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© Datamonitor

the home of Business Intelligence

innovative deliveryexpert analysisquality data

© Datamonitor

Biosimilars: Pipeline TrendsMonoclonal antibodies dominate biosimilar pipelines

December 2011 (HC00149-002)

the home of Business IntelligenceBiosimilars: Pipeline Trends, HC00149-002, December 2011© Datamonitor

2

About the presentation and report

This executive presentation is a summary of the key analysis in the accompanying written report, which provides more in-depth analysis of the information presented here. The written report is organized into the following chapters:

An executive summary which provides key biosimilar/copy-biologic development metrics

An explanation of the methodology used by Datamonitor in this report

An overview of key biosimilar/copy-biologic molecules in development and launched

The bibliography.


3

Key findings (1/3)

• Datamonitor has identified a total of 397 biosimilars/copy-biologics across 125 companies as being in development/marked. Products and pipeline candidates were identified using publically available information (where available). For each candidate, the stage of development was determined using company reported information as well as secondary sources such as clinical trial databases.

• Marketed products – Biosimilar and copy-biologic markets are dominated by versions of simple biologic molecules such as erythropoietin, somatropin, filgrastim and insulin products.

• Pipeline candidates – There is an increasing trend towards the development of high value biologics such as monoclonal antibodies (MAbs), fusion proteins, and second-generation biologics, with 57 MAb biosimilar candidates currently in development, versus only 46 therapeutic protein candidates. Rituximab is the most targeted molecule, with 14 pipeline biosimilar candidates currently in development.

• Target therapy areas/indications – Reflecting the focus on MAbs and therapeutic proteins such as erythropoietin and filgrastim, oncology, neutropenia and anemia as well as various cancer and immunological and inflammatory indications are the most frequently targeted by developers.

• Geography – The EU leads in terms of the number of marketed and pipeline biosimilar candidates followed by South Korea, while India continues to lead the way in the copy-biologics market, followed by China.

• Company – Based on company reported information, Sandoz was highlighted as the leading company in terms of marketed and pipeline biosimilars, while Zydus Cadilla leads in terms of copy-biologic development.


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Key findings (2/3)

Top 5 Biosimilars Number of biosimilars

Copy-biologics Number of copy-biologics

Marketed

1 erythropoietin 7 filgrastim 35

2 somatropin 5 erythropoietin 30

3 filgrastim 4 insulin 23

4 insulin 1 interferon alfa-2b 17

5 follicle-stimulating hormone 1 interleukin-2 8

Pipeline

1 rituximab 14 rituximab 3

2 filgrastim 9 teriparatide 3

3 trastuzumab 8 erythropoietin 2

4 erythropoetin 8 pegfilgrastim 2

5 etanercept 7 darbepoetin alfa 2

Company (marketed and pipeline)

1 Sandoz 13 (4 + 9) Zydus Cadila 15 (5 + 10)

2 Gene Techno Sciences 10 (0 + 10) Cipla 12 (0 + 12)

3 Celltrion 8 (0 + 8) Dr. Reddy's 12 (5 + 7)

4 Harvest Moon 8 (2 + 6) Laboratorios Beta 10 (10 + 0)

5 Teva 6 (1 + 5) Biocad 9 (2 + 7)


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Key findings (3/3)

Top 5 Biosimilars Number of biosimilars

Copy-biologics Number of copy-biologics

Therapy area (marketed and pipeline)

1 Oncology 71 (11 + 60) Oncology 106 (89 + 17)

2 Immunology & Inflammation 35 (0 + 35) Hematology 40 (35 + 5)

3 Hematology 21 (7 + 14) Infectious Diseases 28 (27 + 1)

4 Growth Disorders 9 (5 + 4) Metabolic Disorders 27 (23 + 4)

5 Central Nervous System 4 (1 + 3) Gender Specific Health 22 (19 + 3)

Indication (marketed and pipeline)

1 Neutrapenia 19 (4 + 15) Neutrapenia 46 (43 + 3)

2 Anemia 15 (7 + 8) Anemia 30 (33 + 0)

3 Non-Hodgkin's lymphoma / rheumatoid arthritis 12 (0 + 12)

Diabetes28 (23 + 4)

