ERA’S JOURNAL OF MEDICAL RESEARCH

VOL.4 NO.1

REVIEW ARTICLE

DOI:10.24041/ejmr2017.13

BIOSIMILARS IN MEDICINE

Zeba Siddiqi

Department of Medicine

Era's Lucknow Medical College & Hospital, Sarfarajganj, Lucknow, U.P., India.-226003

ABSTRACT

Biopharmaceutical drugs or biologicals have become an essential part of modern pharmacotherapy. Biosimilars or similar biologics have been defined as drugs that have shown to have comparable quality, safety and efficacy to the original biopharmaceutical drugs. The past decade has seen a significant increase in interest in these products from the biotechnology industry. Major developments in order to establish a regulatory path for approval of these products have taken place . In order to understand how the different quality attributes of a biosimilar impact its safety and efficacy we need further efforts. India is globally regarded to have great potential for development and commercialization of biosimilars

KEYWORD: Biosimilars, Biopharmaceuticals.

Received on : 06-04-2017

Accpected on : 09-05-2017

Address for correspondence

Dr.Zeba Siddiqi

Department of Medicine,

Era's Lucknow Medical College & Hospital, Lucknow-226003

Email: zsiddiqi9@gmail.com

Contact no: +91-9415612669

INTRODUCTION

What are biosimilars ?

Biopharmaceutical drugs comprise proteins derived from recombinant DNA technology and hybridoma technique. Examples include biological proteins (cytokines, hormones, and clotting factors), monoclonal antibodies, vaccines, cell and tissue based therapies. Living organisms such as plant and animal cells, bacteria, viruses and yeast are employed for the production of biopharmaceuticals.

Biopharmaceuticals have potential to reach up to 50% share in global pharmaceutical market in the next few years.(1)

The expiry of patent protection of many biopharmaceuticals has initiated the development of a category of alternative versions of innovator biopharmaceuticals known as biosimilars or similar biologics. Because of the structural and manufacturing complexities, these biological products are considered as similar, but not generic equivalents of innovator biopharmaceuticals. The term “biosimilar” is in common use in the European Union, while the term “follow on biologics” is more popular in the American context.(1)

Biosimilars : How are they different ?

Unlike structurally well-defined, low molecular weight chemical drugs, biopharmaceuticals are high molecular weight compounds with complex three- dimensional structure. For example, the molecular weight of aspirin is 180 Da whereas interferon-β is 19,000 Da. The typical biologic drug is 100 to 1000 times larger than small molecule chemical drugs and

possesses fragile three-dimensional structure as compared to well-characterized one-dimensional structure of chemical drug. While chemical drugs are easy to reproduce and specify by mass spectroscopy and other techniques, there is a lack of appropriate investigative tools to define the composite structure of large proteins.(2,3)

The first biosimilar medicine, Omnitrope® (biosimilar recombinant human growth hormone [rhGH]; Sandoz, Kundl, Austria), was approved in Europe by the E A(European Medical Association) in 2006.Since then, 20 biosimilars have been approved in Europe; these medicines are based on hematopoietic growth factors (such as filgrastim and epoetin), insulin, follitropin, and monoclonal antibodies (such as infliximab and etanercept).(4)

DISCUSSION

Efficacy and safety of biosimilars

There has been a concern regarding the efficacy and safety of biosimilars.Different manufacturing processes use different cell lines, protein sources, and extraction and purification techniques, which result in heterogeneity of biopharmaceuticals. Versatile cell lines used to produce the proteins may have an impact on the gross structure of the protein, and may affect glycosylation and other post-translational modifications. Such alterations may significantly impact receptor binding, stability, pharmacokinetics and safety. Immunogenic potential of therapeutic proteins is another unique safety issue which is not observed with chemical generics.(2,3)

A study compared quality parameters (such as identity, purity, content and efficacy) of several biosimilar

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BIOSIMILARS IN MEDICINE

brands taken from the Indian market and with those of the innovator drug products.The study was carried out on 16 commercial brands covering three different biopharmaceuticals.A marked lack of comparability between biosimilars and innovator products was seen. Also, a significant difference in the level of purity was observed among various brands of biosimilars of G- CSF and erythropoietin.(5)

