National Institute for Biological Standards and Control

Assuring the quality of biological medicines

Recent developments, trends

and prospects for biosimilars.

Robin Thorpe PhD.,FRCPath.

Head, Biotherapeutics Group, NIBSC.,UK.email: Robin.Thorpe@nibsc.hpa.org.uk

Biotherapeutic Products

• Many biotech derived products are available for treatment of life-threatening diseases

• Patent expiry of some licensed biotherapeutic products has meant that ‘copy’ versions have become available widening patient access to these medicines

• Biological products are different to chemical drugs and cannot be treated as ‘generic’ drugs.

Biotherapeutic Products

• Biotechnology derived proteins –

complex, large molecules

Etanercept1

Aspirin

Chemical Drugs Biotherapeutics

Size Small Large

Structure Simple Complex

Stability Stable Unstable

Manufacturing Chemical processSimple and consistent

Unique biological expression system & process

Characterization Easy to characterize fully

Difficult to characterize fully

Generics Yes. Identical copy No. Identical copyimpossible

1.http://www.drugbank.ca/system/protein_structures/full/DB00005.png?1266600390

What is a biosimilar?

Legal Framework - Directive 2001/83/EC (as amended) = European Drug Law“

Article 10: ‘Generics’ and legal basis for ‘ Biosimilars’

Article 10(2a): ‘Generic medicinal product’ shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, (…).

Article 10(4): Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.

Regulatory Framework –Definition - A company may choose to develop a new biological medicinal product claimed to be similar (Similar Biological Medicinal Product) in terms of Quality, Safety and Efficacy to an original, reference medicinal product, which has been granted a marketing authorisation in the Community (see Guideline on Similar Biological Medicinal Products, CHMP/437/2004).

Biosimilars in EU

Comparability studies are needed to demonstrate the similar nature, in terms of quality, safety and efficacy, of the new similar biological medicinal product and the reference product authorised in the EU.

QualityComprehensive characterisation of product

Head-to-head comparisons using state-of–art methods

How similar is similar? Criteria

• Identical aa sequence, • Same dose, delivery route

Major differences

Product not a biosimilar

Extensive postmarketing pharmacovigilance commitments

Non-clinical (some comparative) & clinical data (comparative)

Similar efficacy & safety profile (incl immunogenicity).

Biosimilars:

Comparability Concept

Comparability studies are needed to generate evidence

substantiating the similar nature, in terms of quality, safety

and efficacy, of the new similar biological medicinal

product and the chosen reference medicinal product

authorised in the Community.

LMWH

Revised

IFN-a

EMA Guidelines on Biosimilars

mAbs

IFN-b,FSH

Additions

Consultation

Final revision

European Medicines Agency http://www.ema.europa.eu/, accessed 23 February 2011.

In revision

Biosimilars Approved in EU

Product Company INN Reference Product Date Approved

Omnitrope Sandoz (owned by Novartis)Somatropin Genotropin (Pfizer) April 2006

Valtropin BioPartners Somatropin Humatrope (Eli Lilly) April 2006

Binocrit Sandoz Epoetin alfa Eprex/Erypo (Janssen-Cilag) August 2007

Epoetin alfa HexalHexal Biotech (owned by

Novartis)

Epoetin alfa Eprex/Erypo (Janssen-Cilag) August 2007

Abseamed Medice Arzneimittel Epoetin alfa Eprex/Erypo (Janssen-Cilag) August 2007

Silapo Stada Arzneimittel Epoetin zeta Eprex/Erypo (Janssen-Cilag) December 2007

Retacrit Hospira Epoetin zeta Eprex/Erypo (Janssen-Cilag) December 2007

Ratiograstim Ratiopharm Filgrastim Neupogen (Amgen) September 2008

Filgrastim

RatiopharmRatiopharm

Filgrastim Neupogen (Amgen) September 2008

Biograstim CT Arzneimittel Filgrastim Neupogen (Amgen) September 2008

Tevagrastim Teva Generics Filgrastim Neupogen (Amgen) September 2008

Zarzio Sandoz Filgrastim Neupogen (Amgen) February 2009

Filgrastim Hexal Hexal Biotech Forschungs GmbH Filgrastim Neupogen (Amgen) February 2009

Nivestim Hospira Filgrastim Neupogen (Amgen) 2010

Alpheon (interferon alfa, being developed by BioPartners) was refused approval in June 2006 and Insulin Human Rapid Marvel, Insulin Human Long Marvel andInsulin Human 30/70 Mix Marvel were withdrawn in 2008 (insulin, being developed by Marvel Life Sciences Ltd).