4 Growth disorders 9 (5 + 4) Hepatitis C 22 (21 + 1)

5 Her-2 positive breast cancer 8 (0 + 8) Infertility 19 (19 + 0)

Geography (marketed and pipeline)

1 EU 66 (9 + 57 India 102 (59 + 43)

2 South Korea 35 (6 + 29) China 50 (39 + 11)

3 US 28 (0 + 28) Argentina 25 (25 + 0)

4 Japan 17 (2 + 15) Russia 15 (8 + 7)

5 Canada 8 (0 + 8) Mexico 14 (13 + 1)


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Definitions and methodology (1/4)

Biologic definitions

Below is a list of definitions used by Datamonitor to classify different types of biologic drug:

Innovative biologic – A novel biologic that has been patented.

Biobetter (biosuperior/second-generation biologic) – An innovative biologic drug that has been structurally and/or functionally altered to achieve an improved or different clinical performance (Biosimilar Medicinal Products Working Party, 2011).

Biosimilar – A copy version of an already authorized biological innovative (biologic/biobetter/biosuperior) drug with demonstrated similarity in physicochemical characteristics, efficacy, and safety, based on a comprehensive comparability exercise, and approved through an official biosimilars pathway (Biosimilar Medicinal Products Working Party, 2011).

Copy-biologic – A copy of an innovative biologic that has been approved in a country where no official biosimilar pathway exists.


7


Methodology

Source: Datamonitor; company-reported information, 2011

A total of 397 biosimilars/copy-biologics across 125 companies are currently in development/marketed (Table 2). Products and pipeline candidates were identified using the MedTRACK Disease Hub database, company websites, and company annual reports (where available).

For the purpose of this analysis, only drugs in development and at market were included, with drugs that have been discontinued, withdrawn, or refused excluded for the analysis.

Biologic type Development Approved/launched Discontinued, withdrawn, refused, and unknown

Biosimilar 126 20 3

Copy-biologic 60 189 1

Copy-biologic/biologic/biosimilar 2 0 1

Total 188 209 5


8


Stages of development

For each candidate, the stage of development was determined using company-reported information as well as secondary sources such as clinical trial databases (e.g. ClinicalTrials.gov, Citeline):

Planned – Refers to candidates which companies have explicitly stated they plan to develop, but for which no product development as yet begun.

Development – Refers to candidates in undefined stages of development, and which have yet to be approved/launched.

Preclinical – Refers to products in preclinical development.

Clinical trials/pre-approval – Refers to candidates in Phase I, II, and III clinical trials, as well as those awaiting application for regulatory approval and those awaiting approval by regulatory authorities.

Approved/launched – Refers to products which have received approval from regulatory authorities and may have launched.

Discontinued/withdrawn/refused – Refers to candidates which have been discontinued, withdrawn from the market, withdrawn from development, or have been refused marketing authorization.


9


Disease indications

For each candidate the target indication was determined as follows:

Where available, Datamonitor has reported the indications for the biosimilar/copy-biologic listed by the company.

Where no information regarding indications was available, Datamonitor has listed all the indications of the reference biologic product.

Geographical regions

For each candidate the target geographical market was determined as follows:

Where available, Datamonitor has reported the geographical region for the biosimilar/copy-biologic listed by the company.

Where no information regarding geographical region was available, Datamonitor listed the geography where the company is headquartered.


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Leading countries in terms of pipeline and marketed biosimilars and copy-biologics

Leading countries for biosimilars and copy-biologics, by stage of development, 2011


In terms of pipeline and marketed copy-biologics, India leads the way with 102 products (encompassing 27 molecules), closely followed by China with 50 products (25 molecules), largely driven by the development of cheap simple biologics approved by regulatory authorities in these markets as new drugs.

The EU is the market with the greatest number of pipeline and marketed biosimilar products, totaling 66 (32 molecules) as of December 2011, reflecting the fact that the European Medicines Agency (EMA) was the first developed market to introduce a biosimilars approval pathway in 2005.

South Korea and the US also have sizable biosimilar pipelines.

0

20

40

60

80

100

120

India EU

Chin

a

South

Kor

ea US

Argen

tina

Japan

Russia

Mexic

o

Brazil

Oth

er

Nu

mb

er

of

can

did

ate

s

Planned Development Pre-clinicalClinical trials/ Pre-approval Approved / Launched biosimilars Approved / Launched copy biologics


11

Biosimilars by molecule type

Biosimilars development, by stage of development and molecule type, 2011


Biosimilar markets are dominated by versions of simple biologic molecules – namely erythropoietin, filgrastim, and somatropin – which are relatively cheap and easy to produce and which have consequently become something of a proof of principle for biosimilars producers, used to test biosimilar pathways.

