Biopharmaceuticals Transforming proteins and genes into drugs

Prepared by:

By-

Kuldeep DabasXIIIth Batch

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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

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Terminology used

Biologics

Biopharmaceuticals

Biosimilars

Follow-on Biologics

Biogenerics

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

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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

Cornerstones in biotechnology history which have influenced the production of Biopharmceuticals

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Traditional Vs Biopharmceuticals

Multiple effect

Short Acting

Non-Immunogenic

Species independent

Small molecules

Stable

Oral administration

General practice

Specific effect

Long acting

Immunogenic

Species dependent

Large molecules

Heat sensitive

Parenteral

Hospital

Traditional Biopharmceuticals

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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

Note: Sources mentioned in the notes section of slide

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Complexity of Biopharmceuticals

Size

Structure

Modification

Stability

Epoetin

Aspirin

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Types of Biologics

Peptides

Non-glycosylated proteins

Glycosylated proteins

Monoclonal antibodies

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Manufacturing Process

UPSTREAM •Cell expansion•Fermentation•Clarification

DOWNSTREAM•Centrifugation•Chromatography•Ultra filtration

Raw materials

In process

Drug substances release

Cell Bank

Drug substances

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Biotech Process

A typical fermentation based biotech process flow

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

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2005 2006 2007 2008 2009

Nu

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of

Ap

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New molecular entities New biologic entities

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

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16

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2005 2006 2007 2008 2009

Nu

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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

2 Infliximab RemicadeJ&J, Schering Plough,

Mitsubishi $5,934 Rheumatoid Arthritis

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

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

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Top 10 companies in Biopharmceuticals

# Rank CompanySales/Revenues

In US$ Million)

R & D spending

(In US$ Million)Therapeutic area

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

2. Genentech 10,531 2,800 Oncology, Immunology, Tissue Repair, Neuroscience,

Ophthalmology

3. Novo Nordisk 8,989 1,550Diabetes care , Haemostatic management , Growth hormone

therapy , Hormone replacement therapy

4. Merck Serono 7,338 1,580 Neurodegenerative Diseases, Oncology, Fertility, Endocrinology,

Autoimmune and Inflammatory, Cardio metabolic care

5.Baxter biopharma

solutions 5,308 868 Hemophilia, Biotherapeutics, Regenerative Medicine, Vaccines

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

Cardiopulmonary

7. Genzyme 3,751 750

Genetics Diseases, Cardio metabolic and Renal, Oncology,

Orthopaedics/Biosurgical Specialties, Transplant,

Genetics/Diagnostics

8. CSL ltd 2,961 202

Dermatology, Urology, Cardiovascular, Antibiotics, Anaphylaxis,

Central nervous system, Analgesia, Emergency Care, Obstetrics

and Gynecology

9. Allergan 1,311 798Neurosciences, Medical Dermatology and Urology, Eye Care,

Medical Aesthetics, Obesity Intervention

10. Alexion Pharma 259 63 Hematology

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

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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

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

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

Infliximab Crohn’s disease $16,500 -

Source- MONROE 2006Cost for indication listed are for 2005

Biosimilar

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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

Note: Sources mentioned in the notes section of slide

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Pre-Clinical

Clinical

Biosimilars -Scientific basis for abbreviated pathway

New Biologic Extensive Characterization

Pre-Clinical

Clinical

Demonstrate Quality, Safety, Efficacy

Surv

eill

ance

Regula

tory

Appro

val

Biosimilar

Extensive Characterization

Extensive Comparison to

Reference

Pre-Clinical

Regula

tory

Appro

val

Surv

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Clinical

Allows for abbreviated pre-clinical & clinical

Regulation of Biosimilars

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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

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

10-year period for innovator

exclusivity, with the opportunity

for an additional year for new

indications5

Currently there is no clear guidelines

and authority for approval of

biosimilars

No equivalent of ANDA under PH&S

act for approval of biosimilars6

A biosimilar could not be approved

until 12 years after the date on which

the reference product was first

licensed5

Requires only Phase III clinical

trials for 100 patients

Pharmaceuticals and medical device

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

Pharmaceuticals and medical device

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

Well Defined FrameworkWell Defined Framework

EUROPEAN5 UNION

Under process of DevelopmentUnder process of Development

USA5

JAPAN 1

No or Minimal FrameworkNo or Minimal Framework

CANADA 4

INDIA2

CHINA 4

Note: Sources mentioned in the notes section of slide

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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

Regulation of Biologics

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Challenges in front of Biopharmceuticals

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)

From Industry perspective

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Continue…

No guidelines (Since Biopharmceuticals are in Nascent stage)

Adverse - effects

From Govt. perspective

From Patients perspective

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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 drug1st generation Biopharmceuticals (small

molecules)2nd Generation Biopharmceuticals (large molecules)

Follow on Biopharmceuticals Biobetters ….….What next???

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