The concern regarding immunogenicity is highlighted by the increase in number of cases of pure red cell aplasia associated with a specific formulation of epoetin alfa.(6 ,7) The development of pegylated thrombopoietin (megakarocyte growth and development factor) was stopped in clinical trials because of treatment-associated-thrombocytopenia in 13 of 325 healthy volunteers.(8)

Approval of biosimilars

Various complexities associated with “approval” of a biosimilar include:

i)Evidence of integrity and consistency of the manufacturing process,

ii)Conformance of manufacturing standards to applicable regulations,

iii)Demonstration of product consistency with appropriate innovator product or comparators using assays that should be relevant and most of all standardized, so that several biosimilars of

the same biologic can be comparable, including c o m p a r a t i v e p h a r m a c o k i n e t i c a n d

pharmacodynamic data and the extent of clinical data.(9)

EMA (European Medicines Agency) is the international regulatory authority for approval of biosimilars.The recent EMA guidelines on comparability of biosimilars, state that preclinical data may be insufficient to demonstrate immunologic safety of some biosimilars. In these cases, the immunological safety can only be demonstrated in cohorts of patients enrolled in clinical trials and post marketing surveillance.(10,11).

The regulatory bodies responsible for approval of 'similar biologics' in India are the Department of Biotechnology (DBT – under the Ministry of Science and Technology), through its Review Committee on Genetic Manipulation (RCGM), and the Central Drugs Standard Control Organization (CDSCO – under the Ministry of Health and Family Welfare). India's list of approved and marketed 'similar biologics' is constantly changing.

It should be noted that 'similar biologics' approved in India might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union. The EMA regulatory requirements ensure the same high standards of quality, safety and efficacy for biosimilars as for originator biologicals, and also include a rigorous comparability exercise with the reference product (12).

Similar Biologics approved and marketed in India (4-6, 9-15)

 

Product

Active substance

Therapeutic area**

Approval/

Company

 

 

name*

 

 

launch date

 

 

 

 

 

 

in India#

 

 

 

AbcixiRel

Abciximab

Angina, Cardiac

23 Apr 2013

Reliance Life

 

 

 

 

ischemia

 

Sciences

 

 

Actorise

darbepoetin alfa

Anaemia, Cancer,

6 Jan 2014

Cipla/Hetero

 

 

 

 

Chronic kidney failure

 

 

 

 

Adfrar

Adalimumab

Ankylosing

11 Jan 2016

Torrent

 

 

 

 

spondylitis, Plaque

 

Pharmaceuticals

 

 

 

 

psoriasis, Psoriatic

 

 

 

 

 

 

arthritis, Rheumatoid

 

 

 

 

 

 

arthritis, Ulcerative

 

 

 

 

 

 

colitis

 

 

 

 

Basalog

insulin glargine

Diabetes

2009

Biocon

 

 

Bevacirel

bevacizumab

Colorectal cancer

10 Jun 2016

Reliance Life

 

 

 

 

 

 

Sciences (Lupin)

 

 

Biovac-B

hepatitis B

Hepatitis B

2000

Wockhardt

 

 

 

vaccine

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Product

Active substance

Therapeutic area**

Approval/

Company

name*

 

 

launch date

 

 

 

 

in India#

 

CanMab

Trastuzumab

Breast cancer

23 Oct 2013

Biocon

 

 

 

 

 

Ceriton

epoetin alfa

Anaemia, Cancer,

NR

Ranbaxy

 

 

Chronic kidney failure

 

 

 

 

 

 

 

Choriorel

chorionic

Female infertility

22 Jun 2011

Reliance Life

 

gonadotrophin

 

 

Sciences

 

hormone r-hCG

 

 

 

Cizumab

bevacizumab

Colorectal cancer

27 Jun 2016

Hetero

 

 

 

 

 

Cresp

darbepoetin alfa

Anaemia, Cancer,

23 Mar 2010

Dr. Reddy’s

 

 

Chronic kidney failure

 

