بسم اهلل الرحمن الرحیم

Biosimilars & Biobetters

What is a biologic drug?

Biologic drugs is a medicine whose active substance is made by

or derived from a living organism.

The first recombinant proteins to be produced - in the 1970s

and 1980s - were insulin and growth hormone.

These biologic drugs range from the simpler and smaller, often

non-glycosylated proteins, such as insulin or growth hormone to

the much more complex and larger biologic drugs, including

glycoproteins and monoclonal antibodies.

E. coli bacterium producing interferon gamma

What is a biosimilar medicine?

The term biosimilar refers to products that are marketed after

expiration of patents, which are claimed to have similar

properties to existing biologic products.

Due to the complexity of biologics, a product can only be

made that is similar, but not identical.

Terminology

Similar biological medicinal product (EMA)

Biosimilar (EMA)

Subsequent entry biologic (Canada)

follow-on biologic (FDA, Japan)

Follow-on protein product (FDA)

Iran?

به فرآروده بیولوژیکی اطالق می : داروهای مشابه بیولوژیکشود که دارای ماده موثره یکسان با داروی اختصاصی اصلی

بوده و از لحاظ کیفیت، ایمنی و اثربخشی مشابه داروی .اختصاصی اصلی و قابل جایگزینی درمانی با آن باشد

Other related terms

Generic

This is a small-molecule drug whose active substance is shown by

appropriate testing to have identical physicochemical, preclinical

and clinical properties to an originator small-molecule drug.

Other related terms

Biobetters : These are drugs that are similar to innovator

biologics but are characterized by some change in the

structure of the protein or the process by which they are made,

with the goal of improved efficacy, safety or immunogenicity.

A major advantage to manufacturers of biobetters is the fact

that they have lower early-stage R & D costs compared to

originator drugs.

Biosimilars vs. Biobetters

More incentives exist to develop biobetters than biosimilars,

particularly in the US.

Companies may be inclined to develop biobetters rather than

biosimilars for a number of reasons.

They are new biologics, rather than copies of old ones.

Biobetters will also command a higher price than a biosimilar

would. the improved function of the drug will add value to

what is currently available on the market.

Why do biological medicines differ

from chemical medicines?

How are biological medicines

manufactured?

Production of the cells Production of the master cell bank

The exact DNA sequence and the

type of host cell used will

significantly influence the

characteristics of the product

No two master cell banks are

exactly alike

How are biological medicines

manufactured?

The conditions under which cells

are cultured can affect the

nature of the end product.

Purifying the protein

Cell fermentation

Any change in the purification process can

affect the clinical characteristics of the

product

Production and purification of biopharmaceuticals is

a complicated process

• Small molecule pharmaceutical: < 100 quality tests

• Biopharmaceutical: > 2000 tests

MethodsAttributes

IE, HPLC, gel electrophoresisPrimary sequence (peptide map and amino acid

sequence analysis), immunogenicity

(immunoassay) other identity indicators

Cell-based bioassay, gene expression bioassay, ADCC, CDCPotency

Near/far UV circular dichroism spectroscopy, Fourier transform infrared,

spectroscopy, X ray crystallography and differential scanning calorimetry

Conformation

Monosaccharide composition analysis, oligosaccharide profile, CE, LC-MS, MS/MS,

ESI, MALDI-TOF

Glycosylation

Peptide mapping with MSPhosphorylation

SE-HPLC, gel electrophoresis, AUC, peptide mapping with MS, RP HPLCTruncation

Peptide mapping with (MS, HPLC), methylation, isomerization (RP HPLC)Glycation

SE-HPLC, gel electrophoresis, Light scattering and AUCAggregation

Peptide mapping with MSOxidation

Capillary IEF, peptide mapping with MS, and CEX-HPLCDeamidation

ELISA, DNA, endotoxin (Limulus amebocyte lysate assay)Host cell proteins

Cell assays, spectroscopy, ELISABinding

Cell assays, animal modelsBiological activity

Analysis

Formulation

Formulation is a key step in stabilizing the protein.

The components of the formulation, and the process

used, can significantly affect the product’s behavior

in patients.

Example: Pure Red Cell Aplasia (PRCA) associated

with EPO treatment Removal of human serum albumin stabilizer

from epoetin alfa

Number of Epoetin Alfa PRCA Cases

year

Formulation

In 1998, HSA was replaced with polysorbate 80 in prefilled

syringes of Eprex®

Factors potentially contributing to the immunogenicity of Eprex ®

• Formation of micelles associated with Epoetin

• Silicon droplets in the pre-filled syringes

• Leachates from rubber stoppers

• Mishandling

Source : N Engl J Med 2004;351:1403-8.

Biosimilars and immunogenicity

• Current analytical methods cannot fully predict biological

properties

• The immune system can detect alterations in products

missed by analytical methods

• Antibodies against the biopharmaceuticals could have

serious clinical consequences

Factors influencing immunogenicity

An immunoblot of different interferon-

ß-1a products

HSA

IFNβ

Timeline for development of a

biosimilar medicine

Biosimilars guidelines

Biosimilars

guidelines

WHO

Europe

USA

Other countries

Iran

• The concept of biosimilars defined.

