Bruno Flamion, MD, PhDProfessor of Physiology & Pharmacology, University of Namur, Belgium

Past Chair of the European Medicines Agency (EMA) Scientific Advice GroupPast Chair of the Committee for Reimbursement of Medicines in Belgium (CTG/CRM)

How are biosimilars assessed

and approved ?

What is a biosimilar?

• A new product that is similar to an originator product• The biosimilar (like generics) can only be approved once the

patent and data protection of the originator have expired (usually, 12 years after marketing authorisation)

• The originator must be a (synonyms): • biological medicinal product (EMA)• biotherapeutic product (WHO)• biologic (FDA)• biological

• However, the biosimilar cannot be a simple copy• It must pass a series of strict comparative tests vs one

particular originator, selected as “the reference product” 3

1. Cannot be synthesized chemically – require a living organism or cell culture

2. Complex manufacturing process3. Intrinsic variability (e.g. glycoforms)4. Variability between production lots / batches5. Changes in manufacturing process may occur and are

tightly controlled by regulatory authorities (need for “comparability exercise” – ICH Q5E)

6. Can generate immune responses7. Require a strict Risk Management Plan (surveillance)

➙ Creating a biosimilar is difficult and costly

Difficulties linked to biological products

3

§ 1921 discovery of insulin (Banting & Best)

§ 1983 first recombinant human insulin (Humulin®)

§ 1985 first recombinant human growth hormone

§ 1989 epoetin-⍺ (first recombinant glycoprotein)

§ 1991 filgrastim (granulocyte-colony stimulating factor)

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Main biologics

§ 1997 rituximab (first non-murine monoclonal antibody) (MabThera®)

§ >1998 trastuzumab (Herceptin®), infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), insulin glargine (Lantus®), …

= “replacement therapies”

= available as biosimilars today

Generics vs biosimilars: different concepts (1)

Generic BiosimilarReference is a small, chemically synthesized molecule.

Reference is a biological product.

aspirin

6

✖ 1000

monoclonal AB

Generics vs biosimilars: different concepts (2)

Generic BiosimilarReference is a small, chemically synthesized molecule.

Reference is a biological product.

Is identical with regard to qualitative and quantitative composition in active substances; has the same pharmaceutical form as the reference.

Is similar in terms of quality, safety and efficacy to an already licensed and extensively characterized reference.Cannot be identical due to biologic variability

Bioequivalence with the reference product has been demonstrated through appropriate bioavailability studies

Bioequivalence with the reference is only one part of a full comparative exercise

The exercise must meet the WHO, EMA or FDA guideline requirements

Complex biologics (like MAbs) are always micro-heterogeneous mixtures of several isoforms, each of which may differ in terms of

potency, half-life and immunogenicity2

1. Rudd, P. M., et al. J. Biol. Chem. 1997;272:7229.2. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. 7

Biologics: intrinsic heterogeneity

Thesamecellalwaysproducesdifferentglycoforms1

All lots of the original product are not identical

Theoretical example – EMA: European Medicines Agency – FDA: Food & Drug Administration (USA)

Biolog

icalactivity

(U/

µg)

1500

1000

500

Acceptable variability

for the company,

EMA & FDA

Year1Year2Year3Year4………..

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Biologics: complex manufacturing process

Theprocessisdifficult(butnotimpossible)toreproduceclosely

CloningintoDNAvector

Transferintohostcellexpression

Differentcellcultureprocesses

Differentpurificationandformulation

protocols

Codinggenemutation

DörnerT,etal.AnnRheumDis.2013;72(3):322-328.AhmedI.ClinicalTherapeutics2012;34(2):400–419

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5 comparative steps required to approve a biosimilar

1. technical qualifications 2. bioassays (for instance, on human cells)3. non-clinical tests in animals4. at least 2 clinical trials in humans: one PK/PD, one

Phase III trial in the most sensitive population with sensitive endpoints (i.e. able to detect a difference if there is one)

5. specific post-marketing surveillance (“Risk Management Plan”), e.g. check for unexpected immunogenicity

• This is called by the EMA a full comparability exercise (although this term officially refers to the “Comparability of Biological Products Subject to Changes in Their Manufacturing Process” – Q5E ICH document)