Laboratories

Darbatitor

darbepoetin alfa

Anaemia, Cancer,

2014

Torrent

 

 

Chronic kidney failure

 

Pharmaceuticals

 

 

 

 

 

Emgrast

Filgrastim

Cancer, Neutropenia

16 Mar 2010

Gennova

 

 

 

 

Biopharmaceuticals

 

 

 

 

(Emcure)

 

 

 

 

 

Epofer

epoetin alfa

Anaemia, Cancer,

NR

Emcure

 

 

Chronic kidney failure

 

 

Epofit/

epoetin alfa

Anaemia, Cancer,

Aug 2005

Intas

Erykine

Chronic kidney failure

Pharmaceuticals

 

 

Eporec

erythropoietin

Anaemia, Chronic kidney

9 Aug 2011

Bioviz Technologies

 

 

failure

 

 

 

 

 

 

 

Epotin

epoetin alfa

Anaemia, Cancer, Chronic

NR

Claris Lifesciences

 

 

kidney failure

 

 

rypro

epoetin alfa

Anaemia, Cancer, Chronic

NR

Biocon

 

 

kidney failure

 

 

tacept

tanercept

Ankylosing spondylitis,

2013 Apr

Cipla

 

 

Rheumatoid arthritis,

 

 

 

 

Psoriatic arthritis,

 

 

 

 

Psoriasis, Juvenile

 

 

 

 

Rheumatoid Arthritis

 

 

 

 

 

 

 

Exemptia

Adalimumab

Rheumatoid Arthritis

25 Sep 2014

Zydus Cadila

 

 

 

 

 

Fegrast

Filgrastim

Cancer, Hematopoietic

NR

Claris

 

 

stem cell transplantation,

 

Lifesciences

 

 

Neutropenia

 

 

 

 

 

 

 

Filgrastim

Filgrastim

Neutropenia

22 Oct 2013

Cadila

 

 

 

 

Pharmaceutical

Filgrastim

Filgrastim

Neutropenia

5 Mar 2013

Lupin

 

 

 

 

 

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Product

Active substance

Therapeutic area**

Approval/

Company

name*

 

 

launch date

 

 

 

 

in India#

 

Filgrastim

Filgrastim

Neutropenia

3 Jun 2013

USV

 

 

 

 

 

Folisurge

follitropin alfa

Female infertility,

14 May 2013

Intas

 

(follicle stimulating

Spermatogenesis in men

 

Pharmaceuticals

 

hormone)

 

 

 

 

 

 

 

 

FostiRel

follitropin beta

Female infertility

30 Apr 2010

Reliance Life

 

(follicle stimulating

 

 

Sciences

 

hormone)

 

 

 

Glaritus

insulin glargine

Diabetes mellitus

Mar 2009

Wockhardt

 

 

 

 

 

Grafeel

ilgrastim

Neutropenia,

NR

Dr. Reddy’s

 

 

Hematopoietic stem cell

 

Laboratories

 

 

transplantation, Cancer

 

 

 

 

 

 

 

Infimab

nfliximab

Ankylosing spondylitis,

15 Sep 2014

Epirus

 

 

Crohn’s disease, Psoriasis,

 

Biopharmaceuticals

 

 

Psoriatic arthritis,

 

 

 

 

Rheumatoid arthritis,

 

 

 

 

Ulcerative colitis

 

 

 

 

 

 

 

Insugen

human insulin

Diabetes mellitus

NR

Biocon

 

 

 

 

 

Insulin

Insulin

Diabetes mellitus

9 Aug 2011

Gland Pharma

 

 

 

 

 

Intacept

Etanercept

Ankylosing spondylitis,

ar 2015

Intas

 

 

uvenile idiopathic

 

Pharmaceuticals

 

 

arthritis Psoriasis,

 

 

 

 

Psoriatic arthritis,

 

 

 

 

Rheumatoid arthritis

 

 

 

 

 

 

 

Intalfa

interferon alfa-2b

Carcinoid tumour, Chronic

Apr 2007

Intas

 

 

hepatitis B,Chronic

 

Pharmaceuticals

 

