Biologics

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Biologics

• A Tutorial

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Growing importance of biotech medicines

• Biotechnology medicines have been proven to be
  safe and effective with an excellent record of
  patient satisfaction and safety
• Biotechnology has produced medicines for some of
  the most serious and intractable diseases

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Hailed by many scientists as the wave of the
future, biologics and the biotechnology to
produce them have made great contributions to
healthcare and have the potential to treat or
cure many of the worlds toughest diseases.
Many biologic medicines currently in use treat
serious diseases with no other effective
treatments. The key to both the power and
challenge of biologic medicines are their size
and complexity. This presentation is designed
to provide a sound basis of understanding the
evolving and important field of biologic
medicines.
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Part OneA Biologic is
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The Basics Biologics are

• derived from living material (plant, animal or
  microorganism)
• usually based on protein and/or nucleic acid
• used for the treatment of diseases in humans

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More Specifically

• Biologics have relatively large molecular weight
  and high structural complexity compared with
  biologically active substances typically made by
  chemical synthesis.
• Biologics are molecularly heterogeneous.
• Biologics may not be completely characterized
  using physicochemical methods.

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How are Biologics Different from Small Molecule
Drugs?
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Composition
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Manufacturing Process

• Chemically-based drugs are made by adding and
  mixing together known chemicals and reagents
  using a series of controlled and predictable
  chemical reactions.
• - This is Organic Chemistry.
• Biologics are made by harvesting the substances
  produced and secreted by constructed cells.
• - This is Genetic Engineering.

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Making a small molecule drug vs. making a biologic
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What are the steps to making Recombinant
Biological Products?
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Step One

• Develop Host A host cell is developed by
  isolating the DNA sequence that codes for the
  desired protein, selecting a vector to carry the
  gene, and then inserting it into a suitable
  bacterial or eukaryotic cell.

Types of cells and the exact sequence of genes
used significantly influence the characteristics
of the protein product.
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Step Two

• Develop Host
• Establish a Cell Bank A cell bank is then
  established using an iterative and elaborate cell
  screening and selection process yielding a unique
  master cell bank.

No two cell master cell banks are ever exactly
alike
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Step Three

• Develop Host
• Establish a Cell Bank
• Protein Production System The engineered cells
  are then cultured on a large scale under growth
  conditions to optimize cellular production and
  secretion of the desired protein.

The vessels used, the components of the solution
(e.g., nutrients, serum, growth factors,
carbohydrates), the type of fermentation process
used, and the physical conditions of the culture
can affect the protein in a way that alters its
biological behavior in the body.
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Step Four

• Develop Host
• Establish a Cell Bank
• Protein Production System
• Purification Cultured cells also produce
  undesired proteins and impurities. Fractions
  containing the desired protein are harvested and
  isolated, and the undesired proteins and
  impurities are separated from the desired protein
  by a series of carefully selected and validated
  steps designed to optimize the purity and yield
  of the desired protein.

Any change in the purification process can alter
the purity profile of the product and affect its
clinical efficacy, safety, and immunogenicity.
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Step Five

• Develop Host
• Establish a Cell Bank
• Protein Production System
• Purification
• Analysis Protein molecules are analyzed for
  uniformity in terms of structure, character, and
  potency and for impurities and contaminants. A
  wide variety of analytical tools, including
  physiochemical and biological tests, are used to
  examine amino acid sequence, glycosylation
  patterns, aggregation, isoform profile,
  heterogeneity, strength and potency.

These tests have become more sophisticated and
are critical, but remain limited in their ability
to detect all product characteristics that may
affect clinical efficacy, safety, and
immunogenicity.
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Step Six

• Develop Host
• Establish a Cell Bank
• Protein Production System
• Purification
• Analysis
• Formulation Therapeutic protein is then
  formulated

As with all of the steps, the components of the
formulation and the process used can
significantly affect the product and its
behavior in patients
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Part Two Special Concerns with Biologics
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Biologics

• All potential clinical effects not always known
• Evaluation of clinical safety use of
  pre-clinical models
• Immunogenicity

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Mechanisms of Action

• Biologics are large and complex, produced from
  living substances and often have multiple effects
  in a patient, from one or more mechanisms of
  action.
• Not all mechanisms of actionthose beyond the
  intended therapeutic effect against a particular
  disease(e.g.)may be known.

