Biopharmaceuticals

Transforming proteins and genes into drugs

By-

Kuldeep DabasPrepared by:

XIIIth Batch
 Flow of presentation

I. Biopharmaceutical

1.Definition
2 Structure
3.Type
4. Manufacturing
5. Top 10 Biopharmaceuticals(2008)
6. Top 10 Biopharmaceutical companies

II. Biosimilars
1.Definition
2.Regulation
3.Strategies

III. Challenges for Biologics

IV. Future

V. Conclusion

2
 Terminology used

 Biologics

 Biopharmaceuticals

 Biosimilars

 Follow-on Biologics

 Biogenerics

3 Note- Following terms are used in different organization in different places

 Cornerstones in biotechnology history which have influenced the
production of Biopharmceuticals

1953: Discovery of DNA structure

1973: Discovery of DNA restriction enzymes

1977: Genentech, first biotech-enterprise founded

1982: First biopharmaceutical approved by FDA: recombinant human insulin

1986: First recombinant vaccine (HepB) is approved for human use, first
recombinant anti-cancer drug (Interferon) is produced

2003: Human genome sequenced

4
 Traditional Vs Biopharmceuticals

Traditional Biopharmceuticals
Multiple effect Specific effect

Short Acting Long acting

Non-Immunogenic Immunogenic

Species independent Species dependent

Small molecules Large molecules

Stable Heat sensitive

Oral administration Parenteral

General practice Hospital

5
 Definitions of Biologics\Biopharmaceuticals

A biologic can be any therapeutic serum, toxin, antitoxin, vaccine, virus, blood, blood component or derivative,
allergenic product, or analogous product, or derivatives applicable to the prevention, treatment, or cure of
injuries or disease of human

Source – FDA

“A biological substance is a substance that is produced by or extracted from a biological source and for which a
combination of physico-chemical-biological testing and the production process and its control is needed for its
characterisation and the determination of its quality

Source – EMEA

“a substance which cannot be completely characterized by physicochemical means alone and which therefore
requires the use of some form of bioassay”.

Source – WHO

6 Note: Sources mentioned in the notes section of slide

 Complexity of Biopharmceuticals

Structure
Epoetin Size

Aspirin
M

Stability
od
ifi
ca
tio
n

7
 Types of Biologics

 Peptides

 Non-glycosylated proteins

 Glycosylated proteins

 Monoclonal antibodies

8
 Manufacturing Process

Cell Bank

UPSTREAM
•Cell expansion
•Fermentation
Raw In
•Clarification
materials process
DOWNSTREAM
•Centrifugation
•Chromatography
•Ultra filtration

Drug substances
Drug release
substances
9
 Biotech Process

A typical fermentation based biotech

process flow

10
 FDA Approvals (2005-2009) Synthetic V/s Biopharmceuticals

25

21

20 19
18 18
16
Number of Approvals

15

10

6
5 4
3
2 2

0
2005 2006 2007 2008 2009

New molecular entities New biologic entities

11
 EMEA Approvals (2005-2009) Synthetic V/s Biopharmceuticals

25
23

20
20 19

16
Number of Approvals

15
13

10
10
8
6
5
5 4

0
2005 2006 2007 2008 2009

New molecular entities New biologic entities

More number of Biopharmceuticals were approved by EMEA as compared to FDA in 2009

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 Benefits of Biopharmaceuticals

 Highly effective and potent action

 Fewer side effects

 Potential to actually cure diseases rather than merely treat the symptoms

 Longer half life

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 Top 10 Biopharmceuticals in 2008

