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Jamie DaviesHead of Pharmaceuticals, Healthcare & Medical Devices

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Overview

• Definitions, descriptions and terminology

• Clinical and scientific considerations

• Stakeholder viewpoints

• Regional notes on biosimilars

• Pricing and market acceptance

• Summary of key issues and outlook for biosimilars

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Zarxio (filgrastim-sndz)

Approval Pathway

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of

the Affordable Care Act that President Obama signed into law in March 2010. The BPCI Act

created an abbreviated licensure pathway for biological products shown to be “biosimilar” to

or “interchangeable” with an FDA-licensed biological product, called the “reference

product.”

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific

knowledge about the safety and effectiveness of the reference product, and enables a

biosimilar biological product to be licensed based on less than a full complement of

product-specific preclinical and clinical data.

• Biosimilar to Amgen’s Neupogen (filgrastim), which was launched in 1991.

• Available as Zarzio in Europe (2009).

• Approved in March 2015 on the basis of:o Structural characterisationo Animal study datao Human PK/PD datao Clinical immunogenicity datao Clinical safety/efficacy data

• Not interchangeable. • INN "placeholder" of 'filgrastim-

sndz‘.

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Definitions

European Medicines Agency

A similar biological or 'biosimilar' medicine is a biological medicine that is similar to another biological

medicine that has already been authorised for use. Biological medicines are medicines that are made by or derived from a biological source, such as a bacterium or

yeast. They can consist of relatively small molecules such as human insulin or erythropoietin, or complex

molecules such as monoclonal antibodies.

Biosimilars can only be authorised for use once the period of data exclusivity on the original 'reference'

biological medicine has expired. In general, this means that the biological reference medicine must have been

authorised for at least 10 years before a similar biological medicine can be made available by another

company.

Food and Drug Administration

A biosimilar product is a biological product that is approved based on a showing that it is highly similar to

an FDA-approved biological product, known as a reference product, and has no clinically meaningful

differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically

inactive components are allowable in biosimilar products.

An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional

standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the

health care provider who prescribed the reference product.

Source: European Medicines Agency, FDA.

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EMA Approved BiosimilarsProduct Name Active Substance Marketing Authorisation Holder Authorisation Date

Abasaglar insulin glargine Eli Lilly 2014Accofil filgrastim Accord Healthcare 2014

Bemfola follitropin alfa Finox Biotech 2014Grastofil filgrastim Apotex 2013Inflectra infliximab Hospira 2013Ovaleap follitropin alfa Teva 2013Remsima infliximab Celltrion 2013Nivestim filgrastim Hospira 2010

Filgrastim Hexal filgrastim Hexal 2009Zarzio filgrastim Sandoz 2009

Biograstim filgrastim AbZ-Pharma 2008Ratiograstim filgrastim Ratiopharm 2008Tevagrastim filgrastim Teva 2008Abseamed epoetin alfa Medice Arzneimittel Pütter 2007

Binocrit epoetin alfa Sandoz 2007Epoetin Alfa Hexal epoetin alfa Hexal 2007

Retacrit epoetin zeta Hospira 2007Silapo epoetin zeta Stada 2007

Omnitrope somatropin Sandoz 2006

Source: European Medicines Agency. List correct as of April 20th 2015.

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Structure Complexity

Source: Protein Data Bank.

Filgrastim

Molecular weight 19,600 g/mol

Infliximab

Molecular weight 144,190 g/mol

Aspirin

Molecular weight180 g/mol

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Terminology

Source: Biosimilars - why terminology matters. Nature Biotechnology. Volume 29 Number 8 August 2011 .

Term(s) Definition Implications

Biosimilar*

Copy version of an already authorised biological medicinal

product with demonstrated similarity in physicochemical

characteristics, efficacy and safety, based on a comprehensive

comparability exercise.

Only very small differences between biosimilar and reference with reassurance that these are of no

clinical relevance. Extrapolation of clinical indications acceptable if scientifically justified.

Me-too biological/biologic Biological medicinal product developed on its own and not

directly compared and analysed against a licensed reference

biological. May or may not have been compared clinically.

Unknown whether and which physicochemical differences exist compared to other biologicals of

the same product class.