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Clinical Safety

• Species specificity limits standard pre-clinical
  models for safety testing
• Usually injected
• Immunogenicity

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Immunogenicity

• Macromolecules (proteins) like biologic drugs are
• capable of triggering an immune response with
• varying but unpredictable consequences
• - Antibodies may have no clinical effect
• - Antibodies may neutralize the molecule making
  it therapeutically ineffective
• - Rare but serious autoimmune responses can be
  life-threatening
• - Small changes in a macromolecule can completely
  shift its immunogenicity profile

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Example- Serious Consequences from Immunogenicity

• Use of a successfully licensed biologic suddenly
  and inexplicably led to an increase in a
  life-threatening condition after a change in the
  products manufacturing processthe formulation
  and vial.

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Part ThreeValue and Importance of Biologics
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Impact of Biologics

• Over the last 25 years, new medicines have
  significantly reduced deaths from major diseases
  such as cancer and HIV/AIDS and improved health
  outcomes for many.
• Reaching a biologics therapeutic potential takes
  time. By the very nature of the science
  underlying them, biologics typically have a
  therapeutic potential well beyond their initial
  therapeutic objective. New treatment advances
  are often realized from biologics that have been
  on the market for a while, but were not known
  until additional research was conducted, which is
  often many years after initial approval.
• With more than 10,000 genetic diseases to tackle,
  biologics hold great promise for future
  diagnosis, prediction, treatment and prevention.
• In 2008, there were more than 630 biotech
  medicines in development including 250 medicines
  for various cancers and 56 for Alzheimers
  disease.

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Selected Milestones in Biotechnology and
Biologics Development

• 1978 First biotech product (synthetic human
  insulin) discovered.
• 1986 First monoclonal antibody (mAb) treatment
  approved.
• 1997 Approval of first mAb-targeted chemotherapy
• 2001 First molecular targeted cancer therapy for
  leukemia
• 2002 New mAb therapy for rheumatoid arthritis
• 2003
• Human genome mapped
• First mAb for allergic asthma
• 2004
• First mAb treatment for colorectal cancer
• First mAb treatment for MS
• First anti-angiogenic medicine for cancer
• First mAb approved to treat EGFR-expressing
  metastatic colorectal carcinoma
• 2006 First vaccine for the prevention of cervical
  cancer

Note all approval dates refer to U.S. approval.
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Examples of Biologics

• Biologics treat or help prevent a range of
  diseases including multiple sclerosis, leukemia,
  hepatitis, rheumatoid arthritis, breast cancer,
  diabetes, congestive heart failure, lymphoma,
  kidney cancer, cystic fibrosis. These medicines
  rely on many cutting-edge technologies and
  include the following
• Vaccines
• Recombinant Hormones/Proteins
• Monoclonal Antibodies (mAb)
• Interleukins
• Interferons
• Growth Factors
• Gene Therapy
• Cell Therapy
• Antisense

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Example of a Biologic Leading to Reduced Rates of
Disability
A biologic to treat rheumatoid arthritis was
found to cut the chance of advanced disability
in half when added to existing treatment.
Percent with Advanced Disability After 54 Weeks
of Treatment
Source J.B. Wong et al., Estimating the
Cost-Effectiveness of 54 Weeks of Infliximab for
Rheumatoid Arthritis, American Journal of
Medicine, 2002.
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Importance of Post-Approval RD
Continued clinical trials after initial approval
help advance patient care by identifying new
uses for medicines
Examples
A golden age of innovation

Why arent post-approval breakthroughs more
widely recognized? One reason is that none of the
treatments described would appear on a list of
innovative new drug approvals over the past few
years. The results all came from clinical trials
involving drugs that had already been approved
for something else often a different stage of
cancer, sometimes a different type of cancer, and
occasionally a different illness altogether. 3
J. Calfee, American Enterprise Institute
Treating Different Conditions

• A biologic initially approved to treat colon
  cancer was subsequently approved to treat lung
  cancer and breast cancer.1

Expanding approved uses or new patient
populations

• A new medicine initially approved for rheumatoid
  arthritis in adults was approved to treat
  children. 2
• A medicine initially approved as a second-line
  therapy for RA patients who had not responded
  well to other treatments was approved as a
  first-line therapy for RA patients.2

Sources 1A. Pollack, FDA Extends Avastins Use
to Breast Cancer, The New York Times, 2008
2PhRMA, Post-Approval Research on Biotech
Medicines Leads to Key Medical Advances, PhRMA
Report, 2007 3J. Calfee, The Golden Age of
Innovation, The American, 2007.
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Example of Additional Indications Post-Approval
in the U.S.
2003
Research into new uses for approved biologics is
an important source of medical advances