• The FDA talks about “a stepwise comparative exercise” 9

1 Omnitrope (somatropin) Sandoz (Novartis) Authorized

2 Valtropin (somatropin) – [yeast] Biopartners Authorized

3 Alpheon (interferon alfa) BioPartners Negative

4 Binocrit (epoetin alfa) Sandoz (Novartis) Authorized

5 Epoetin alfa Hexal (epoetin alfa) Hexal (Novartis) Authorized

6 Abseamed (epoetin alfa) Medice Authorized

7 Silapo (epoetin zeta) Stada Authorized

8 Retacrit (epoetin zeta) Hospira Authorized

9 Insulin Marvel Short (human insulin) Marvel Life Sci Negative

10 Insulin Marvel Intermediate (human insulin)Marvel Life Sci Negative

11 Insulin Marvel Long (human insulin) Marvel Life Sci Negative

12 Filgrastim Ratiopharm (filgrastim) Ratiopharm Authorized

13 Biograstim (filgrastim) AbZ-Pharma GmbH Authorized

14 Tevagrastim (filgrastim) Teva Authorized

15 Zarzio (filgrastim) Sandoz (Novartis) Authorized

16 Filgrastim Hexal Hexal (Novartis) Authorized

17 Biferonex (interferon beta-1a) BioPartners Negative

18 Nivestim (filgrastim) Hospira Authorized

Biosimilars at the European Medicines Agency (1)

1

3

4

5

6

7

2006

2007

2007

2008

2009

2010

2−withdrawn

These 3 products are

identical !!

19 Remsima (infliximab) Celltrion Authorized

20 Inflectra (infliximab) Hospira/Pfizer Authorized

Biosimilars at the European Medicines Agency (2)

82013

921 Ovaleap (follitropin alpha) Teva Authorized

1022 Gastrofil (filgrastim) Apotex Authorized

23 Bemfola (follitropin alpha) Finox Biotech AG Authorized 112014

First MAb In all indications !!

24 Abasaglar (insulin glargine) Lilly-Boehringer Authorized 12NB. At FDA: Basaglar2 (not a biosimilar – 505(b)(2) procedure) FDA-approved

Identical products

Some data not developed by the Applicant

25 Benepali (etanercept) Samsung-Bioepis Authorized 132016

26 Flixabi (infliximab) Samsung-Bioepis CHMP app. 14

Biosimilars under evaluation at the EMA

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INN Reference product Month of submissionenoxaparin Clexane March 2015 (2 dossiers)rituximab Mabthera November 2015etanercept Enbrel December 2015pegfilgrastim Neulasta December 2015 (3 doss.)adalimumab Humira December 2015 (2 doss.)insulin glargine Lantus January 2016teriparatide Forsteo January 2016 (2 doss.)

What about the FDA?

§ Have approved “follow-on biologics” based on regular BLA (biological license application), e.g. Teva’s tbo-filgrastrim (equivalent to Tevagrastim® in the EU)

§ New (2012) “BPCI Act”, framework, and guidelines on abbreviated BLA for biosimilars now available

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§ FDA approved Sandoz’ Zarxio® (filgrastim-sndz) in March 2015 and Celltrion’s Inflectra(infliximab-dyyb) on 5 April 2016

§ FDA could also approve “interchangeable”products (none so far) to which patients can be switched from an originator (and vice versa)

§ NB. EMA does not rule on interchangeability (and certainly not on automatic substitution)

FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.

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Regulations on biosimilars/copies vary across the world

EMA-like biosimilar regulation

Europe (EMA) since 2005WHO since 2009USA (FDA) since 2012Canada, AustraliaJapan, South Korea, TaiwanSaudi Arabia

Regulation inspired from EMA but lower (clinical) requirements

South Africa, JordanTurkeyBrazil, Argentina

Generics-like regulation (“biocopies”)

Mexico, Peru, ChileIndia (eg. Reditux® retuximab by DrReddy’s; CANMab® trastuzumab by Biocon/Mylan; BOW015® infliximab by Ranbaxy…)

No or unclear regulation

RussiaChina

1. Dorner T, et al. Ann Rheum Dis 2013; 72:322–328.2. http://www.ft.com/cms/s/2/301a779c-302e-11e2-a040-00144feabdc0.html#axzz3XHrf22l4

Examples of reference vs biosimilarcomparative tests and trials

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RemicadeTM Batch #2

RemicadeTM Batch #1

CT-P13 batches

JungSKetal.mAbs,2014;6(5):1163-1177.

Secondary structure:FT-IR spectrometry

CT-P13 (infliximab) vs Remicade: ex. of analytical data

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Park W, et al. Ann Rheum Dis 2013; doi:10.1136/annrheumdis-2012-203091.

n= 221

PLANETAS

CT-P13 (infliximab) vs Remicade PK trial in AS patients

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CT-P13

100 –90 –80 –70 –60 –50 –40 –30 –20 –10 –

0 –

CT-P13 Phase III equivalence trial in RA patients

• N= 606. Primary efficacy endpoint: ACR20 response at week 30

• Safety: Treatment-emergent adverse events were seen in 35.2% of patients treated with CT-P13 and 35.9% of patients treated with INX

• Immunogenicity: Equivalent levels of anti-infliximab antibodies were detected in both treatment arms at week 14 and week 30

Yoo DH, et al. Ann Rheum Dis. 2013;72(10):1613-1620.