Non-innovator biological/biologicClinical comparison alone usually not sensitive

enough to pick up differences of potential relevance. Therefore, extrapolation of clinical

indications problematic.

Second-generation (next-generation) biological/biologic

Biological that has been structurally and/or functionally altered to

achieve an improved or different clinical performance.

Usually stand-alone developments with a full development programme.

Biobetter

Clear (and intended) differences in the structure of the active substance, and most probably different clinical behaviour due to, for example, different

potency or immunogenicity.

From a regulatory perspective, a claim for ‘better’ would have to be substantiated by data showing a

clinically relevant advantage over a first- or previous-generation product.

* Comparable terms defined by the same/similar scientific principles include the WHO’s ‘similar biotherapeutic products’ and Health Canada’s (Toronto) ‘subsequent-entry biologicals’.

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Biosimilar/Originator Clinical Comparison• CT-P13 (Remsima/Inflectra) is

produced in the same type of cell line (Sp2/0-Ag14).

• Has an identical amino acid sequence to originator infliximab.

Source: Annals of the Rheumatic Diseases. 2013 Oct; 72(10): 1605–1612.

Image: pharmacokinetics comparison of CT-P13 versus infliximab

Conclusions

CT-P13 and infliximab were shown to be equivalent in terms of AUC and Cmax in patients

with active AS.

Clinical efficacy endpoints were highly similar.

CT-P13 was well-tolerated with an immunogenicity and safety profile comparable

to infliximab up to week 30.

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Protein Glycosylation• Glycosylation is the attachment of sugar

moieties to proteins.

• For non-glycosylated proteins, the structure of the biosimilar is the same as the originator.

• Glycosylated protein complicate matters…

• Glycan structures are dependent on:o Nature of production cello Conditions of cellular cultureo Downstream processing methods

• Glycan structures exhibit micro-heterogeneity and are defined physico-chemically by their glycoform profile.

Image: Various glycosidic linkages

Source: Thermo Fisher Scientific .

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GPhA Citizen Petition – September 2013

• Post-manufacturing change biologics share INNs with pre-change versions.

• European biosimilars sharing INNs with reference protein product (RPP) are successfully tracked and traced.

• Unique INNs for every biosimilar could jeopardise patient safety.

• NDCs are effective in pharmacovigilance.

GPhA's core purpose is to improve the lives of consumers by providing timely access to

affordable pharmaceuticals. Toward this end, GPhA advances the interests of our member

companies through initiatives in the scientific, regulatory, federal and state forums,

international agencies, and in the public affairs arena.

Image: example National Drug Code (NDC) number

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Novartis Citizen Petition – October 2013

Source: Novartis.

• INNs are not the primary tool for tacking and tracing.

• FDA approves manufacturing changes of originator biologics without new INNs.

• Different INNs for biosimilars would contravene United States Pharmacopeia (USP) regulations.

• INNs for biosimilars would be detrimental to patient safety.

Table: Examples of FDA Approved/Licensed biologic products that share INNs (listed alphabetically by INN)

Brand/Trade Name

Common Name (established generic, INN,

USAN)Sponsor Original

Approval DateFDA

Application Number

MyozymeAlglucosidase

Alfa

Genzyme April 28, 2006 BLA 125141

Lumizyme Genzyme May 24, 2010 BLA 125291

Kogenate FSAntihemophilic

Factor (Recombinant)

Bayer Corp June 26, 2000 BL 103332

ReFacto Genetics Institute March 6, 2000 BL 980137

Recombinate Baxter Healthcare Corporation

January 21, 2010 BL 103375

Advate Antihemophilic Factor

(Recombinant) - Plasma/Albumin

Free

Baxter Healthcare Corporation July 25, 2003 BL 125063

XynthaWyeth

Pharmaceuticals, Inc.

February 21, 2008 BL 125264

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J&J Citizen Petition – January 2014

Image: bone marrow of patient with antibody-mediated pure red cell aplasia (PRCA)

Source: American Society of Nephrology.

• Reliable pharmacovigilance mechanisms are needed for detection and investigation of post-market safety signals.

• Products may change over time in clinically meaningful ways.

• Effective pharmacovigilance depends on the ability to identify which product a patient has received.

• When patients are switched between or among products, it can be difficult or impossible to identify the product responsible for an adverse event.

