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Acknowledgement and Thanks
NYU ResearchersDr. Jason Blum
CollaboratorsDrs. C. Klein (NYU School of Med)D. Cory-Slechta (U. of Rochester)
M. Aschner (Albert Einstein)J. Schwartzer (Mt. Holyoke)
Funding SupportNYU NIEHS Center Pilot Grant
NYU NIEHS Molecular, Biostatistics and Bioinformatics Coresd
Discovery Sciences Discovery Sciences
Drug Discovery Toxicology: From Target Assessment to Translational Biomarkers
J. Eric McDuffie, PhD, MBAScientific DirectorPredictive & Investigative ToxicologyNonclinical Safety
What Do You Think It Takes to Make a Prescription Drug?
Presentation by J. Eric McDuffie, PhD, MBA
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Presentation Overview
• Candidate drug discovery, target engagement, and preclinical efficacy
• Drug target validation and lead generation
• Preclinical testing and Investigational New Drug (IND) application filing
• Clinical trials (Phases 1, 2, and 3)
• New Drug Application (NDA) filing
• NDA review/decision on approval
• Phase 4 clinical studies
Image from: Timothy B. Durham and Maria-Jesus Blanco. Target Engagement in Lead Generation. Bioorganic & Medicinal Chemistry Letters. 25(5), 1 March 2015, Pages 998–1008.
On Average, How Many Years Does It Take to Generate Sufficient Research Data to
Support Approval of a Prescription Drug?
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Phase I Phase IIa Phase IIIDiscovery
1 Month
3 Month
6 Month Rat/9 Month Nonrodent
Carcinogenicity
Phase IIb Regulatory Review
Safety Pharmacology
Drug Development and Metabolism (DMPK)
Reproductive/Developmental Toxicity
Genetic Toxicology
5–14 Day
New Medical Entity (NME) Declaration
Drug Development Process Timeline
Investigational New Drug (IND) Application
Clinical Proof of Concept (POC) New Drug
Application (NME)
The Importance of Preclinical Safety Testing
• The estimated cost for developing a new drug is ~$2.6 billion
• Preclinical safety studies constitute ~15% of total drug development costs
• Clinical trials constitute ~30% of total drug development costs
• Approximately 70% of all discovery compounds do not become drugs due an earlyidentification of preclinical safety findings
• The approval rate for candidate drugs entering clinical development is <12%
• The importance of preclinical safety testing is to decrease discoveryresearch efforts for toxic compounds that are unlikely to become drugs
Thomas Sullivan.https://www.policymed.com/2014/12/a-tough-road-cost-to-develop-one-new-drug-is-26-billion-approval-rate-for-drugs-entering-clinical-de.html
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During the Initial Discovery Phase, How Many Steps Do Chemists Often Perform in Efforts to
Discover a Candidate Prescription Drug?
Drug Discovery, Target Engagement, and Preclinical Efficacy
The drug discovery and target validation processes are intended to demonstrate potential correlations between preclinical and clinical readouts:
• Demonstrating drug-like properties (Target Engagement)
• Preclinical data (e.g., efficacy biomarker profiles) should inform backupcompound selections
Image from: Timothy B. Durham and Maria-Jesus Blanco. Target Engagement in Lead Generation. Bioorganic & Medicinal Chemistry Letters. 25(5), 1 March 2015, Pages 998–1008.
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What Emerging Technology Do You Believe May Be Used to Help
Validate a Candidate Prescription Drug?
Drug Target Validation
Image Source: https://www.sygnaturediscovery.com/drug-discovery/integrated-drug-discovery/target-validation/
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Lead Candidate Drug Generation
The identification of a “lead compound” to progress toward preclinical safety testing includes:
• In vitro assays and in vivo studies aid the prioritization of compounds toidentify a “lead compound” to progress toward preclinical safety testing
• Predict compound-induced toxicologic risks to humans using in vitro,in vivo, and/or in silico models
Image from: Timothy B. Durham and Maria-Jesus Blanco. Target Engagement in Lead Generation. Bioorganic & Medicinal Chemistry Letters. 25(5), 1 March 2015, Pages 998–1008.