Biosimilars in EU: An Update

• Uptake of biosimilars variable in MS; • EPO – 8% (France), 60% (Germany);• G-CSF – 15% (F), 35% (G);

• Cost reduction -15 -30% lower than the innovator product

• Significant gains in market share• No safety concerns identified.

Slide from Presentation by Paul Cornes, MD at EGA Annual

Conference on Biosimilars 14 April 2011, London

• Slow acceptance by physicians• Lack of understanding (some)• Concern & misconceptions

• Terminology • Concept of ‘biosimilarity’• Extrapolation of indications – difficultand ‘cautious ‘

• Scepticism

Biosimilars In EU

Global Situation in 2011

• USA – Patient protection & Affordable Care Act (2010);process very complex; biosimilar and interchangeable

– Omnitrope previously approved via a different regulatory pathway,Enoxaparin (recent)

• Some countries with regulations e.g., Japan, Singapore,Canada, Australia, Turkey, Malaysia, Korea

– Omnitrope (Growth Hormone) - most. EPO, Omnitrope - Japan

• Other countries e.g., Brazil & Jordan – developingregulations, China & India – no coherent pathway;

– currently have several marketed ‘copy’ products; approval basisunclear (minimal clinical data).

Global consistency and harmonization needed

• Different terminologies - EU, Australia - Biosimilars; Japan - Follow-on;Canada - Subsequent entry biologics (SEB)

• In other countries, ‘Copy’ versions often misquoted as biosimilars; thesehave not been evaluated using comprehensive comparability studies and are

NOT biosimilars !

Importance of TerminologyEPO products

Schellekens H et al. EJHP Practice 2004;,3,43–7 Brockmeyer and Seidl, EJHP Practice 2009, 15, 34-40

Isoelectric Focussing Gels

‘Copy’ Products’ Approved Biosimilar in EU

‘Not Similar’ to Reference E ‘Similar’ to Originator

E – reference 2, 4 – reference

Biosimilars: Unwanted

Immunogenicity

Quote from EMEA BMWP chairmen:

‘Unwanted Immunogenicity

is the biggest challenge for

the approval of Biosimilars’

Unwanted Immunogenicity

• Biological products can induce antibodies with different

characteristics :

- Non-neutralizing (binding) antibodies against

active (and/or inactive) product related substance(s).

- Binding antibodies against contaminants.

- Neutralising antibodies.

- Mixtures of the above.

• Different assays are needed for detection and measurement of

these antibody types.

Potential Clinical Consequences

of immunogenicity

• Can range from benign, non-significant to serious life-

threatening depending on the therapeutic

• Consequences on efficacy-reduction of the clinical

response to the biotherapeutic

• Consequences on safety - safety issues can occur even

when there is no loss of efficacy

• Acute consequences

- Infusion reactions, anaphylactic reactions

• Non-acute consequences

- Delayed-type hypersensitivity/immune complexes

- Cross-reactivity with an endogenous counterpart

Unwanted Immunogenicity

Current Position

Testing for unwanted immunogenicity is integral to

product development (clinical & post-marketing phase)

for ensuring:

– The clinical safety of a biotherapeutic

– Product Comparability

– When a Biosimilar product is developed.