However, there is an increasing trend towards the development of high value biologics such as MAbs, fusion proteins, and second-generation biologics.

Global monoclonal MAb sales are forecast to reach $63bn in 2015, making this market an attractive target for biosimilar developers, with interest in biosimilar MAbs having intensified since the drafting of the EU MAb guidelines in November 2010. Reflecting this there are currently 57 MAb biosimilar candidates in development, versus only 46 therapeutic protein candidates.

0

10

20

30

40

50

60

70

Therapeuticprotein

Monoclonalantibody

Hormone therapy Insulin Blood factor Unknown atpresent

Nu

mb

er

of

can

did

ate

s

Planned Development Pre-clinical Clinical trials / Pre-approval Approved / Launched


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Copy-biologics by molecule type

Copy-biologics development, by stage of development and molecule type, 2011


Copy-biologic markets have historically been dominated by simple biologics such as therapeutic proteins, which are cheap and relatively simple to manufacture.

Only a handful of pharmaceutical companies including Dr. Reddy’s, Zydus Cadila, BioCad, Shanghai CP Guojian Pharmaceutical, and Probiomed have the technology, expertise, and finances to develop copy-biologic MAbs, with Dr. Reddy's Reditux (rituximab) is the world’s first and only copy-biologic MAb.

0

20

40

60

80

100

120

140

160

180

Therapeuticprotein

Insulin Monoclonalantibody

Hormonetherapy

Blood factor Unknown atpresent

Num

ber

of c

andi

date

s



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Rituximab is the biologic most targeted by biosimilar developers

Leading molecules targeted by biosimilar developers


Rituximab has received significant attention from biosimilar developers, with 14 candidates at various stages of development (from planned to Phase III clinical trials).

Herceptin (trastuzumab; Roche) is the only MAb used in the treatment of HER2-positive metastatic breast cancer. It has also been a major target for biosimilar developers, with eight candidates currently in development.

Biosimilar developers are also looking to develop other more complex products such as biosimilar versions of second-generation biologics such as pegfilgrastim, darbepoetin alfa, and pegylated interferon alfa. These drugs have improved half-lives and dosing regimens over their first-generation counterparts.

0

2

4

6

8

10

12

14

16

eryth

ropo

ietin

ritux

imab

filgra

stim

som

atro

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uzum

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etan

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pt

pegf

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inflix

imab

adali

mum

ab

darb

epoe

tin a

lfa

insu

lin

Num

ber

of c

andi

date

s



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Simple biologics dominate the copy-biologic market

Leading molecules targeted by copy-biologic manufacturers, 2011


There are currently 36 copy-biologic versions of filgrastim, 31 copy-biologic versions of erythropoietin, and 25 copy-biologic insulins at market, with these products accounting for 49% of all copy-biologics currently available.

Due to the rising prevalence of diabetes in emerging markets, together with the high cost of advanced insulin products such as insulin glargine and lispro, lower cost human insulin and bovine/porcine insulins will continue to prove popular among copy-biologic manufacturers and patients.

Interferon alfa-2a and -2b products have proved to be popular molecules. Hepatitis C virus infection is particularly prevalent in many emerging markets, and as a result companies have tapped into this lucrative market.

0

5

10

15

20

25

30

35

40

filgra

stim

eryt

hrop

oietin

insulin

interfe

ron a

lfa-2

b

inter

leukin

-2

som

atro

pin

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in-11

pegf

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interfe

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Oncology is the therapy area most targeted by biosimilar developersLeading therapy areas targeted by biosimilar developers, 2011


Oncology is currently the focal therapy area for biosimilar developers, with 60 candidates in development and 12 biosimilars already launched. This group represents 11 different molecules across a variety of oncology and associated indications, from simple biologics such as filgrastim to more complex high value targeted therapies such as trastuzumab.

Diseases within the immunology and inflammation field have also received significant attention from biosimilar developers, with 35 candidates currently in development across a number of distinct indications. The molecules for which there is active clinical development within this group include infliximab, etanercept, adalimumab, and rituximab.