Case Example—In Vitro Assay: Receptor Selectivity for Ibrutinib
Kinase IC50 (nM)Median Cmax (unbound)/
IC50 Ratio(a)
Irrev
ersi
bly
Inhi
bite
d
Btk 0.53 12.27Blk 0.94 6.92
Bmx/Etk 1.1 5.91
ErbB4/Her4 1.23 5.29
Txk 2.87 2.27Tec 5.49 1.18Itk 11.7 0.56
EGFR 11.86 0.55
ErbB2/Her2 21.57 0.30
Jak3 21.9 0.30
Rev
ersi
bly
Inhi
bite
d
Fgr 2.86 2.27Lck 3.49 1.86Yes 3.94 1.65Csk 6.17 1.05Brk 10.01 0.65Hck 16.98 0.38
Ibrutinib • Bruton’s Tyrosine Kinase (BTK) inhibitor• Used to treat B cell malignancies• Hits several other kinases at clinically
and toxicologically relevant levels
Image adapted from: Honigberg et al. PNAS v107;29:13075–13080. 2010.
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What Do You Think It Takes to Ensure a Candidate Drug Is Safe for Humans?
Preclinical Safety Testing
Image from: Cavagnaro, J. Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Nat Rev Drug Discov 1, 469–475 (2002) doi:10.1038/nrd822.
13
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Preclinical Safety Testing
Image from: Brown, C. et al. Metabolomics and Age-Related Macular Degeneration. Metabolites 2019, 9(1), 4; https://doi.org/10.3390/metabo9010004.
Preclinical Safety Study Design Considerations• Species selection:
• Typically default to rat and dog• Dosing formulation testing• Dose level testing:
• At high enough exposure in good laboratory practice (GLP)studies to support Phase 1 clinical trial
• Study duration:• 5–14 days
• Clinical endpoints:• Clinical observations, body weights, and food consumption
• Pathology endpoints:• Clinical, routine, and molecular pathology
IMAGING
Some images have been removed from this slide.
What Is Your Perceived Definition of a Translatable Safety Biomarker?
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Translatable Safety Biomarkers
LLO FIH PoCTV LO Preclin. Dev.
Phase II/III
On-target related TOX
Expected potential TOX
Unexpected TOX during single/ repeated dosing
Adverse drug reactions during clinical development
Safety biomarkers for compound selection and mechanistic understanding
Candidate translational safety biomarker analysis to enable early prediction of ADRs, mechanistic understanding in issue solving, and patient selection
H2L
Investigational New Drug (IND) Application Filing
• US FDA/CDER has 30 days to assess safety per the IND application– No comments or minor proceed with Phase I trial– Phone call or letter clinical hold
• Why?– Duration of toxicology studies (in two species) insufficient to support
proposed clinical duration
– Doses/exposures not high sufficient enough in toxicology studies
– NOAEL not established in toxicology studies
time
concentration
Cmax
AUC
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Clinical Trials
Image retrieved from: https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/144/clinical-trial
List a Toxicity That Would Cause Regulatory Authorities to Enforce a “Clinical Hold” (aka
Delay or Suspend Ongoing Research) for a Candidate Drug Trial in Humans.
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https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.42
Clinical Trial Holds: Partial or Complete
https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/clinical-hold-products-intended-life-threatening-conditions
https://www.biopharmadive.com/news/regenxbio-rgx-314-fda-clinical-hold-wet-amd-gene-therapy/566733/
A Few Key Example Reasons for a Clinical Trial Hold
The reason for a clinical hold is concern for the safety of clinical trial participants.
• Partial Clinical Hold– Drug Delivery Device–Related Issues
• When a gene therapy (e.g., brain) delivery device poses risk to humans
• Complete Clinical Hold– Developmental or Reproductive Toxicology
• When a candidate drug is intended to treat a life-threatening diseaseor condition affecting both genders
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Case Example: Candidate Drug-Induced Testicular Toxicity
• Candidate drug-induced testicular toxicity can lead to a clinical hold orvery restrictive clinical enrollment and/or robust monitoring
Some images have been removed from this slide.
Questions?
La et al. Efferent Duct Toxicity with Secondary Testicular Changes in Rats Following Administration of a Novel Leukotriene A4 Hydrolase Inhibitor.
Toxicologic Pathology, 40: 705-714, 2012) .
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