Patient samples taken at appropriate time-points

Screening Assay-ve samples rejected +ve samples

Confirmatory Assay

Neutralization Assay Confirmed +ve samples Characterization

Assess correlation of characterized antibodies

with clinical responses to biological therapeutic

Assays for clinical markers and assessment

of clinical response in patients

Strategy for Antibody Detection

and Characterization

Guideline On Immunogenicity

Assessment Of Biotechnology-

Derived Therapeutic Proteins • Executive Summary

• Introduction

• Scope

• Legal Basis

• Main Guideline Text• Factors that may influence the development of an immune response against a therapeutic protein

• Patient and disease related factors,

• Product related risk factors of immunogenicity

• Non-clinical assessment of immunogenicity and its consequences

• Development of assays for detecting and measuring immune responses in humans. • Assay strategy

• Antibody assays

• Assay validation

• Characterization of antibodies to a therapeutic protein

• Potential clinical consequences of immunogenicity• Consequences on Efficacy

• Consequences on Safety

• Immunogenicity and Clinical Development• Rationale for sampling schedule and kinetics of the antibody response

• Consequences on pharmacokinetics of the product

• Methodology aspects to assess comparability of immunogenicity potential as part of a comparabilityexercise

• Immunogenicity in paediatric indications

• Risk Management Plan

• References• ANNEX 1 - Further details on methods for assessment and characterisation of immunogenicity

• ANNEX 2 - An example of a strategy for antibody detection and characterisation.

Comparative Immunogenicity

Compares immunogenicity of different products ;

Studies need to be designed to demonstrate whether the immunogenicity of the products is the same or significantly different.

This may affect the design of the studies & their interpretation.

For this, a homogeneous and clinically relevant patient population should be selected. Head-to-Head studies needed. Same assays & sampling strategy should be used.

The consequences of immunogenicity also must be compared.

Post-approval assessment may be necessary, usually as part of pharmacovigilance surveillance.

Comparative Immunogenicity

Conclusions on immunogenicity of products

obtained by comparing data from different

studies using different products are usually

invalid.

Immunogenicity Studies:

Biosimilars

The immunogenicity of the marketed product does not influence the need for comparative immunogenicity studies.

However, if the immunogenicity profiles of marketed and biosimilar products are significantly different, they can be considered DISSIMILAR

Antibody Frequency for Biosimilars (presubmission studies)

Biosimilar Ab incidence Reference Ab incidence

Omnitrope (SC) 0/51 (0.0%) Genotropin 1/44 (2.3%)

Valtropin (SC) 3/98 (3.4%) Humatrope 1/49 (2.0%)

Binocrit (IV) 2/314 (0.6%) * Erypo 3/164 (1.8%) *

Silapo (IV)

Silapo (SC)

0/305 (0.0%)

0/323 (0.0%)

Erypo

Erypo

0/304 (0.0%)

0/230 (0.0%)

Ratiograstim (SC) 7/356 (2.0%) Neupogen 2/134 (1.5%)

Zarzio (IV / SC)

(Phase 1, crossover)

0% Neupogen 0%

Nivestim 3/183 (1.6%) Neupogen 0/95 (0.0%)

Alpheon (SC) § † 31/111 (27.9%) ** Roferon-A 38/99 (38.4%) **

Insulin Marvel § † T1DM: 25/114 (21.9%) *

T2DM: 14/131 (10.7%) *

Humulin T1DM: 16/114 (14.0%) *

T2DM: 17/136 (12.5%) *

•prevalence; ** at end of treatment; § Application refused or withdrawn; † Assay validation insufficient

•Table courtesy of Martina Weise

Antibodies and Adverse Effects - EPO

Pure red-cell aplasia and anti-EPO antibodies in patients treated with EPO (EPREX)

• 2002 - 13 cases in CRF patients, rapid development of severe transfusion dependence within months of therapy,resistant to other EPO products.

• Pre 1998 – 2/3 cases•1998 to June’05 – 260+cases worldwide

Casadevall et al – NEJM 2002; 346 :469-475

Safety Study for Binocrit Suspended− No increased immunogenicity from IV use in patients with renal anaemia or SC use in cancer patients (both licensed)− Postmarketing SC trial in previously untreated renal anaemia patients: two cases of neutralising Ab

Binocrit approved - 2007

Rigorous physico-chemical, biological

characterisation & clinical trial data

Brockmeyer & Seidl (2009) Biologicals

>60 PRCA cases identified in Thailand. 14 EPO products marketed. Link to product(s) ?

Cause(s) ?

‘Biosimilar’ EPO is Immunogenic?