• Biosimilars guidelines issued.

• The concept of biosimilars

defined.

• Biosimilars guidelines issued.

• The concept of biosimilars defined.

• Biosimilars guidelines issued.

• Obama government plans to support

biosimilars.

• The definition and guidelines of

biosimilars in preparation.

• Draft guidelines on biosimilars

prepared in Japan, China, Turkey,

Malaysia and Taiwan.

• Biosimilars guidelines being

prepared in other countries.

(European Medicines Agency (EMA

European Medicines Agency (EMA) was the first

Regulatory authority to specially adapt its approval procedure

to authorize subsequent versions of previously approved biologics,

which are termed “similar biological medicinal products” or for

short, often called biosimilars.

This procedure is based on a thorough demonstration of

“comparability” of the “similar” product to an existing approved

product.

Guidelines for production, characterization, preclinical and clinical

studies and registration of these products have been issued.

EMA plans to revise biosimilar guidelines.

comparability of the biosimilars

World Health Organization

(WHO)

The World Health Organization (WHO)

also got involved and issued draft of Guidelines on

Evaluation of Similar Biotherapeutics (SBPs). These

were finalized on October 2009.

Based on WHO guidelines, some regulatory

authorities such as Malaysia, Singapore, Republic of

Korea, Turkey, Saudi Arabia, Japan, Brazil, South

Africa, Jordan, Mexico and Iran have prepared

guidelines for registration of these medicinal products.

Draft guideline biosimilars WHO

• Quality

• Non-clinical evaluation

• Clinical evaluation

• Pharmacovigilance

• Prescribing information and label

A reference biotherapeutic product (RBP) is used as the comparator for head-to-head comparability studies with the similar biotherapeutic product (SBP) in order to show similarity in terms of quality, safety and efficacy.(The principles of such studies are described in relevant ICH guidelines)

International Conference on

Harmonisation

Harmonisation of regulatory requirements was pioneered by

the European Community (EC), in the 1980s, as the EC (now the

European Union) moved towards the development of a single

market for pharmaceuticals. The success achieved in Europe

demonstrated that harmonisation was feasible. At the same

time there were bilateral discussions between Europe, Japan

and the US on possibilities for harmonisation. It was, however,

at the WHO Conference of Drug Regulatory Authorities

(ICDRA), in Paris, in 1989, that specific plans for action began

to materialise.

ICH guidelines

• International Conference on Harmonisation – Efficacy

ICH E (For pharmacovigilance planning ICH E2E)

• International Conference on Harmonisation - Joint

Safety/Efficacy (Multidisciplinary)

ICH M (ICH M6 for gene therapy)

• International Conference on Harmonisation – Quality

ICH Q (For changes in the manufacturing process ICH Q5E)

• International Conference on Harmonisation – Safety

ICH S (ICH S6 Guideline for non-cilinilal study)

US

The BPCI Act is part of the healthcare reform

legislation, which was signed into law on 23 March

2010 by President Barack Obama. The BPCI Act

establishes an abbreviated approval pathway for

biological products that are demonstrated to be

‘highly similar’ (biosimilar) to, or ‘interchangeable’

with, an FDA-licensed biological product.

Iran

• Until 2002, there were no specific instructions or guidelines for

production and registration of biological medicinal products,

nor recombinant proteins. All the relevant documents have

been prepared in the period of 2002-2010.

• The Iran NRA prepared a draft guideline on the registration of

biosimilars based on the WHO draft guideline of 2009. This

was revised in two steps based on WHO draft guideline

changes. It has been finalized and approved in September

2010 by the Iran expert committee on biologicals and as the

last step approved by the Head of the Iran FDA in February

2011.

Biosimilars guidelines in Iran

The framework of the guideline is very similar to the WHO

guideline and consists of the following sections:

a) Introduction and Scope: definition of biosimilars, original brand, registration

process and general consideration

b) Quality: production process, characterization( physiochemical, biological activity,

immunochemical, accelerated stability test), specifications, analytical techniques, stability

c) Non clinical evaluation

d) Clinical evaluation: pharmacokinetic/pharmacodynamic studies, efficacy studies,

safety and immunogenicity

e) Pharmacovigilance

f) Prescription and labeling information

Product name* Active ingredient Therapeutic area Company Reference product Originator company

AryoSeven anti-haemophilic factor VII

(human)

Haemophilia

Von Willebrand disease

AryoGen Alphanate/ Hemofil M/

Koate-DVI/ Monoclate-P

Grifols/

Baxter/

Kedrion Biopharma

Arvestin bevacizumab Cancer AryoGen Avastin Roche

CinnaFact Buserelin acetate Advanced prostate cancer (stage D)

