Biosimilars in rheumatology

Suppose a company develops a new drug
say, prednisolone
It markets it under the name “Wysolone”
it sells this drug for 20 years
And then its patent expires

Now, prednisolone has a simple chemical structure
So it is easy to manufacture

So now another company make prednisolone
And sells it with the brand name “Omnacortil”
Because manufacturing process is very easy,
Omnacortil is IDENTICAL to Wysolone
This is a generic drug

Suppose a company develops etanercept
it markets it under the name “Enbrel”
It sells the drug for 20 years
then its patent expires

Now, etanercept has a very large and complicated structure
So it is difficult to manufacture

Now another company makes etanercept
and sells it with the name “etacept”
Because of the complex manufacturing process,
this is NOT IDENTICAL to enbrel
this is a biosimilar

What is a biological ?
• A biological is a drug produced from a cell or
living organism.
• Large, intricate proteins with unique tertiary
and quaternary structures.

• Companies which make biologicals do not share information
about the manufacturing process.
• So the drug which will be produced will be “similar” but not
identical.
• But their manufacturing process will not be the same.
• After the patent expires, other companies attempt to make it.
What is a biosimilar ?

Europe Biosimilars
USA Follow-on biological agents
Canada Subsequent entry biological
(SEB) agents
India Similar biologics
WHO Similar biotherapeutic
products
Other names

Even minor changes in these
manufacturing steps will lead
to variability of the biosimilar
molecule.
How is a biological/biosimilar manufactured ?
Bottling
Product goes through a series of processes
(fermentation, purification, pharmaceutical
formulation)
Large proteins undergo folding, assembly of
subunits into multimers and post-translational
modifications, such as glycosylation, oxidation
and deamidation.
genetically altered cells are then meticulously
perpetuated and stored in the form of a master
cell bank
introduce the gene for the required protein into a
living cell.
This may affect its biological
function / immunogenicity /
safety / efficacy.

Three major steps are
employed.
How is a biosimilar declared fit for use

A comprehensive physicochemical and biological
characterisation is done to prove similarity on the molecular
level (including in vivo and in vitro assays).

A pharmacokinetic (PK) study is done to show
bioequivalence

An efficacy study (usually a RCT) is done to demonstrate
clinical equivalence.
Also required are Phase III clinical trials, which may be of
equivalence or non-inferiority.
This is the only way to sufficiently assess the efficacy and
safety.

What is an “intended copy” ?
If the comparison fails at any stage, the product cannot be
termed as a biosimilar.
The term intended copy is applied to such products
They do not present similar safety and efficacy to the
innovative product.
Don’t meet FDA/EMA criteria for biosimilarity.

Advantages
• Deliver comparable clinical, safety, and
efficacy results as the originator drug.
• Less costly to develop.
• Require less development time.

The argument favouring biosimilars
• Even for an innovator drug itself, two batches are not exactly
alike.
• Slight variation is possible between different commercial lots
produced using different batches of medium or at different
manufacturing sites.

 Chemical characterization of different commercial lots of
rituximab and etanercept produced between 2007 and 2011
revealed variations in both C-terminal lysine content and
glycosylation.
 The increase in unfucosylated G0 glycans in the later batches of
rituximab resulted in more potent antibody-dependent cellular
cytotoxicity.
 Despite these differences each product was marketed with no
change in label throughout this time.
Case in point
Schiestl, M. et al. Acceptable changes in quality
attributes of glycosylated biopharmaceuticals. Nat.
Biotechnol. 29, 310–312 (2011).

The guidelines for approval set by the EMA/FDA are so
stringent that the cost of developing a biosimilar would come to
nearly as much as the innovator.

High prices of innovator biologics have been straining
healthcare budgets.

The advent of biosimilars may force innovator companies to
lower prices.

In UK, Merck cut the price of Remicade by 25% after biosimilars
started to eat up into its market share.
Case in point

In India, the price of Reditux was half that of the innovator
rituximab product, MabThera (Roche).
Roche tied up with Emcure pharma for local manufacture of
MabThera. It was marketed with the brand names Ristova and
Ikgdar.
Their prices were lowered to reflect that of Reditux.
Case in point

Issues with biosimilars
Developing a biosimilar with a safety profile similar to the
reference product can be challenging due to the complex
molecular structure and complicated manufacturing process
involved.
The molecular structure of biologic products is sensitive to
changes in formulation, packaging, and storage.

Safety can become compromised by process-related
impurities from:
Cell substrates (e.g. host cell DNA and proteins),
Cell culture components (e.g. antibiotics and media
components)
Downstream processing steps (e.g. reagents, residual
solvents, leachables, endotoxins, and bioburden).

