Biologics Introduction, The Critical Path for Medical Product Development

Biologics Introduction, The Immune System Modulators

Biologics Introduction, Interactive Exercise: Is It a Small Molecule or a Biologic?

Biologics Introduction, FDA Approval for Biologics, Clinical trial Phases: I, II, III, IV

Biologics Introduction, FDA Approval for Biologics, Components of Product Development

Biologics Introduction, FDA Approval for Biologics, Clinical Trial Phases: I, II, III

Biologics Introduction, FDA Approval for Biologics

Biologics Introduction, The Market for Biologics Therapy

Biologics Introduction, Biologics, the Start

Biologics Introduction, Define a Biologic (Clarification of Terminology, FDA Changes): Drugs

Biologics Introduction, Define a Biologic (Clarification of Terminology, FDA Changes)

Biologics Introduction, Define a Biologic (Clarification of Terminology, FDA Changes)

Biologics Introduction, Protein Structure and Function

Discovering and bringing one new drug into the market typically costs as much as $800 to $900 million.

The development cycle can take up to 15 years.

Only 10% of new drugs win FDA approval.

Bringing a new biologic to the market is enormously expensive, and 90% do not make it.

Intro → Target → Discovery → Target → Validation → Assay → Development → Screening & Hits to Leads →  Lead → Optimization → Development → IND → Clinical Trials → NDA or BLA Market

The critical path for medical product development:

• Basic research
• Prototype design or discovery
• Preclinical development
• Clinical development
• FDA filing/approval & launch preparation
• Market application
• Approval

64 biologics were introduced in Europe and the US between 2000 and 2003.

Immune system modulators:

• transplant rejection 
• rheumatoid arthritis 
• multiple sclerosis 
• hepatitis

Cancer targets:

• colorectal cancer  
• non-Hodgkins lymphoma

Growth factor modulation:

• angiogenesis  
• erythropoiesis

Enzymes:

• Thrombolytics

Hormones

How well do you know the difference between a biologic and a conventional therapeutic?

Biologic:

• Procrit
• Herceptin
• Lantus

Therapeutic:

• Lipitor
• Nexium
• Viagra

After a drug receives approval from the FDA, studies are conducted to evaluate the long term safety, referred to as phase IV studies.

Phase IV:

• Additional endpoints and safety
  • evaluation of long-term safety

PKDM program:

• Consists of studies required to characterize absorbtion, distribution, metabolism, and excretion properties of the drug

Safety pharmacology:

• Deals with exposures that fall within the therapeutic range of the drug

CMC program:

• Identifies strength and dosage form used in first study of human subject

The FDA provides specific guidelines for phase I through III studies in different therapeutic areas, but generally the goal of each phase is the same across therapeutic areas.

Phase I:

• Safety, toxicity, and dose:
  • first time humans are exposed to medication
  • often evaluate the new drug on healthy volunteers

Phase II:

• Efficacy and safety:
  • determine effects of drug
  • evaluate occurrence of adverse effects

Phase III:

• Efficacy and safety; role in clinical practice:
  • evaluate effectiveness of an intervention and its safety relative to the best available treatment or placebo

The FDA plays an instrumental role in determining whether a  potential new drug can be brought to market. 

The FDA has prepared guidelines on the type of data that is required for the Investigational New Drug (IND) application.

Preclinical drug data consists of:

• Toxicology
• Drug metabolism and pharmacokinetics
• Chemistry, manufacturing and control

Preclinical studies:

• in vitro: cell-based assays
• in vivo: rodents, non-rodents

FDA approval is required for all pharmaceuticals sold within the United States.

The approval process not only includes the clinical efficacy and safety, but also the manufacturing process.

In 1987, Center for Drugs and Biologics split into:

• Center for Drug Evaluation and Research  (CDER)            
• Center for Biologics Evaluation and Research (CBER)

CDER:

• FDC section 505 - “Conventional Drugs”

CBER:

• Public Health Service Act section 351 - Most Biologics

Biologic medicines:

• ~$32bn in 2003
• $53bn. In 2010 (forecasted)

Biologic therapies may offer best options for treating illnesses and conditions that presently have inadequate or no treatments available.

These modern therapies are often targeted to specific cell types or to specific molecules.

Around 150 biologics on the market today have helped approximately 250 million people.

