Challenges with Investigating Biological Drug Candidates

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Healthy Volunteers and new Biological Drugs
Dr David R Glover
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The Promise of New Biological Drugs ?
( courtesy of MSD Ltd )
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Presentation Outline

• Introductory remarks
• Personal relevant experience in Industry
• Some key lessons learned
• Comments on TGN1412
• My perspective of the future
• Summary and conclusions

4
Biotech Product Development
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Biotech Products

• Recombinant DNA derived molecules including
• Hormones , Growth factors
• Interleukins
• Interferons
• Monoclonal antibodies
• Soluble receptors
• Ig fusion molecules
• Vaccines
• Antisense
• Gene therapy
• Also blood derived products, cell therapy

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Challenges in PreClinical Phase

• Human protein drug candidates used in animal
  studies - pharmacology and toxicology
• Specificity for animal target
• Potency against animal target
• Pharmacokinetics / pharmacodynamics
• Validity of biomarkers and disease scores
• Immunogenicity of human protein
• Statistics may not help (n is often small)
• Relevance of experiments ?
• Ethics of experiments ?

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Feasible Toxicology Experiments
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Disease Models
Animal disease models can mislead
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Hippocrates
Primumnon nocere
First do no harm
National Library of Medicine
Extreme remedies are most appropriate for
extreme diseases
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To get relief you must take some risk
(Lawrence D and Black J, 1978)
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Early experience - alpha interferon
Non-haematologic toxicity ( patients)
Dose adjustment
Maintenance
All
Grades 34
All
Grades 34
97.7
45.5
Flu-like symptoms
73.3
13.3
27.3
Fatigue
84.1
66.7
16.7
Confusion
25.0
6.8
6.7
6.7
Anorexia
65.9
18.2
46.7
10.0
Diarrhoea
38.6
16.7
0.0
6.8
Somnolence
30.0
40.9
9.1
13.3
36.4
Dry mouth
13.3
0.0
2.3
Depression
13.6
4.5
16.7
3.3
Hypotension
9.1
0.0
0.0
2.3
(Schering-Plough)
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Adverse Effects Biological drugs
Description
Type
Augmented - predictable from pharmacological mode
of action
A
Bizarre - unpredictable, idiosyncratic, generally
rare
B
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Monoclonal Antibodies
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Monoclonal Antibodies

• Many lessons can be learned from past
• mAbs against soluble molecules
• mAbs against cell surface molecules
• Role of Fc
• Mechanisms of action
• Importance of specificity for human
• Relevance of healthy volunteers in trials ?

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TGN1412 some key points

• Humanized IgG , anti human CD28 agonist
• Concept was to kick start the immune system
• Late change of intended therapeutic use
• Mechanism of action - included cytokine release
• No potency assay available
• No assessment of relative potency by species
  available
• Important role of Fc largely overlooked
• Inappropriate calculation of starting dose for
  man
• Relevance of testing in healthy volunteers ?

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TGN1412 some key points

• Also worth noting ..
• No physician in developing company
• Rejected for in-licensing by major companies
• MHRA failure to ask any questions of CTA
• Roles of Parexel Regulatory and phase I unit
• .. Northwick Park Hospital ICU staff were heroic
  

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Developing New Medicines
Biopharmaceuticals in the 21st Century
Confirmatory Trials
Reduction to practice
Building the case
Proof of concept
Proof of concept
Confirmatory Trials
Proof of concept
Confirmatory Trials
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Focus on Human
Man is the frontier for biomedical research
and the experimental model for the 21st century
T Yamada, GSK. 2004
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Creative Customised Solutions

• Think Human !
• Must be based on sound science
• Ex vivo - fluids , cells , tissues , biopsies /
  explants
• In Vivo - Skin blisters , wounding studies
• Avoid reliance on transgenics , animal models
• Parallel reagents are seldom the answer
• Mechanism of action should be a major factor in
  determining whether to use healthy subjects

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The science and the ethics appear to have a
close and multifacetted relationship
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Focus on Human

• Ethical considerations
• Protection of the individual
• Informed consent
• Freedom to withdraw
• Legal considerations
• Clinical Trial Directive
• Human Tissue Bill
• Data Protection

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Inputs At Key Decision Points

• Scientific
• Medical
• Ethical
• Commercial
• Economic

Weighing the evidence for and against
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Summary of my experience

• Biological drugs have become increasingly
  important and prevalent
• Getting into man can be very challenging
• Serious limitations of animal models and
  conventional toxicology
• Sound scientific basis is needed for right
  decisions in development
• Importance of gaining early understanding of
  mechanism of action
• The future is human .. creative solutions are
  required
• Ethics have become more complex
• Case by Case approach regarding healthy
  volunteers
• A lot can be learned from the successes and the
  failures of the past .but there is an awful lot
  we have still to learn