There is a possibility of :
 immunogenicity
 hyper- sensitivity reactions
 increased risk for other adverse effects.

Many adverse effects may appear only after a biosimilar drug is
used more extensively, for a longer period of time, in a greater
number of patients.

All biological agents are immunogenic because they are
non-self; even humanised and ‘fully human’ mAbs and Cepts
can result in measurable immune responses
Immunological responses
US Food and Drug Administration. Prescribing information for
adalimumab. http://
www.accessdata.fda.gov/drugsatfda_docs/label/2011/125057s0276lbl.
pdf (accessed
10 Aug 2012).

The effects of antibiological antibodies include reduction in
serum levels, adverse events and formation of neutralising
antibodies.
Strand V, Kimberly R, Isaacs JD. Biologic therapies in
rheumatology: lessons learned, future directions. Nat
Rev Drug Discov 2007;6:75–92.

Antiinfliximab antibodies have been associated with
infusion reactions in patients with Crohn’s disease
Baert F, Noman M, Vermeire S, et al. Influence of
immunogenicity on the long-term efficacy of infliximab
in Crohn’s disease. N Engl J Med 2003;348:601–8.

Antiadalimumab antibodies may heighten the risk of rare
thromboembolic events in patients with RA and psoriatic
arthritis.
Korswagen LA, Bartelds GM, Krieckaert CL, et al. Venous and arterial
thromboembolic events in adalimumab-treated patients with
antiadalimumab
antibodies: a case series and cohort study. Arthritis Rheum
2011;63:877–83.

Postmarketing surveillance of TNFi mAbs has identified
a potential link between antibiological antibodies and
treatment-related vasculitis, albeit very rare events.
Doyle MK, Cuellar ML. Drug-induced vasculitis. Expert Opin Drug Saf
2003;2:401–9. Ramos-Casals M, Perez-Alvarez R, Perez-de-Lis M, et al.
Pulmonary disorders induced by monoclonal antibodies in patients with
rheumatologic autoimmune diseases. Am J Med 2011;124:386–94.

Biosimilar epoietins were introduced in the market without
proper attention to the possibility that they could generate
autoantibodies against the natural erythropoietin
resulting in cases of drug-derived pure red cell aplasia mainly
outside the USA.
Genazzani AA, Biggio G, Caputi AP et al. Biosimilar
drugs:
concerns and opportunities. BioDrugs
2007;21:3516.
Casadevall N, Nataf J, Viron B et al. Pure red cell
aplasia and erythropoietin antibodies in patients treated
with recombinant erythropoietin. N Engl J Med
2002;346:46975.

A rituximab biosimilar has produced anaphylactic reactions
after the patients were switched to the
biosimilar in Mexico.
COFEPRIS. Comunicado a los profesionales de la salud. Reacciones
anafilácticas por el
uso de Rituximab. Available from:
www.cofepris.gob.mx/AZ/Documents/Farmacovig
ilancia/Comunicado%20Rituximab.pdf

In studies with infliximab, the biosimilar [Inflectra (Hospira)],
displayed nearly identical immunological responses to the
reference drug [Remicade (Janssen)].
Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-
group study to demonstrate equivalence in efficacy and safety of CT-P13
compared with innovator infliximab when coadministered with methotrexate in
patients with active rheumatoid arthritis: The PLANETRA study. Ann Rheum
Dis. 2013;72:1623-1620.
Park W, Hrycaj P, Jeka S, et al. Randomised, doubleblind, multicentre,
parallel-group, prospective study comparing the pharmacokinetics, safety, and
efficacy of CT-P13 and nnovator infliximab in patients with ankylosing
spondylitis: The PLANETAS study. Ann Rheum Dis. 2013;72(10): 1605-1612

A biosimilar called SB2 was equivalent to INF in terms of
ACR20 response at week 30.
It was well tolerated with a comparable safety profile,
immunogenicity and PK to INF.
Choe, J., Prodanovic, N., Niebrzydowski, J., Staykov, I., Dokoupilova, E. and
Baranauskaite, A. et al. (2015a) A randomized, double-blind, phase III study
comparing SB2, an infliximab biosimilar, to the infliximab reference product
(Remicade®) in patients with moderate to severe rheumatoid arthritis despite
methotrexate therapy: 54-week results [abstract]. Arthritis Rheumatol 67(Suppl. 10).