#Rank Biopharmceuticals Brands Company Sales(08)(US$ million) Therapeutic area

1 Etanercept Enbrel Amgen, Wyeth $6,580 Rheumatoid Arthritis

J&J, Schering Plough,

2 Infliximab Remicade $5,934 Rheumatoid Arthritis
Mitsubishi

3 Bevacizumab Avastin Roche $5,777 Colorectal cancer.

4 Rituximab Rituxan Roche $5,653 Head and Neck Cancer

5 Adalimumab Humira Abbott $5,488 Rheumatoid Arthritis

6 Epoetin alfa Epogen Amgen $5,033 Renal anemia

7 Trastuzumab Herceptin Roche $4,890 Breast cancer

8 Insulin Lantus Sanofi Aventis $4,180 Diabetes

9 Pegfilgrastim Neulasta Amgen $3,355 Neutropenia

10 Darbepoetin Aranesp Amgen $2,871 Anemia

14 Source- La Merie Business intelligence (R&D Pipeline news 10 March 2010)

 Top 10 companies in Biopharmceuticals

Sales/Revenues R & D spending

# Rank Company Therapeutic area
In US$ Million) (In US$ Million)

1. Amgen 14,687 $2,900 Oncology, kidney disease, rheumatoid arthritis

Oncology, Immunology, Tissue Repair, Neuroscience, Ophthalmology

2. Genentech 10,531 2,800

Diabetes care , Haemostatic management , Growth hormone

3. Novo Nordisk 8,989 1,550
therapy , Hormone replacement therapy

Neurodegenerative Diseases, Oncology, Fertility, Endocrinology,

4. Merck Serono 7,338 1,580
Autoimmune and Inflammatory, Cardio metabolic care

Baxter biopharma
5. 5,308 868 Hemophilia, Biotherapeutics, Regenerative Medicine, Vaccines
solutions

6. Biogen Idec 3,968 1,072 Neurology, Oncology, Immunology, Hemophilia, Cardiopulmonary

Genetics Diseases, Cardio metabolic and Renal, Oncology,

7. Genzyme 3,751 750 Orthopaedics/Biosurgical Specialties, Transplant,
Genetics/Diagnostics

Dermatology, Urology, Cardiovascular, Antibiotics, Anaphylaxis,

8. CSL ltd 2,961 202 Central nervous system, Analgesia, Emergency Care, Obstetrics and
Gynecology

Neurosciences, Medical Dermatology and Urology, Eye Care,

9. Allergan 1,311 798
Medical Aesthetics, Obesity Intervention

10. Alexion Pharma 259 63 Hematology

15 Source-Contract Pharma Articles » 2009 » July/August 2009

 Cost of Biopharmceuticals

Drug Indication Cost Duration

Cerezyme Life-threatening enzyme deficiency $200,000 to $500,000 12 Month

Trastuzumab (Herceptin) Breast Cancer $36,000 6 Month

Rituximab (Rituxan) Non-hodgkin’s lymphoma $32,500 2 Month

Bevacizumab (Avastin)/ Cetuximab

Metastatic Colorectal Cancer $28,500 2 Month
(Erbitux)

Infliximab (Remicade), Rheumatoid arthritis $18,000 -

Infliximab Crohn’s disease $16,500 -

Cost for indication listed are for 2005 Source- MONROE 2006
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Biosimilar
 Definitions and Terminologies

A biosimilar medicine is a medicine which is similar to a biological medicine that has already been authorised (the
‘biological reference medicine’)1
Source – EMEA

“A follow-on biologic (FOB) is “a protein product which is intended to be a similar version or duplicate of an already
approved or licensed protein product”.4
Source – FDA

A new biological medicinal product claimed to be “similar” with regard to quality, safety and efficacy to an already
approved reference medicinal product3
Source – WHO

“A drug to be developed by a different marketing approval holder as a drug that is bio-equivalent/quality-equivalent to

biotechnology-derived drug already approved domestically” 2
Source – PMDA ,Japan

Commonly used
terminologies/synonyms
• Biosimilars
• Biogenerics
• Follow on Biopharmceuticals
• Follow on Protein

18 Note: Sources mentioned in the notes section of slide

 Biosimilars -
Scientific basis for abbreviated pathway

Demonstrate Quality, Safety, Efficacy

Surveillance
Regulatory
Extensive

Approval
New Biologic Clinical
Characterization

Pre-Clinical

Clinical
Extensive

Regulatory

Surveillance
Characterization

Approval
Clinical
Biosimilar
Extensive Pre-Clinical
Comparison to Pre-Clinical
Reference

