The Future of Pharmaceutical Innovation
The Significant Achievements of the Modern Pharmaceutical Innovation
Sector
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20th century saw dramatic improvements in number and effectiveness of
medicines for many diseases
e.g. cancer, viral, bacterial, cardiovascular disease, etc
Better awareness of drug toxicity and how to diminish it
Better knowledge of how drugs work, what happens to them in the body,
etc
Developments in chemistry provided more molecules for drug testing
But Finding New Drugs Steadily Became More Challenging, Complex and
Costly
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Post‐1990s, big improvements in understanding human disease (i.e.
genes, cell pathways, etc)
Powerful new “OMICS” technologies (measure tens of thousands of
genes, proteins or metabolites in body samples)
“Big Pharma” an early adopter of these methods – to better find new “drug
targets” (receptors)
Growth of government regulation made drug approval more complicated
Have these changes yielded more drugs, more effective drugs, or safer
drugs? Diagram Next Page
The Needle in a Haystack Problem
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Masses of detailed experimental data – very easy to find lots of disease‐
associated protein changes
Uncertainty over which proteins will make best drug targets
Huge costs associated with poor target choices
Is There a Productivity Crisis in Pharmaceutical Innovation? Long‐term
R&D Trends in the Industry
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Eroom’s Law- The number of new drugs approved by the US‐FDA per
billion US dollars (inflation‐ adjusted) spent on research and development
(R&D) has halved roughly every 9 years.
R&D Expenditure by Big Pharma in USA
The Drug Development Phase of Pharmaceutical Innovation (“Human
Testing”) has Gotten Expensive
Most Classic Drugs Covered in PHAR1101 are “Small Molecules”
(Absorbed from GI‐tract)
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Aspirin- MW = 180 g/mol
Chlorpromazine- MW = 319 g/mol
Ibuprofen- MW = 206 g/mo
Modern Therapies can be Enormous
What is a Drug ? Older versus Newer Concepts
Some Examples of Biopharmaceuticals Produced by the Biotechnology
Industry (1990s & Beyond)
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Therapeutic Proteins
• Growth factors & cytokines
• Haemopoietic factors (stimulate white blood cell growth after
chemotherapy)
• Erythropoietin (EPO, stimulates red blood cell growth)
• Hormones (e.g. insulin, human growth hormone, etc)
• Coagulation factors & antithrombotic factors
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Therapeutic Antibodies (e.g. Remicade)
• Antisense Nucleic Acids (e.g. Fomiversen)
Areas of Medicine Where “Biologics” Have Had a Key Impact in the Past 20
Years
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Hormone deficiencies
“Blood tumours”
Autoimmune diseases
Solid tumours
Two Classic Problems with Protein‐Based Drugs
Options for Administering Large Molecule Drugs
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Oral Route – not very effective (proteins broken down by proteases in GI‐
tract)
Lung Route – quite effective if proteins delivered deep as micron‐sized
particles
Nasal Route – reasonably effective for some proteins, but often low
absorption
Skin Route – may work if skin barrier transiently disrupted (sonic energy,
electric current)
An Example of a Pioneering Modern Biopharmaceutical: Infliximab
(“Remicade”)
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Approved by US‐FDA in 1998
Belongs to “TNF Inhibitor” class of Anti‐inflammatories (many now)
A therapeutic antibody that neutralises role of tumour necrosis factor‐α
(TNF)
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Developed by Drs Jan Vilcek and Junming Le (NY University)
Changed the treatment of RA Sales ≈US$5 billion/p.a.
Rheumatoid Arthritis (RA)
• A serious and disabling “autoimmune” disease (affects ≈1% of population)
• 2-3 × more common in women
• Painful inflammation and swelling in joints (e.g. hands, knees, feet, etc)
• Involves “self-reacting” antibodies, loss of cartilage and bone, destroyed
joints
• Morning stiffness & fatigue
• Probably caused by imbalance between pro- & anti-inflammatory T-cells
(immune cells made in thymus gland)
• Patients often die from infections, heart disease, strokes, etc
Role of TNF‐α in RA Inflammation
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TNF- is a powerful molecule made in body by immune cells (a “cytokine”
- mainly made by macrophages)
o TNF has strong tissue damaging properties
High TNF levels occur in synovial fluid in RA joints
o Causes permanent cartilage damage and bone loss
Blocking its effects with antibodies can slow RA progression
The Development of Infliximab
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1933, Jan-Vilcek born in Slovakia
o Received M.D. and PhD
o 1964, defected to USA
Worked at NYU School of Medicine
Developed interest in cytokines
1989 with Junming Le, created a monoclonal antibody against TNFo Collaborated with the biotechnology company Centocor (now
Janssen)
o Led to first anti-TNF drug Remicade
How TNF Inhibitors Suppress Inflammatory Joint
Damage...
How Infliximab is Used Clinically
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Given via intravenous infusions (“IV”) over 2 hr period
o Repeat at 2 and 6 weeks, then every 8 weeks
Doses increased if response suboptimal after 12 weeks
o Very effective in rheumatoid arthritis (usually combined with
methotrexate)
Also used against other chronic inflammatory disorders
E.g. Crohn’s
disease, ulcerative colitis, psoriasis, ect
Problems with Infliximab
1) Potential for Toxic Effects:
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E.g. unpleasant allergy symptoms during infusion (vary in severity)
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Risk of liver damage (rare)
Makes some diseases worse (e.g. MS)
2) Reduced Ability to Fight Infections
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Activation of “dormant” tuberculosis
Nasty fungal infections
3) It is Expensive
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>$20K per year per RA patient (US)
Social access concerns
Other Immunomod ulatory Biopharmaceuticals
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There are now many “TNF Inhibitors” available for use
Significant successes in many patients
All must be given by injection
All face similar problems with allergies, TB, cost, etc
Challenge for the Future: Can we make cheaper, small molecular weight
TNF blockers?
Conclusion
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The pharmaceutical industry is in a prolonged state of flux
o More success in making large protein‐ based drugs than traditional
small, orally‐administered drugs
What sort of drugs will be made in future decades remains unknown
Still lots of ongoing health challenges needing drug innovation!
o Latest trend sees small molecules being made after the success of
protein‐based therapies is proven