Studies indicate that the development of biosimilars with lower
aggregation and/or immunogenicity than the reference products
may be possible.
Barbosa MDFS. Immunogenicity of biotherapeutics in the context
of developing biosimilars and biobetters. Drug Disc Today.
2011;16(7-8):345-353.
Overview of research on safety and immunogenicity of
biosimilars in 2012. GaBIJ. http://gabi-journal.net/news/overview-
of-research-on-safety-and-immunogenicity-of-biosimilars- in-
2012. Accessed March 16, 2015.

Can you switch from a biological to a biosimilar and back ?
Still under much clinical and regulatory debate.
No established criteria for interchangeability currently exist.
Substitution
British Society for Rheumatology Position statement on
biosimilar medicines (February 2015)

The acceptance of interchangeability may vary from country to
country.
In practice, replacement is not permitted in any European
country1, and it is not recommended by WHO2 or medical
societies.
1.European Generic Medicines Association (EGA) (2011)
Biosimilars
handbook, 2nd ed. EGA. Accessed 12 December 2013
2.Hodgson J (2009) WHO guidelines presage US
biosimilars
legislation? Nat Biotechnol 27:963–965.
Substitution

While writing the prescription, brand name must be used to
avoid substitution.
If a decision is made to substitute, it should be for clinical
reasons, not economic.
Substitution
British Society for Rheumatology Position statement on
biosimilar medicines (February 2015)

A biosimilar is approved for RA, can you use it for PsA ?
Again not clear.
Efficacy/safety has to be justified / demonstrated.
Extrapolation

There is no protocol of standardized procedures for
the manufacture of biosimilars.
There is lack of a sharing of know-how on new successful
processes between companies.
Manufacturing issues

Originator companies have been devising newer strategies to
combat the biosimilar competition.
Frequent process changes by the originator gives rise to
reference standards that are considerably different.

They frequently change delivery devices (switching from vials to
prefilled syringes to autoinjectors) and media (from liquid to
lyophilized) combined with the withdrawal of older media
/device.

The estimated costs of developing a biosimilar product for
highly-regulated markets such as Europe or the US still ranges
from $75 to $250 million.
Economic issues

Name Innovator
brand
Company Approval Patent
expiration
Europe
Patent
expiration
USA
Infliximab Remicade Janssen-Merck 1998 Feb 2015 Sep 2018
Etanercept Enbrel Amgen/Pfizer 1998 Feb 2015 Nov 2028
Adalimumab Humira AbbVie 2002 Apr 2018 Dec 2016
Golimumab Simponi Centocor 2009 Feb 2024
Rituximab MabThera,
Rituxan
Roche 1997 Nov 2013 Sep 2016
Abatacept Orencia BristolMyers
Squibb
2005 Dec 2017 Oct 2019
Tocilizumab Actemra Genentech Roche 2010 Jul 2010 Dec 2015
Anakinra Kineret Amgen 2001 May 2009 Feb 2022
Certolizumab
pegol
Cimzia UCB 2008 Feb 2022

World scenario
The first true biosimilar in rheumatology was registered in Korea in
October 2012 and is a copy of infliximab1. [Remsima (code name CT-
P13, Celltrion, Incheon, Korea)]
The trial that led to this license appears to be well done and powered to
detect differences in efficacy and safety.
It was approved by the EMA in 2013 and is currently approved in 50
countries, including South Korea , Colombia , Canada and Japan.
1. Rheumatology 2014;53:389390 doi:10.1093/
rheumatology/ ket 210 Advance Access publication 22
July 2013
EMA/CHMP. CHMP summary of positive opinion for Remsima. 2013.
http://www.
ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-
_Initial_
authorisation/human/002576/WC500144832.pdf (accessed 6 Mar
2015).

World scenario
The EMA (European Medicine Agency) was the first to issue
criteria for biosimilar approval in 2006.
The FDA followed suit in 2012.
Both guidelines are similar & very stringent.
FDA/EMA

FDA/EMA criteria :
Manufacturers must provide substantial data showing that, as compared to the
reference product, the biosimilar has :
 a highly comparable chemical structure
 the same mechanism of action
 the same route of administration.
 same dosage form.
 same potency.
 comparable clinical safety and efficacy outcomes

FDA/EMA criteria :
 Human immunogenicity data are required by a phase III clinical study to
exclude an increase in immunogenicity compared to the reference product.
 Only minor differences in clinically inactive components are allowable.

FDA/EMA criteria :
Once approved, companies must continue monitoring the safety of their
biosimilar products through pharmacovigilance programs [Postmarketing
surveillance data (ie, adverse event reporting)].
 As an example of postmarketing surveillance, the EMA has required the
manufacturer of the biosimilar infliximab to maintain registries of patients
with RA and inflammatory bowel diseases for the purpose of monitoring the
risk of serious infections.