Under the generic drug paradigm of the Thai Food and Drug

Administration, 14 biosimilar r-HuEpos were licensed by 1

January 2009. These products came from various countries such

as Argentina, China, South Korea, and India.

The number of cases using biosimilar r-HuEpos have increased

enormously because of their more affordable prices. With their

usage, adverse effects of the less than identical therapeutic

agents have started to increase.

Many clinicians in Thailand were starting to see an increase in

PRCA cases which raised an important issue whether the

immunogenicity of biosimilar therapeutic agents were indeed

equivalent to the innovative r-HuEpo.

Worldwide consensus - A biosimilar is a

biotherapeutic accepted by a regulatory

pathway which requires biological and

clinical comparison with the original

licensed product .

Misleading definition

Are all Biosimilars really Biosimilars?

• Terms ‘Biosimilars’, ‘Similar Biological Products’ & ‘Non-

Innovator Products’ etc often used interchangeably. Can

be incorrect.

• Non-Innovator Products or ‘Me-to’ products usually have

not been evaluated using comprehensive comparability

studies. They are not biosimilars

• This can be very important from the immunogenicity

viewpoint.

Importance of Terminology

• Terms ‘Biosimilars’, ‘Similar Biological Products’ & ‘Non-

Innovator Products’ etc often used interchangeably. Can

be incorrect.

• Non-Innovator Products or ‘Me-to’ products usually have

not been evaluated using comprehensive comparability

studies. They are not biosimilars

Implications in terms of efficacy & safety

• This can be very important from the immunogenicity

viewpoint.

Biosimilars-Definition

Biosimilars-Definition

Example: Interferon-beta (IFN-β) products

IFN-β – 166 amino acid N-glycosylated α-helical protein. Two IFN-β-1a products, Avonex (Biogen-IDEC)and Rebif (Merck-Serono) approved for RRMS.

We compared the in vitro potency and molecular properties of these with four non-innovator‘copy’products

• Jumtab (Probiomed, Mexico),• Clausen (Laboratorio Clausen, Uruguay),• Blastoferon (BioSidus, Argentina),• Cinnovex (Cinnagen, Iran).

Except for Avonex, all products contained HSA as an excipient protein. Where possible, two or more batches of individual products were analysed.

Carbohydrate

side chain

A1 A2 A3 A4 A5 A6 B1 B2 B3 C1 D1 E1 E2 F1 F2 F31.0

3.5

6.0

8.5

11.0

13.5

16.0

18.5

Product

Po

ten

cy M

IU/d

ose

Potencies derived from antiviral 2D9 assays

Innovator A- Avonex, 6MIU

B- Rebif, 12MIU

Non-innovator C-Jumtab, 6MIU

D-Blastoferon,12MIUE-Clausen, 12MIUF-Cinnovex 6MIU

Meager A., Dolman, C., Dilger P., Bird C., Giovannoni G., Schellekens H., Thorpe R., Wadhwa M

An assessment of biological potency and molecular characteristics of different innovator and non-innovator

Interferon-beta products. Journal of Interferon and Cytokine Research 2010 (in press)

A

Different IFN-β products

M

I- Innovator - 1 - Rebif, 3, 7 - Avonex, 6 – Avonex (+HSA), NI- Non-innovator - 2- Clausen, 4, 5 – Cinnovex, 8 - Jumtab

Adducts

D

ImmunoblotHPLC Profile

Avo

Cin

Cla

M

I NI I NI NI I I NI

Immunogenicity of IFN-β-1a products

• All innovator products are immunogenic

• Incidence of neutralizing antibodies (NAb) –– Avonex 2-6% (13%); Rebif 12-28% (30 -39%); Blastoferon 8%;

loss of efficacy and treatment failure; abs are cross-reactive

• Removal of HSA from formulation of final product reduces immunogenicity. – NAb seroprevalence for Rebif New Formulation (no HSA) of 17.4%

compared to 27.3% for Rebif with HSA. Also fewer injection-site reactions.

• All non-innovator IFN-β-1a products contain HSA and are likely to be immunogenic!

Acknowledgements

• Meenu Wadhwa, Chris Bird, Isabelle Cludts, Tony

Meager.

• Members of the BMWP.