Scientific advances continue to forge the growth of biologics by:

• Aiding in search for clinical targets
• Tailoring of specific therapies for greatest efficacy

Therapeutic biologics range from:

• Natural sources
• Blood and blood components
• Antitoxins
• Modern recombinants
• Monoclonal antibodies
• Cytokines
• Growth factors
• Vaccines directed against non-infecious disease targets
• Gene transfer products

Conventional therapeutic drugs:

• Usually chemically synthesized compounds with particular structures and physical and chemical properties
• Characterized by their defined active ingredients
• Often small, (MW 100–300 Daltons)
• Formulated for oral delivery

Biologic drugs:

• Complex in structure
• Not fully characterized  
• Prepared from a living source
• Usually protein or carbohydrate based
• Larger than conventional drugs (MW 10,000-300,000 Daltons)

The first modern biologic, Humulin, was approved in the early eighties.

Humulin:

• Recombinant insulin that is grown in bacterial cell culture

Bacteria can be genetically engineered to produce mammalian proteins, however they cannnot make modifications that mammalian cells can make, so mammalian cells are still used to manufacture the majority of mammalian proteins.

Synthesis of drugs for commercial production:

• Conventional drug:
  • Fairly simple process of scaling up the laboratory reactions and formulation processes
• Biologic drugs:
  • Scaling up the processes used to create biologics on a commercial scale is much more difficult.
  • Administration is often problematic as these large molecules rely on easily broken interactions for their function.
  • Held together with peptide bonds and even weaker interactions.
  • Oral administration forms have been difficult to formulate.
  • Most rely on injections or infusions which can pose problems of severe allergic reactions and anaphylaxis. 

• A protein is flexible, so increasing temperature causes the atoms of the protein molecule to move around more and more.
• A protein's native structure can be disrupted by high temperature.
• Denaturation disrupts or abolishes a protein's normal interactions with other molecules.

• A protein can be denatured by acids or bases and oxidizing or reducing agents that interfere with the normal interactions between the protein's atoms.
• Denaturation destroys the protein's structure biological activity. 

Changes in temperature affect the shape of a protein.

• To function normally, many folded polypeptide chains form stable complexes.
• Sometimes complexes form from several identical chains.
• Complexes contain copies of different chains.

• Surrounding conditions affect the characteristics, and sometimes structure, of a protein.
• The characteristics of the solution in which a protein molecule is dissolved can be important.

• A pair of charged amino acids may form a strong ionic interaction within a protein.
• Pairs of amino acid cysteine can form a strong covalent bond in which two sulfur atoms are joined, creating a disulfide bridge.

Side chains of the amino acids that end up on the surface of the protein affect the chemical characteristics of the region of the surface at which they're found.  

• Particular regions of the surface will be perfectly suited for interacting with other molecules as part of the protein's function.
• Pockets or other surface shape features may fit and bind to a target molecule.

• Within a protein, there are levels of structure.
• A protein's primary structure is its sequence of amino acids.

Secondary structures have:

• alpha helices
• beta sheets

Tertiary structures:

• Secondary structures assembled into organized bunches to form domains 

A single polypeptide may fold to form one or more domains.

Proteins and DNA:

• Both linear polymers
• Molecules made up of chains of smaller units called monomers

Cellular machinery translates the genetic information in a gene's DNA into a protein molecule.

Amino acids:

• Monomers of the protein polymer
• Linked by peptide bonds to form the polypeptide chains

• Chain of amino acids fold into a precise three-dimensional structure.
• Each amino acid has a side chain that branches off the main chain of the polypeptide.
• The side chain has chemical properties specific to the particular amino acid.

Side chain may: 

• Bear a positive or negative electrical charge
• Be uncharged
• Be repelled by water in the surrounding solution
• Have an affinity for water molecules

• Protein molecules are macromolecules.
• Proteins are the products of genes.
• Information specifying any particular protein molecule is encoded in molecules of DNA.

The Biogenerics Market Outlook, January 2005, Business Insights.

Walsh, Gary Biopharmaceutical benchmarks-2003, Nature Biotechnology August 2003 865-870.

Baumann A, Early development of therapeutic biologics--pharmacokinetics., Curr Drug Metab. 2006 Jan;7(1):15-21.

Trimming the costs, IBM in drug discovery collaboration 17/04/2003.

The Tufts report, Outlook 2005.

Walsh, Gary Biopharmaceutical benchmarks-2003, Nature Biotechnology August 2003 865-870.

BLA - Biological License Application

IND - Investigational New Drug Application

NDA - New Drug Applications

Denaturation - high temperature disrupts or completely abolishes a protein's normal interactions with other molecules.

Quaternary structure - the level of structure describing the spatial arrangement of two or more polypeptide chains in a complex.