 

hepatitis C, Hairy cell

 

 

 

 

leukaemia, Chronic

 

 

 

 

myelogenous leukaemia,

 

 

 

 

BCR-ABL positive,

 

 

 

 

Follicular lymphoma,

 

 

 

 

Malignant melanoma,

 

 

 

 

Multiple myeloma

 

 

Maball

Rituximab

Lymphoma, Non-

3 Feb 2015

Hetero Group

 

 

Hodgkin’s Lymphoma

(12)

 

 

 

 

 

 

MabTas

Rituximab

Lymphoma, Non-

26 Feb 2013

Intas

 

 

Hodgkin’s Lymphoma

 

Pharmaceuticals

 

 

 

 

 

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Product

Active substance

Therapeutic area**

Approval/

Company

name*

 

 

launch date

 

 

 

 

in India#

 

Molgramostim

Recombinant human

Neutropenia

14 May 2013

Zenotech

 

granulocyte

 

 

Laboratories

 

macrophage colony

 

 

 

 

stimulating factor

 

 

 

 

(molgramostim)

 

 

 

Mirel

reteplase (tissue

Myocardial infarction

2009

Reliance Life

 

plasminogen

 

 

Sciences

 

activator)

 

 

 

Myokinase

streptokinase

Acute myocardial

NR

Biocon

 

 

infarction, Deep venous

 

 

 

 

thrombosis, Acute

 

 

 

 

pulmonary embolism

 

 

 

 

 

 

 

Neukine

Filgrastim

Neutropenia,

Jul 2004

Intas

 

 

Hematopoietic stem cell

 

Pharmaceuticals

 

 

transplantation, Cancer

 

 

Neupeg

Pegfilgrastim

Cancer, Neutropenia

Aug 2007

Intas

Pharmaceuticals

 

 

 

 

Nufil

Filgrastim

Cancer, Neutropenia

NR

Biocon

 

 

 

 

 

Pegex

Pegfilgrastim

Cancer, Neutropenia

29 Jan 2010

Gennova

 

 

 

 

Biopharmaceuticals

 

 

 

 

(Emcure)

 

 

 

 

 

Peg-

Pegfilgrastim

Cancer, Neutropenia

3 Sep 2013

Lupin

filgrastim

 

 

 

 

Peg-

Pegfilgrastim

Cancer, Neutropenia

10 ay 2011

Dr Reddy’s

grafeel

Laboratories

 

 

 

 

 

 

 

 

Peg-

Pegylated

Chronic hepatitis B,

 

Intas

recombinant

25 Apr 2013

interferon

human interferon

Chronic hepatitis C

Pharmaceuticals

alfa 2b

 

alfa 2b

 

 

 

 

 

 

 

Platelet

rh-PDGF-BB+β-

Peridontal defect, Gingival

28 Apr 2010

Virchow Biotech

derived

TCP

recession

 

 

growth

 

 

 

 

factor

 

 

 

 

Rasburicase

Rasburicase

Malignancy associated

28 Aug 2012

Virchow Biotech

 

 

hyperuricemia

 

 

 

 

Wet macular degeneration,

19 Jun 2015

 

Razumab

Ranibizumab

Macular edema, Degenerative

Intas

myopia, Diabetes

(13)

Pharmaceuticals

 

 

 

 

complications

 

 

 

 

 

 

 

Reditux

Rituximab

Leukaemia, Lymphoma,

30 Apr 2007

Dr. Reddy’s

 

 

Rheumatoid arthritis

 

Laboratories

Relibeta

interferon beta-

Multiple sclerosis

2 May 2011

Reliance Life

 

1a

 

 

Sciences

 

 

 

 

 

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BIOSIMILARS IN MEDICINE

Product

Active substance

Therapeutic area**

Approval/

Company

name*

 

 

launch date

 

 

 

 

in India#

 

Reliferon

interferon alfa-

BCR-ABL positive, Carcinoid

2008

Reliance Life

 

2b

tumour, Chronic hepatitis B,

 

Sciences

 

 

Chronic hepatitis C, Chronic

 

 