As of 2007, 47 of BLAs for recombinant DNA
products and monoclonal antibodies regulated by
CDER had at least one additional FDA-approved
indication after the initial approval. One-third
of all additional indications of
biotechnology-derived protein drugs studied were
approved by the FDA more than seven years after
approval of the initial indication. Boston
Consulting Group
1998
For use in combination with Rebetol to treat
pediatric hepatitis C.2
1997
For use in combination with Rebetol capsules for
chronic viral hepatitis C in patients with
compensated liver disease who have relapsed
following alfa Interferon therapy. To treat
hepatitis B in pediatric patients.2 For use in
combination with Rebetold capsules for chronic
viral hepatitis C in patients with compensated
liver disease previously untreated with alfa
Interferon therapy.
1995
For treatment of clinically aggressive
follicular non-Hodgkins lymphoma in conjunction
with antracycline-containing combination therapy.
1993

For use adjuvant to surgical treatment for
malignant melanoma for those patients free of
disease but at high risk for systemic recurrence
within 56 days of surgery.
1992
For use in condylomata acuminata with podophyllin.
1991
For treatment of hepatitis B in patients 18
years or older with compen-sated liver disease.
1Orphan Indication 2Pediatric Indication
To treat patients with chronic hepatitis non-A,
non-B/C with compensated liver diseases and
history of blood or blood product exposure
and/or who are HCV anti-body positive.
1988
For intralesional treatment of select cases of
condylomata acuminata involving external surfaces
of genital and perianal areas. For treatment of
select patients with AIDS-related Kaposis
sarcoma¹
1986
Example Intron-A (interferon-alfa-2b)
FDA Approval of Original Indication To treat
hairy cell leukemia
Sources Boston Consulting Group, Continued
Development of Approved Biological Drugs, White
Paper, December 2007 PhRMA, Post-Approval
Research on Biotech Medicines Leads to Key
Medical Advances, PhRMA Report, October 2007.
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For More InformationPlease visit the following
links

• U.S. Food and Drug Administration Center for
  Biologics Evaluation and Research (CBER)
  http//www.fda.gov/Cber
• U.S. Department of Health and Human Services
  http//www.hhs.gov/drugs/biologics
• National Center for Biotechnology Information
  (affiliated with the NIH) http//www.ncbi.nlm.ni
  h.gov/
• World Health Organization http//www.who.int/bio
  logicals/en/
• National Biological Standards Board (UK)
  http//www.nibsc.ac.uk/
• Registry of biomedical companies
  http//hum-molgen.org/biotechnology/
• American Institute for Medical and Biological
  Engineering (AIMBE) http//www.aimbe.org/index.p
  hp

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Reference Definitions

• Acquired Immunodeficiency Syndrome (AIDS)
• Life-threatening viral disease characterized by
  the breakdown of the bodys immune defenses.
• Autoimmune Disease
• A disease that results when the immune system
  mistakenly attacks the bodys own tissues.
  Examples include rheumatoid arthritis and
  systematic lupus erythematosus.
• Biological Response Modifiers
• Either natural or synthesized substances that
  boost, direct, or restore normal immune defenses.
• Deoxyribonucleic Acid (DNA)
• Carrier of genetic information found in the
  nucleus of the cell.
• Enzyme
• Protein produced by living cells that
  accelerates chemical processes needed for life
  without itself being altered.

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Reference Definitions

• Hybridoma Technology
• Two cells (a secreting cell from the immune
  system and a long-lived cancerous immune cell)
  are fused within a single membrane to create a
  hybrid cell that can be cloned. The daughter
  cells then secrete harvestable quantities of
  antibodies (called monoclonal antibodies) and
  lymphokines.
• Immunoassay
• Test using antibodies to identify and quantify
  substances. Often the antibody is linked to a
  marker such as a fluorescent molecule, a
  radioactive molecule, or an enzyme.
• Monoclonal Antibodies
• Antibodies produced by a single cell or its
  identical progeny, specific for a given antigen.
  As a tool for binding to specific protein
  molecules, monoclonal antibodies are invaluable
  in research, medicine, and industry.
• Nucleic Acids
• Large, naturally occurring molecules composed of
  chemical building blocks known as nucleotides.
  There are two kinds of nucleic acids DNA and RNA.

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Reference Definitions

• Pharmacodynamics
• The study of how drugs affect the body.
• Pharmacokinetics
• The study of what the body does to
  pharmaceutical drugs.
• Specificity
• The ability of the immune response to interact
  with specific antigens.