Allows for abbreviated

19 pre-clinical & clinical
Regulation of Biosimilars
 No Harmonized Worldwide Regulatory Framework for
Biosimilars

 Small molecule generics model is inappropriate

 In many regions limited or no regulatory processes exist

 Lack of minimum regulatory standards presents a risk for patients

because of the potential issues relating to the quality, efficacy and safety
of biosimilars developed and approved without defined requirements

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 Biosimilars – Regulatory Perspective

Well Defined Framework Under process of Development No or Minimal Framework

EUROPEAN5 USA5 INDIA2

UNION
 Comparability studies are required
to substantiate evidence for safety,
efficacy and quality5
 Guidelines, including specific clinical
and non-clinical data requirements
for four product types:
Recombinant insulin, human
growth factor, erythropoietin and
CSFs 6
 Currently there is no clear guidelines
and authority for approval of biosimilars  Requires only Phase III clinical
trials for 100 patients
 No equivalent of ANDA under PH&S act
for approval of biosimilars6
CHINA 4
 A biosimilar could not be approved until
12 years after the date on which the
reference product was first licensed5

 10-year period for innovator

exclusivity, with the opportunity for
JAPAN 1
an additional year for new
 Pharmaceuticals and medical device
indications5
Agency (PMDA )
Japan's regulator, expects to finalize a
new guideline for the regulation of
follow-on Biopharmceuticals this year,

 First draft put out for public comment

last September

CANADA 4
22 Note: Sources mentioned in the notes section of slide
 Biosimilars In the Market Today

 Europe - Sandoz –Omnitrope (hGH), Binocrit (“EPO” or erythropoietin);

Biopartners -Valtropin (hGH);
Hexal –EPO version;

 U.S. –Sandoz -Omnitrope

 China –EPO versions, Interferons, IL-2, IL-11, GM-CSF, hGHs

 India –hGH. EPO, Interferon alpha 2b, insulin

 Australia –Omnitrope (Sandoz)

 Cuba, Egypt, Africa –EPO versions

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 Strategic Options to Tap Biosimilar Market

Generics firms enter successfully into the biosimilars

market

Pharmaceutical companies expand their Biopharmceuticals

business and enter biosimilars market opportunistically

New types of cooperation between Pharma, Biotech

or Generics

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 Biosimilars successful if all hurdles passed

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 The other side of the Biopharmceuticals…….

Safety issue …………??????????

 Biologic drugs are orders of magnitude more complex than small

molecule drugs

 Safety & efficacy of final product is exceptionally sensitive to small

changes in manufacturing process

 It is difficult to impossible to predict the effect of these small changes—

experience counts

 Potential for dramatic negative health consequences

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 Key Success Factors for Biosimilars

1. Consistent long term strategy

2. Healthy financial structure

3. Comprehensive competitive intelligence

4. Core competencies for manufacturing process

5. Deep clinical development and regulatory expertise

6. Effective marketing & sales skills

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Regulation of Biologics
 Challenges in front of Biopharmceuticals

From Industry perspective

 Long and costly clinical trials

 Efficacy

 Difference in Sero – Prevalence (Virus etc) and Genetic makeup (Human

beings)

 Low cost advantage (due to costly raw materials, equipments and labor)

 Difficult to copy (Standardization process)

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 Continue…

From Govt. perspective

 No guidelines (Since Biopharmceuticals are in Nascent stage)

From Patients perspective

 Adverse - effects

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 Future of Biopharmceuticals

 More diseases will come under the treatment

 Effective manufacturing

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 Conclusion

 Biopharmceuticals or PERISH!!!!!!!

 Traditional drug1st generation Biopharmceuticals (small

molecules)2nd Generation Biopharmceuticals (large molecules)
Follow on Biopharmceuticals Biobetters ….….What next???

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