 

 

myelogenous leukaemia,

 

 

 

 

Follicular lymphoma, Hairy

 

 

 

 

cell leukaemia, Melanoma

 

 

 

 

Multiple myeloma

 

 

 

 

 

 

 

Religrast

Filgrastim

Neutropenia

2008

Reliance Life

Sciences

 

 

 

 

Relipoietin

 

Anaemia, Autologous blood

 

Reliance Life

epoetin alpha

transfusion, Chronic kidney

2008

Sciences

 

 

failure, HIV

 

 

 

 

 

Repoitin

erythropoietin

Anaemia, Chronic

29 Nov 2011

Serum Institute of

kidney failure

India

 

 

 

Rituximab

Rituximab

Non-Hodgkin’s Lymphoma,

12 Feb 2015

eliance Life

Rheumatoid arthritis

Sciences

 

 

 

Rituximab

Rituximab

Non-Hodgkin’s Lymphoma

27 Feb 2013

Zenotech

Laboratories

 

 

 

 

Shankinase

streptokinase

Arterial occlusions, Deep vein

Jun 2004

Shantha

thrombosis, Pulmonary

Biotechnics/Merieux

 

 

embolism

 

Alliance

 

 

BCR-ABL positive, Carcinoid

 

 

 

 

Tumour, Chronic hepatitis B,

 

Shantha

Shanferon

interferon alfa-2b

Chronic hepatitis C, Chro,nic

Apr 2002

myelogenous leukaemia,

Biotechnics/Merieux

 

 

Follicular lymphoma, Hairy cell

 

Alliance

 

 

leukaemia, elanoma, ultiple

 

 

 

 

 

 

Shantha

Shanpoietin

erythropoetin

Anaemia, Chronic kidney failure

Jan 2005

Biotechnics/Merieux

 

 

 

 

Alliance

Terifrac

teriparatide

Post menopausal women with

1 Nov 2010

Intas Pharmaceuticals

 

(parathyroid

osteoporosis who are at high risk

 

 

 

hormone)

for fracture

 

 

Teriparatide

teriparatide

Post menopausal women with

21 Aug 2012

Cadila Healthcare

 

(parathyroid

osteoporosis who are at high risk

 

 

 

hormone)

for fracture

 

 

Teriparatide

teriparatide

Post menopausal women with

13 Aug 2012

USV

 

(parathyroid

osteoporosis who are at high risk

 

 

 

Hormone)

for fracture

 

 

Wepox

epoetin alfa

Anaemia, Cancer, Chronic

Mar 2001

Wockhardt

 

 

kidney failure

 

 

Wosulin

human insulin

Diabetes mellitus

13 Aug 2003

Wockhardt

 

 

 

 

 

Zavinex

interferon alfa-2b

Chronic hepatitis B,

21 Jun 2011

Cadila Healthcare

 

 

Chronic hepatitis C

 

 

 

 

 

 

 

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Product

Active substance

Therapeutic area**

Approval/

Company

name*

 

 

launch date

 

 

 

 

in India#

 

Zyrop

erythropoietin

Chronic kidney failure

28 Apr 2010

Cadila Healthcare

 

 

 

 

 

* Where brand -name is not known active substance name is given;

**Therapeutic area taken from company information, from originator product information on EMA website or from CDSCO information; NR: not reported; # ‘similar biologics’ launched in India before the Indian ‘similar biologics’ guideline came into effect on 15 September 2012, were approved using an ad-hoc abbreviated procedure on a case by -case basis.

Source: CDSCO (Central Drugs Standard Control Organization)

CONCLUSION

Biosimilars offer a new ray of hope to patients who need these life saving medicines.The regulatory environment for biosimilars continues to evolve g l o b a l l y, i n r e c o g n i t i o n o f a d v a n c e s i n technology/analytical methods and the availability of new targets for their use.It is high time that in our country too strict regulatory policies are formulated and executed for the overall benefit of our needy and financially weak patients.

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How to cite this article :Siddiqi Z., Biosimilars In Medicine, Era's Journal of Medical Research.2017;4(1):56-62.

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