0

10

20

30

40

50

60

70

80

Onco

logy

Imm

unology &

Infla

mm

ation

Hemato

logy

Gro

wth D

isord

ers

Cen

tral N

ervous

Sys

tem

Infe

ctious

Dise

ases

Gende

r Spec

ific H

ealth

Meta

bolic

Oth

er Dise

ases

Cardiova

scula

r

Geria

trics

Res

pirato

ry

Unk

nown

Nu

mb

er

of

pro

du

cts

Single therapy area Oncology/Hematology Oncology/Immunology & Inflammation


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Oncology is the therapy area most targeted by copy-biologic manufacturersLeading therapy areas targeted by copy-biologic developers, 2011


As with biosimilar developers, oncology is the focal therapy area for copy-biologic manufacturers, with 17 candidates in development and 86 products already launched. This group is primarily made up of copy-biologic versions of molecules. The majority of these products are filgrastim, which are low cost and easy to produce by manufacturers, and affordable to patients.

The infectious disease group consists exclusively of interferon alfa and peginterferon alfa copy-biologics for the treatment of hepatitis C virus infection, which is particularly prevalent in many emerging markets.

0

20

40

60

80

100

120

Oncolog

y

Hemato

logy

Infe

ctiou

s Dise

ases

Met

abolic

Gende

r Spe

cific

Hea

lth

Imm

unolo

gy &

Infla

mm

atio

n

Centra

l Ner

vous

Sys

tem

Cardiov

ascu

lar

Growth

Dis

orders

Oncolog

y/Im

muno

logy &

Infla

mm

ation

Unknown

Nu

mb

er

of

pro

du

cts

Single therapy area Oncology/Hematology Oncology/Immunology & Inflammation


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India dominates the market in terms of approved products

Leading countries for biosimilars and copy-biologics development, 2011


In terms of launched copy-biologics, India leads the way with 59 products (encompassing 22 molecules), followed by China with 39 products (16 molecules), followed by the Latin American markets of Argentina, Mexico, and Brazil.

Argentina's ANMAT published biologics and biosimilar approval guidance in September 2009.

In Mexico, despite the creation of biosimilar guidelines in 2009, the pathway remains impossible to navigate. However, copy-biologics have existed in the country for a number of years, are accepted by patients and physicians alike, and are often considered to be interchangeable with branded products.

Brazil has traditionally been a small market for biologic products given the low rates of reimbursement. However, legislation relating to biosimilars was introduced in 2005.

0

10

20

30

40

50

60

70

Indi

a

China

Argen

tina

Mex

ico EUBra

zil

Egypt

Russia

South

Kor

ea

Bangl

ades

hO

ther

Num

ber

of c

andi

date

s

Approved / Launched biosimilars Approved / Launched copy biologics


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The EU dominates in terms of biosimilar development the EU dominates in terms of product developmentLeading leading markets for biosimilar development


The EU leads the field in terms of biosimilar development with 57 candidates (encompassing 32 molecules) – although 20 of which are only in the “planned” stage – reflecting the significant commercial opportunity for biosimilars in this region.

India is the leading country in terms of copy-biologic development, with 40 candidates (eight molecules) undergoing active development, and a further three candidates planned. However, given the limited availability of company-reported development information, the size of the Indian pipeline may be under-represented here.

While only having launched six products to date, South Korea is ranked third in terms of biosimilar development with 29 candidates (13 molecules) currently in development.

0

10

20

30

40

50

60

EUIn

dia

South

Korea US

Japa

n

China

Canad

a

Russia

Taiwan

Brazil

Mex

ico

Latin

Am

erica

unsp

ecifie

d

Nu

mb

er

of

can

did

ate

s

Planned Development Pre-clinical Clinical trials / Pre-approval


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Biosimilar/copy-biologic company analysis (1/4)

The leading companies for biosimilar research and development, 2011


The largest copy-biologic producer is India-based Zydus Cadila, reported to have 10 candidates in preclinical development, with a further five at market.

Sandoz is the leading biosimilar developer, with nine candidates in development and four at market. Omnitrope (somatropin; Sandoz) was the first biosimilar to be marketed in the EU, Japan, Australia, and Canada.

