Pharmacology and Toxicology Information in Support of Protein Therapeutics

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Pharmacology and Toxicology Information in
Support of Protein Therapeutics

• Anne M. Pilaro, Ph.D.
• FDA/CDER/ODE VI/DTBOP
• NCI Small Business Initiative
• Workshop on Clinical Development
• June 24, 2004

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Objectives for Todays Presentation

• Summarize some differences between small
  molecules and protein therapeutics
• Brief review of pharmacology and toxicology
  information in support of IND application for
  protein therapeutics
• Introduce current guidance for toxicology testing
  of protein biotherapeutics

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What Does ODE VI Regulate?

• Classes of Biological Products
• Natural
• leukocyte-derived (IFNs, interleukins)
• enzymes, other cell-derived proteins
• Biotechnology-derived
• recombinant proteins (E. coli, CHO, yeast)
• monoclonal antibodies (in vivo, in vitro)
• recombinant proteins produced in transgenic
  animals
• Synthetic

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What Does ODE VI Regulate?

• Recombinant proteins
• cytokines
• enzymes
• hematopoietic growth factors
• neuroactive peptides
• Thrombolytics and fibrinolytics
• Monoclonal Abs (diagnostic, therapeutic,
  preventative)
• Peptides greater than 20 amino acids
• Other non-vaccine immunotherapies

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Some Basic Differences Between Drugs and Biologics

• Traditional Drugs
• Low molecular weight
• Previous examples
• Historical data base
• Maximal tolerated dose
• Species-independent
• Specific mechanisms
• Metabolized
• Guidelines

• Biologic Therapies
• High molecular weight
• Unique
• Concurrent controls
• Optimal biologic dose
• Species-specific
• Pleiotropic mechanisms
• Degraded
• Guidances

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Traditional Drugs are small

• FLUDARA (fludarabine phosphate)
• Molecular weight 365.2 daltons
• Chemical formula C10H13FN5O7P

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Biological Drugs are BIG!

• RITUXAN (rituximab)
• Molecular weight 145,000 daltons
• Chemical formula (non-glycosylated IgG1k)
  C3264H5002N840O998S20

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Review of Preclinical Studies for Small Molecule
Drugs vs. Biologics

• Small molecule drugs
• pharmacology establishes rationale, but proof
  is in clinical trial
• toxicology testing by standard paradigms
• two test animal species to maximize chances of
  detecting toxicities
• duration of tox testing gt support clinical use
• genotoxicity testing required before first in man
• ADME studies generally useful
• demonstration of safety ultimate goal

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Review of Preclinical Studies for Small Molecule
Drugs vs. Biologics

• Protein therapeutics
• pharmacology establishes rationale
• allows selection of pharmacologic active dose
• used to establish therapeutic window
• toxicology testing has no standard paradigm
• toxicities are often extensions of pharmacologic
  activity
• follows the principles set forth by ICH S6
  guidance
• margins of safety are frequently lt 10-fold
• demonstration of safety ultimate goal

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The ICH S6 Document

• Title Preclinical Testing of Biotechnology-Derive
  d Pharmaceuticals
• usage of relevant vs. nonrelevant species
• usage of animal models of disease
• immunogenicity testing and its implications
• genotoxicity testing
• chronic toxicity testing
• carcinogenicity testing
• preclinical study design

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Toxicology Testing of Biotech-Derived Agents
ICH-S6

• General Principles
• sufficiently well-characterized products
• rely on purification processes to remove
  impurities/contaminants
• comparability of test material demonstrated
  throughout development
• conventional approaches to toxicity studies often
  NOT appropriate to address unique issues
• GLP compliance

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Characterization of General Toxicity

• Administration/Dose Selection
• ROA, dosing regimen should mimic proposed
  clinical use
• alternative routes/regimens acceptable in some
  cases
• attainment of toxic dose NOAEL desirable
• multiples of human dose needed to determine
  adequate safety margins can vary with product
  class clinical indication
• Sec 3.5

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Animal Species/Model Selection

• Standard toxicology paradigms often not adequate
  or appropriate
• Use of relevant species
• single relevant species with justification
• limited toxicology in a single nonrelevant
  species
• Alternative approaches
• transgenic animals
• homologous proteins
• animal models of disease Sec 3.3

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Single/Repeat Dose Toxicity Studies

• use relevant animal species
• include TK, Ab measurement, recovery period
• short-term clinical use/acute life-threatening
  disease toxicology studies of up to 2 weeks
  duration
• chronic use toxicology studies up to 6 months
  duration
• Sec 4.4

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Characterization of Specific Toxicities

• Genotoxicity
• Chronic toxicity
• Immunogenicity
• Repro/Developmental Toxicity
• Carcinogenicity

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Characterization of Specific Toxicities

• Genotoxicity
• for protein therapeutics
• standard mutagenicity assays not applicable
• effects on proliferation, transformation in human
  cell lines may be more appropriate for in vitro
  testing
• integration not usually an issue for proteins
• scientific basis to justify method selection
• most sensitive, appropriate technique available
• use data to predict risk of mutagenesis in vivo
• frequency/risk analysis