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Biological Qualifiers – July 2014

• To uniquely identify the manufacturer and manufacturing site of the active substance in a biologic product.

• Code will consist of four letters assigned at random. Vowel excluded. Over 160,000 codes available.

• Applies prospectively and retrospectively. Stored on database maintained by WHO.

• Front page meeting with INN Stakeholders on 16th June 2015(Review of comments on "Biological Qualifier An INN Proposal").

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Americas

Country Notes On Biosimilars

ArgentinaFirst biosimilars introduced in 2008. A regional leader. Biosimilars are referred to as 'medicamento biológico similar'.

BrazilANVISA’s Rule #55/2010, which does not use the terms “biosimilar” or “biogeneric”, but instead refers to a “new biologic product” for an innovator product and a “biologic product” for a biosimilar.

CanadaIn April 2015, the Canadian Generic Pharmaceutical Association (CGPA) announced the establishment of a new CPGA Biosimilars Board. Biosimilars are referred to as 'subsequent entry biologics'.

ChileIn 2011, Chile's National Drug Agency (ANAMED) released draft guidelines for biosimilar evaluation, but official regulatory steps have not been taken. Biosimilars are referred to as 'biosimilares'.

ColombiaIn September 2014, Colombia released new regulations for the approval of biosimilars in the country. Biosimilars are referred to officially as 'medication of successor biological origin'.

MexicoMexico's health authority COFEPRIS published official guidelines for biosimilar evaluation in 2011. Biosimilars are referred to as 'biocomparables'.

PeruMinisterio de Salud Peru (MINSA) provides regulations covering biosimilars, which are referred to as 'Producto biológico similar (similar biological product)'.

US First approval of a biosimilar was only in 2015.Venezuela Venezuela drafted guidelines for biosimilars in 2012, but the country has yet to formalise any regulation.

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Middle East And Africa

Country Notes On Biosimilars

EgyptRegulations take into account both EMA and WHO guidelines, and aim to facilitate the registration of biosimilar products through an abbreviated pathway.

GhanaBiosimilar registration guidelines were published in 2013, with the decision for substitution based on clinical data.

IranDomestic companies manufacture numerous biosimilars, including filgrastim, pegfilgrastim, follitropin alpha, chorionic gonadotropin and infliximab.

IsraelPharmacists are not allowed to switch between a biosimilar and the reference product and vice versa, without explicit directions from the prescribing physician.

Jordan

The JFDA follows the EMA guidelines on similar biological medicinal products for specific active biological substances for non-clinical and clinical studies requirements. A post marketing surveillance study is requested after a biosimilar product is authorised.

Nigeria NAFDAC released guidelines for the registration of biosimilars in December 2012.

Saudi ArabiaGuidelines contain specific chapters on biosimilar products including insulin, interferons, erythropoietin, granulocyte colony stimulating factor and growth hormone.

South AfricaBiosimilars are not allowed to be interchangeable with their reference product and automatic substitution cannot apply to biosimilars.

Tunisia Epomax (epoietin alfa) is manufactured in Tunisia by Medis Laboratories.

UAELocal firm Julphar has manufactured biosimilars since 2012, and its facility is the only plant in the Middle East producing insulin crystals derived from r-DNA technology.

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Central And Eastern EuropeCountry Notes On BiosimilarsCroatia Automatic substitution of biologics prohibited by law.

Czech RepublicNo specific guidelines or regulations in place currently against interchangeability of biosimilars. Nevertheless, biosimilar uptake of filgrastim is high.

GreeceGreece's National Organization for Medicines (EOF) has rejected the interchangeability of biosimilars with reference/originator biologics.

Hungary Automatic substitution of biologics with biosimilars is not allowed by law.Lithuania tbo-filgrastim, marketed by Teva, is manufactured by local drugmaker Sicor.

PolandRemsima (infliximab) is included on the national reimbursement list, at a 30% discount to Remicade. No regulations on biosimilar interchangeability yet, but automatic substitution is occurring.

RomaniaBiosimilar substitution of originator is potentially possible. Biosimilar substitution/penetration of filgrastim is almost 100% in Romania.

Russia

Does not have an official biosimilar pathway yet so full clinical development programme needs to be carried out. But because of local clinical trials requirement, local drugmakers at a distinct advantage. However, by July 2015, government will define interchangeability rules which could expedite biosimilar drug registration, based on bioequivalence and other parameters.

