis & prediction of neurotoxicity
• Serum, plasma, urine and cerebrospinal
fluid used
• Several biomarkers confirmed
Fluidic Biomarkers for
Neurotoxicity

45. Thanks for listening