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Characterization of Specific Toxicities

• Chronic Toxicity
• designed to assess potential cumulative toxicity
• support long-term administration in the clinic
• most protein therapies are of limited duration
• single, or small number of administrations over
  short time span
• limited number for lifetime replacement therapies

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Characterization of Specific Toxicities

• Chronic Toxicity, contd
• need for chronic toxicology determined by
  product-specific issues, patient indication
• assess potential delayed or extended toxicity
• daily, repeat administrations probably not
  feasible
• antibody development/host response
  (immunogenicity)
• limits duration of pharm/tox effects
• limits duration of administration

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Characterization of Specific Toxicities

• Repro/Developmental Toxicity
• need for studies determined individually
• dependent on product class, patient population,
  duration of treatment
• studies expected for product used in pregnant
  females, WCBP
• species-specificity limits testing to Seg 2/3
• stand-alone fertility studies not useful with
  NHP
• small litter size (n 1) with NHP means large n,
  
• alternative approaches are encouraged, e.g.
  hormone surrogates
• ODE VI works with sponsors to design studies to
  address specific safety questions as needed

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Characterization of Specific Toxicities

• Carcinogenicity
• standard rodent models not likely appropriate
• species-specificity
• lifetime administration of protein not feasible
• immunogenicity limits duration of treatment
• immune effects may also affect tumor response
• product-specific studies case-by-case
• dependent on product class, duration of clinical
  dosing, patient population, risks of long-term
  exposure
• may be obviated by long-term, clinical follow-up
• ODE VI works with sponsors to design studies to
  address specific safety questions as needed

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Review so far

• Preclinical studies for therapeutic proteins have
  no set study paradigm
• design and implementation must consider clinical
  indication, population, and product
  characteristics
• Traditional animal toxicology models may not be
  appropriate or feasible
• Often studies have to be individualized to
  address specific safety concerns

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Safety Issues Will Vary With Each Product Class

• Monoclonal antibodies (naked or conjugated)
• cross-reactivity with normal tissue
• immunogenicity/antibody production
• conjugate and/or linker toxicity
• bystander toxicity of radiolabeled species

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Safety Issues Will Vary With Each Product Class

• Cytokines and/or growth factors
• frequency/duration of therapy
• species-specificity
• interaction with host endogenous cascade
• tumor-promoting potential
• immunogenicity/antibody production

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Summary

• Toxicology programs for therapeutic proteins
  require novel approaches to obtain data
• no one size fits all paradigm for biologics
• traditional animal toxicology models may not be
  appropriate or feasible
• studies may have to be individualized to
  address specific safety concerns

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Summary

• Toxicology studies for therapeutic proteins
  should be
• rational , scientifically designed, and problem
  solving
• based on the best available technology, methods
  to date
• follow guidance set forth by ICH S6
• careful design, judicious use of animals

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Summary

• Current approach is to design preclinical
  toxicology studies to consider
• basic biology of the product
• clinical indication, e.g. life-threatening or not
• patient population under study

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Summary

• Animal studies to determine safety are selected
  based on
• body of information available
• question being asked
• Information may be obtained in alternative animal
  models
• non-human primates are not a priori necessary

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Summary

• but... animal studies really only give you a
  best guess of what to expect
• no animal model, including humans is 100
  predictive of response in man
• sometimes animal studies can give a false sense
  of security
• however, these models may be useful in evaluation
  of mechanism, other toxicities

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Some Further Resources

• ICH Guidances
• ICH S6 Safety Studies for Biotechnological
  Products
• ICH M3 Timing of Pre-clinical Studies in
  Relation to Clinical Trials
• ICH S5a Detection of Toxicity to Reproduction
  for Medicinal Products
• ICH S2b Standard Battery of Genotoxicity Testing
• Available at www.ich.org/ich5s.html

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Some Further Resources

• Points to Consider
• http//www.fda.gov/cber/guidelines
• Points to Consider in the Manufacture and Testing
  of Monoclonal Antibody Products for Human Use -
  2/28/97
• Points to Consider in the Manufacture and Testing
  of Therapeutic Products for Human Use Derived
  from Transgenic Animals - 1995

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Some Further Resources

• Guidance Documents
• http//www.fda.gov/cber/gdlns.htm
• Guidance for Industry Clinical Development
  Programs for Drugs, Devices, and Biological
  Products for the Treatment of Rheumatoid Arthritis

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Toxicology Staff in ODE VICAPT M. David Green
Ph.D., Chief

• DTBOP Staff
• Wen-Yi Gao, M.D., Ph.D.
• Melanie Hartsough, Ph.D.
• Anne M. Pilaro, Ph.D.
• Andrea Weir, Ph.D.
• Alexandra Worobec, M.D.
• [phone]

• DTBIMP Staff
• Hanan Ghantous, Ph.D.
• Anita OConnor, Ph.D.
• Barbara Wilcox, Ph.D.
• [phone]