World scenario
In the European Union, the first patents on biopharmaceuticals
expired in 2001, and the first biosimilar medicines were approved
by EMA in 2006.
These were for non-rheumatological diseases.
EU

World scenario
They have demonstrated similar safety and efficacy to their
reference products.
Most EU countries have developed postmarketing
pharmacovigilance programs.
EU

World scenario
The first biosimilar for rheumatology to be approved in EU was
Remsima, a biosimilar of Remicade (Infliximab), developed by
Celltrion healthcare.
Approved in June 2013.
EU
EMA/CHMP. CHMP summary of positive opinion for Remsima. 2013.
http://www.
ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-
_Initial_
authorisation/human/002576/WC500144832.pdf (accessed 6 Mar
2015).

World scenario
A biosimilar of etanercept called Benepali (Samsung Bioepis) was
approved in Jan 2016.
EU
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medic
ines/human/medicines/004007/human_med_001944.jsp&m
id=WC0b01ac058001d124

World scenario
The USA is reportedly biosimilar unfriendly, as it favors
everlasting and perpetual patents
USA

US Food and Drug Administration. Zarxio (filgrastim-sndz).
March 2015. http://www.fda.
gov/NewsEvents/Newsroom/PressAnnouncements/
ucm436648.htm. Accessed August 31, 2015.
World scenario
On March 6, 2015, the US Food and Drug Administration
approved Zarxio (filgrastim-sndz, Sandoz) as the first biosimilar
in the United States.
USA

World scenario
There are no biosimilars definitively approved by FDA for
treatment of rheumatic diseases in the USA.
Several randomized controlled trials (RCTs) are complete or on
going.
USA
Dorner T, Strand V, Castaneda-Hernandez G, et al. The role
of biosimilars in the treatment of rheumatic diseases.
AnnRheum Dis 2013;72:322-8.

World scenario
An infliximab biosimilar may be approved in April, 2016
USA
http://www.biosimilarnews.com/fda-panel-backs-
celltrion-and-pfizers-remicade-infliximab-biosimilar

World scenario
In regions other than USA/EU, regulations for approval of biosimilars
are less stringent.
It is felt that this might have led to approval of agents which are not
entirely proven to be safe / efficacious.

*Azevedo VF, Sandorff E, Siemak B, Halbert RJ (2012)
Potential regulatory and commercial environment for
biosimilars in Latin America. Value Heal Reg Issues
1:228–234
World scenario
• In Latin America many copy products have been approved
without adequate evaluation, lacking in particular, in good-
quality clinical trials.
• Two copies of etanercept already marketed in Mexico and
Columbia cannot be considered biosimilars.*
South america

World scenario
Like in Asia, registration of intended copies of rituximab and
etanercept are already in place without any clinical trials in
patients with RA.
Africa

2.Wu B, Wilson A, Wang F et al (2012) Cost
effectiveness of
different treatment strategies in the treatment of
patients with
moderate to severe rheumatoid arthritis in china. PLoS
World scenario
In China, Shanghai CP Guojian Pharmaceutical Co. Ltd launched
a new compound in 2006 called Yisaipu, that is supposedly a
copy of etanercept.
Data are needed on its non-inferiority in relation to etanercept to
determine its biosimilarity1,2.
1.Kay J (2011) Biosimilars: a regulatory perspective
from America.
Arthritis Res Ther 13:112.
China

World scenario : Infliximab biosimilars

World scenario : Etanercept biosimilars

World scenario : Adalimumab biosimilars

World scenario : Rituximab biosimilars

Profile of companies that are developing biosimilars or ‘intended copies’ around

World scenario
Biosimilars 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.
India

World scenario
India is a semi-regulated market for biosimilars and only short
trials are required to assess bioequivalence for licensing
procedures.
Rheumatology
2014;53:389390doi:10.1093/rheumatology/ket210
Advance Access publication 22 July 2013
India

World scenario
Required :
In vitro analytic chemical and biological characterization.
In vivo animal toxicity studies.
A Phase III clinical trial.
Post-marketing pharmacovigilance program.
Malhotra, H. Biosimilars and non-innovator
biotherapeutics in India: an overview of the current
situation. Biologicals 39, 321–324 (2011).
India

World scenario
However, a head-to-head clinical trial that compares the
biosimilar agent to the innovator biopharmaceutical is not
required.
Malhotra, H. Biosimilars and non-innovator
biotherapeutics in India: an overview of the current
situation. Biologicals 39, 321–324 (2011).
India

World scenario
Guidelines were announced in 2012.
India
The New India Guidelines on Similar Biologics. 2012. Oct, [Last accessed on
2013 Jul 16]. Available
from: http://www.biospectrumasia.com/biospectrum/analysis/3021/biosimilars-
guidelines-a-step-direction-india#.UehBf6DRiSo .