184/302 178/304 182/248 175/251

Treatment difference =2% (95% CI: 6%, 10%)

Treatment difference =4% (95% CI: -4%, 12%)

CT-P13

60.9 58.6

73.4 69.7INX

PP PopulationITT Population

Res

pons

e R

ate,

%

19

PLANETRA

1999 2000 2001 2002 2003 2004 2005 2006

RA: signs and symptoms

FistulizingCD maintenance

Ankylosing Spondylitis

Luminal CD maintenance

Early RA

Psoriatic Arthritis

Moderate/Severe

Psoriasis

Ulcerative Colitis

RA:joint damage

Crohn’s Disease

RA: physical function

Evolution of Remicade indications in EU

Basis for extrapolation of indications for

Remsima® /Inflectra®

+ Post-approval commitment for a Ph III trial in Crohn’s disease

+ Paediatric indications

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Extrapolation of indications (1)

– Means that one Phase III clinical trial comparing biosimilarand original can serve as the basis to approve all other indications of the original

– Is the key concept for biosimilars (only way to decrease the cost of development)

– Requires that the Phase III trial is carefully selected: the patient population and the endpoints must be the most sensitive to detect a difference if it exists

– Extrapolation is granted on a case-by-case basis: IF the mechanism of action, safety, and immunogenicity are expected to be similar in these indications (= value judgment by regulators and experts)

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22

Extrapolation of indications (2)

Regulators Clinicians

The goal of a biosimilar development is to demonstrate similarity, not clinical benefit, which was proven for the original product.

« We need studies proving efficacy and safety of the

biosimilar in our indications »

More clinical trials will not improve the demonstration of similarity. In vitro assays

are usually most sensitive to detect differences in pharmacological activity.

Blood. 2014;124(22):3191-3196

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Extrapolation of indications (3)

Numerous publications by clinicians…

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The clinical issues are not different from other biosimilars but extrapolation may be “technically” more difficult

Very complex mechanisms of action

Biosimilar MAbs in oncology

Complex (oncology) indications

Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010.

– Efficacy and safety of switching between reference and biosimilar not fully demonstrated in clinical trials of biosimilars (would mean long and difficult studies)

– EMA does not rule on interchangeability or switch– Can lead to automatic substitution by pharmacists and

to lack of traceability– May entail some risks, e.g. increased immunogenicity

(but this is unproven)– Any change in therapy can destabilize a well-treated

patient

“Switching” patients to biosimilars

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Interchangeability ?

Recent initiative towards interchangeability

• NOR-SWITCH study 2• Target = 500 patients• Ended recruiting in June

2015 2• Patients with all

indications of Remicadeare randomised to blindly stay on drug or switch to Remsima 2

• Primary endpoint is occurrence of disease worsening at 52 weeks 2

• Several secondary endpoints

261. Stanton D. Norway to facilitate switch to biosimilars with $3m Remicade study. BioPharma, 2013.2. Clinicaltrials.gov. The NOR-SWITCH study. https://clinicaltrials.gov/ct2/show/NCT02148640.

Conclusions

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1. A biosimilar is NOT a “biogeneric” of the reference biologic, due to intrinsic variability and non-identical production steps.

2. Approving biosimilars is a complex exercise overseen by regulatory authorities such as EMA, FDA, WHO… This exercise ensures a very low likelihood of clinically significant differences.

3. The comparative physicochemical characteristics of the biosimilarand the reference product are scrutinized. In vitro assays are most sensitive to detect differences in pharmacological activity.

Summary

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4. One comparative PK study and one therapeutic equivalence study are requested. Extrapolation of indications is key to the biosimilar concept but needs to be justified in all cases (e.g., similar mechanism of action in all indications).

5. Detection of immunogenicity and a good Risk Management Plan (role of pharmacists) are key elements of safety.

6. Traceability should be ensured by prescribing under brand names and keeping good records. Interchangeability is a health policy issue dealt with at national level.

Summary

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Belgian biosimilar?

Suggested by Prof. Wolgang Jelkmann

La Reproduction Interdite (portrait d’Edward James),René Magritte, 1937

Boymans-van Beuningen Museum, Rotterdam

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Thank You!!

Bruno.Flamion@unamur.be 31