Endometriosis

CinnaGen Suprefact sanofi-aventis

Epolyrec epoetin alpha Anaemia

Cancer

Chronic kidney failure

Pasteur Institute of Iran

Poyesh Daro

Recpharma

Erypo Janssen-Cilag

Betapoietin epoetin beta Anaemia

Autologous blood transfusion

Cancer

Chronic kidney failure

CinnaGen Zahravi Neorecormon Roche

Altebrel etanercept Arthritis

Psoriasis

AryoGen Enbrel Pfizer

PDgrastim Filgrastim Cancer

Hematopoietic stem cell transplantation

Neutropenia

Poyesh Daro Neupogen Amgen

hepatitis B vaccine Hepatitis B Pasteur Institute of Iran Recombivax HB/

Engerix-B

Merck/GSK

PDferon-B interferon alpha Antitumour

Chronic hepatitis C

Leukaemia

Pasteur Institute of Iran

Poyesh Daro

IntronA Merck Sharp & Dohme

Cinno Vex interferon beta 1a Multiple sclerosis CinnaGen Avonex/Rebif Biogen Idec/ Merck Serono

ReciGen interferon beta 1a Multiple sclerosis CinnaGen Avonex/Rebif Biogen Idec/ Merck Serono

Ziferon interferon beta 1b Multiple sclerosis Zistdaru Danesh Betaferon/ Betaseron/

Extavia

Bayer Healthcare/ Novartis

Immunex interferon gamma Chronic granulomatous disease (CGD)

Severe, malignant osteopetrosis

Recpharma Actimmune Vidara Therapeutics

Cinno Par parathyroid hormone Osteoporosis CinnaGen Forteo Eli Lilly

Pegaferon peg-interferon alpha Chronic hepatitis C Poyesh Daro PEG-Intron Schering-Plough

Reditux/

Zitux

Rituximab Rheumatoid arthritis

Non-Hodgkins lymphoma

Leukaemia

CinnaGen/AryoGen MabThera Roche

Hebreastin trastuzumab Stomach neoplasms

Breast neoplasms

AryoGen Herceptin Roche

*product names given where available

Growth barriers for the biosimilars market

Uncertainties in regulatory frameworks and greater manufacturing

and clinical development complexities have limited the growth of the

biosimilars market

• Complex regulations

• Currently long approval times

• The US (the largest biologics market) just recently introduced a legislative framework for biosimilar

Regulatory framework

• Manufacturing is complex

• Higher costs for pre-clinical and clinical studies

Higher manufacturing complexity and

cost

• Biosimilars are not granted automatic substitution

• Traditionally, physicians opposed to biosimilars on efficacy and safety grounds

Physicians reluctance to

prescribe

Biosimilars prescribing and uptake

PHYSICIAN CONCERNS

• Safety and efficacy concerns

• Lack of information

• Lack of experience

• Inability to establish trust

Outcome:

Modest sales of

Biosimilars

Lack of experience and concerns on safety and efficacy of

biosimilars have acted as barriers to widespread physician

acceptance

Growth drivers for the biosimilars market

• Biologics have managed to leverage higher prices

• Prices of biosimilars are approximately 20-30% lower than the original biologics

Healthcare cost savings

• Continuing expiry of biologics patents

• More companies are expected to enter biosimilarspace

Biologics patent expiry

• Higher rate of approval of biosimilars

Increased regulatory approvals

Potential cost savings for healthcare providers and patent

expiry of blockbuster biologics are the key drivers

Global Biosimilars Market Forecast,

2010-2021

Number and value of biologic drugs set to lose

patent protection per year through 2015

Estimates for the biosimilars market

(2015)

Key success factors for biosimilars players

The capabilities needed for success in the biosimilars market are

significant and will limit the number of entrants in the near to mid term

Manufacturing capabilities

Clinical development experience and

regulatory know-how

Customized sales & marketing skills

Key s

ucc

ess

fact

ors

Manufacturing process

Tests to control quality

Select the right molecule (high sales potential)

Infrastructure and knowledge for clinical

trials

Deep understanding of regulatory

guidelines

Customized sales and marketing team

Continuous scientific communication and

marketing activities

Monoclonal Antibodies Market Forecast

Patent Expiries for Leading Monoclonal

Antibodies 2011-2021

EU Patent

Expiry

US Patent

Expiry

CompanyDrug

20142014J&J/Merck &

Co/Mitsubishi Tanabe

Remicade

(infliximab)

20192017RocheAvastin

(bevacizumab)

20132015Roche/Biogen IdecMabThera

(rituximab)

20142014RocheHerceptin

(trastuzumab)

20142014Eli Lilly/BMS/Merck KGaAErbitux

(cetuximab)

Reditux: The World's First Biosimilar

Monoclonal Antibody

Dr. Reddy's launched the world's first biosimilar monoclonal antibody, Reditux (rituximab), in India in April 2007.

The drug is a biosimilar of Genentech's and Roche's rituximab, marketed as Rtuxan by Genentech and Biogen Idec in markets including the US and MabThera by Roche in many other international markets.

Dr. Reddy's reportedly spent more than $10m developing Reditux, with the drug achieving approximately $3m in sales in its first year.

Dr. Reddy's apparently markets Reditux at about half the price of MabThera. That situation has reportedly forced Roche to lower the recommended price of its product in India.

Growth in sales will be slow, however, as sales for the year ended 31 March 2010 were reportedly only $4m, representing a CAGR of 15.5%.

Thank you, any question?