0

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4

6

8

10

12

14

16

Zydus

Cadila

Sandoz

Cipla

Dr R

eddy's

Gen

e Tec

hno Scie

nce

Labor

ator

ios Beta

Bioca

d

Probio

med

Celltrion

Harves

t Moon

Pha

rmace

utica

ls

USV Lim

ited

Bioco

n

Inta

s Biop

harm

aceutic

als

Don

g-A

LG Life

Scie

nces

Relianc

e Life

Scie

nces

Sedico

Shangha

i CP G

uojian P

harm

aceut

ical

Teva

Varifarm

a

Nu

mb

er

of

ca

nd

idat

es

Development Biosimilars Launched Biosimilars Development Copy-biologics Launched Copy-biologics


20


The leading producers with products launched, 2011


All of the top 10 companies in terms of marketed products are copy-biologic manufacturers, reflecting the more relaxed regulatory requirements for the approval of such products in the emerging markets.

The leading companies in terms of launched copy-biologics are Laboratorios Beta and Probiomed, both of which are Latin America-based companies along with Varifarma, Landsteiner Scientific, and Sidus, which also rank among the top 10 companies based on number of marketed copy-biologics. The remaining companies are all India-based, with the exception of Sedico, based in Egypt.

0

2

4

6

8

10

12

Nu

mb

er o

f ca

nd

idat

es

Therapeutic protein Insulin Hormone therapy Blood factor Monoclonal antibody Unknown at present


21


The leading producers with products in development


India-based Cipla is the leading developer with 12 copy-biologics in development (although the nature of these products has not been disclosed), followed by Zydus Cadila – also based in India – which has a range of therapeutic protein and monoclonal antibody (MAb) candidates in development.

In terms of biosimilar development, Japan-based Gene Techno Science leads with 10 biosimilars (MAbs and therapeutic proteins) in development, followed by Sandoz with nine candidates (of which only one – rituximab – has been disclosed).

0

2

4

6

8

10

12

14

Nu

mb

er

of

ca

nd

idat

es

Therapeutic protein Monoclonal antibody Unknown at present Insulin Blood factor


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Biosimilar and copy-biologic MAb development activities, 2011

Overall, 30 companies have biosimilar/copy-biologic MAbs in their portfolios, with Reditux (rituximab; Dr. Reddy’s) currently being the only copy-biologic MAb on the market.

BioXpress leads in terms of the number of MAb candidates. However, all 16 are "planned," with no reference to any clinical development having been initiated (BioXpress, 2011).

Celltrion currently has eight MAb candidates, two of which are in clinical development, with five in preclinical development and a further one at the “planned” stage. These eight biosimilars are due to appear in the US, Europe, Australia, Canada, and New Zealand through a marketing agreement between Hospira and Celltrion signed in October 2009 (Berkrot, 2009).

Biosimilar originator company

Total MAb candidates

Lead molecule Stage of lead molecule

BioXpress 16 Various Planned

Celltrion 8 infliximab, trastuzumab Clinical trials/pre-approval

Gene Techno Science 7 Unknown at present Development

Dr. Reddy’s 6 Reditux (rituximab) Approved/launched

Zydus Cadila Total 5 Unknown at present Preclinical

Mabion 4 Unknown at present Development

Biocad 3 bevacizumab, rituximab, trastuzumab

Development

PharmaPraxis 3 Unknown at present Development

Shanghai CP Guojian Pharmaceutical

3 efalizumab, rituximab, trastuzumab

Clinical trials/pre-approval

Aprogen 2 infliximab Clinical trials/pre-approval

Dong-A 2 trastuzumab Preclinical

LG Life Sciences Total 2 adalimumab, infliximab Preclinical

Samsung Biologics 2 rituximab Clinical trials/pre-approval

Others 16 Various Various


23

Appendix

Ask the analyst• The Strategic Analysis (Healthcare) Knowledge Center Writing team

• Alistair Sinclair [email protected]

Disclaimer• All Rights Reserved.

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• The facts of this report are believed to be correct at the time of publication but cannot be guaranteed. Please note that the findings, conclusions and recommendations that Datamonitor delivers will be based on information gathered in good faith from both primary and secondary sources, whose accuracy we are not always in a position to guarantee. As such, Datamonitor can accept no liability whatever for actions taken based on any information that may subsequently prove to be incorrect.

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