acknowledgement and thanks - toxicology.org

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


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


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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/


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


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


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


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


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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acknowledgement and thanks - toxicology.org

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