World scenario
The drafters of the guidelines included the drug regulator
Central Drugs Standard Control Organization, the Department
of Biotechnology, academics, and surprisingly staff of major
biotech companies, such as Biocon, Dr. Reddy’s and Roche.
India
The New India Guidelines on Similar Biologics. 2012. Oct, [Last accessed on
2013 Jul 16]. Available
from: http://www.biospectrumasia.com/biospectrum/analysis/3021/biosimilars-
guidelines-a-step-direction-india#.UehBf6DRiSo .

World scenario
Lax regulation ? : The Roche-Biocon lawsuit
Roche makes a biological called trastuzumab, marketed as
Herceptin.
After its patent expired, Biocon-Mylan jumped into the fray with
a version called Canmab.
It was granted approval quickly by DGCI.
India

World scenario
The procedure for approval is multi –step requiring a lot of time.
Approval for the drug could not have been granted legally in
such short span of time.
Roche argued that there is no public record available in the
clinical trial registry of India or elsewhere to show that these
firms actually conducted phase-I or phase-II clinical trials for
the drug.
India

World scenario
Delhi High Court, accordingly restrained Biocon and Mylan from
launching Canmab.
India

World scenario
A parliamentary standing committee had accused the Central
Drugs Standard Control Organization of acting under the
influence of the industry which it is supposed to regulate.
Parliament of India. Department-Related Parliamentary Standing
Committee on Health and Family Welfare: 66th Report on Action Taken
by the Government on the Recommendations/Observations Contained
in the Fifty-Ninth Report on the Functioning of the Central Drugs
Standards Control Organisation (CDSCO) 2013 Apr
India

World scenario
The health ministry plans to revamp the guidelines further.
The Economic times, Nov 18, 2015
India

World scenario
Reditux (Dr Reddy’s) has been produced and marketed in India
since 2007.(prior to release of guidelines)
It was licensed with data from a non-comparative open-label
study in 68 patients.
India

World scenario
Cipla is marketing an intended copy of etanercept, which is
produced by the Chinese company Shanghai CP Goujian
Pharmaceutical Co., the company that produces Yisaipu.
This molecule lacks data based on the international legislation
for it to be accredited as a biosimilar molecule.
Biosimilarnews (2013) Cipla launches first biosimilar
etanercept
in India. http://www.biosimilarnews.com/cipla-
launchesfirst-
biosimilar-etanercept-in-india. Accessed 26 Nov 2013
India

World scenario
The Indian company Avesthagen has conducted preclinical
trials on AVG01 (AVENT™).
The molecule demonstrated high structural and pre-clinical
similarity with etanercept.
However, there is a need for clinical trials to compare efficacy
and safety in humans.
Maity S, Ullanat R, Lahiri S et al (2011) A non-innovator
version
of etanercept for treatment of arthritis. Biologicals
39:384–
395.
India

Drug Type Brand Company Launch Cost
Infliximab Innovator Remicade Merck ₹41039/100mg
Biosimilar Infimab Ranbaxy-
Epirus
Sep 2014 ₹30476
Etanercept Innovator Enbrel Wyeth ₹7983/25mg
Biosimilar Etacept Cipla Apr 2013 ₹6150
Intacept Intas Mar 2015
Adalimumab Innovator Humira AbbVie $1000/40mg
Biosimilar Exemptia Zydus
Cadila
Sep 2014 $200
Adfrar Torrent Jan 2016

Drug Type Brand Company Launch Cost
Rituximab Innovator MabThera Roche ₹70870/500mg
Ristova,
Ikgdar
Roche-
Emcure
₹37500
Biosimilar Reditux RA Dr Reddy’s Apr 2007 ₹39996
Toritz RA Torrent Feb 2015 ₹39957
Maball Hetero Feb 2015
Mabtas Intas Feb 2013 ₹26995
Tocilizumab Innovator Actemra Genentech
roche
₹7392/100mg
Abatacept Innovator Orencia BristolMyers
Squibb
₹26208 /80mg

Take home messages
A biosimilar product can only really be classified as a biosimilar
copy with proper head-to-head trials against the innovator.
A biosimilar may have been licensed using relaxed standards
and may not be truly bioequivalent.

Biosimilars in rheumatology

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