SerbiaSerbia is adopting EU legislation on biosimilars and medicine regulatory approval as part of its EU accession plans. Serbian biosimilar guidelines are nearly identical to EMA guidelines.

SlovakiaAutomatic substitution of biologics with biosimilars is recommended against by healthcare authorities guidelines.

Slovenia Guidelines from healthcare authorities state not to interchange biosimilars with originators.

TurkeyAll drugs marketed in Turkey require a Turkish Good Manufacturing Practice (GMP) certificate. Therefore, domestic players are at an advantage as are those with local manufacturing established.

UkraineBiosimilar pathway instated in Jan 2013, by amending order of Ministry of Health No. 426 and introducing order no.582.

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Asia Pacific

Country Notes On Biosimilars

Japan

Biosimilar naming regulations introduced in 2009, and revised in 2013. As of June 2014, a total of seven biosimilars approved, from a mix of local and foreign firms. Domestic clinical trials. PDMA consultations 'strongly recommended'. Naming convention example: Filgrastim BS Injection 75µg syringe [SANDOZ]

Australia

Has adopted EMA guidelines. In January 2015, the Therapeutic Goods Administration announced that it will not be continuing with a previously proposed naming convention for biosimilars. In the interim biosimilars will use the Australian biological name without a specific biosimilar identifier suffix, for example a biosimilar to the reference product Neupogen filgrastim would be named 'TRADENAME' filgrastim.

South KoreaSouth Korean firms are heavily invested in the biosimilar space. It has also attracted conglomerates such as Samsung, which established Samsung Bioepis, the company's biosimilar arm.

Hong KongHong Kong's local pharmacists association highlights that the introduction of biosimilar medicines into the healthcare system can save the public hospitals HK230mn (USD30mn) annually.

China China implemented its first biosimilar regulatory pathway in February 2015.

India

India's low levels of patent protection have allowed Indian generic drugmakers to develop extensive capacities in biosimilars. Companies actively involved include Biocon, Dr Reddy's Laboratories and Zydus Cadila. As well as Ranbaxy Pharmaceutical, which has been acquired by Sun Pharmaceutical. These companies have also exported their biosimilar products into the emerging markets of South East Asia.

IndonesiaThe country is currently developing biosimilar guidelines with Indonesia-based Kalbe Farma, which is looking to expand into this product category.

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Western EuropeCountry Notes On Biosimilars

Austria

One of the most challenging pricing policies in Europe is the mandated discounting policy found in Austria. It is important to note that Austria does not have a specific biosimilar pricing mechanisms, but simply applies the country's generic pricing policy. The biosimilar discount against the originator is predetermined and significant.

Italy

Italy also presents an unfavourable environment for biosimilars, with a strict price regulation system which requires a mandatory discount of 15%-22% for their prices relative to those of the reference brand. The discounts were introduced as a way to encourage the uptake of biosimilars.

France

In January 2014, France approved legislation enabling prescribers to substitute a biosimilar in place of an originator biologic or hospital pharmacists to do so at their discretion if prescribers had not ruled out substitution explicitly.

Netherlands

The Dutch Medicines Evaluation Board (MEB) published a new position on biosimilars, in which it accepts substitution or interchangeability of biosimilars under certain conditions. The MEB's revised position on biosimilars was published on 31 March 2015 and replaces its previous position of 2010. The 2010 position provided that patients should be kept at the same biological medicinal product if the patient responded well to such biological medicinal product.

Germany

The Ministry of Health has issued directives mandating a quota of biosimilar uptake on a regional basis. Additionally, to push the uptake of biosimilars, initiatives include: education sessions for clinicians on biosimilars; the endorsement of biosimilars as safe and effective via "dear doctor" letters to address potential concerns and stress the savings potential of biosimilars; and the publication of real-world data supporting biosimilars' safety and efficacy.

UK

For hospital prescribed biosimilars, regional hospital tenders award a single preferred agent through a transparent bid process which is not solely based on the lowest price. Furthermore, hospitals also publish success stories on the impact of biosimilars on the hospital's savings to raise awareness and boost uptake.

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Pricing

“If you are in an EU country where prices are referenced, they’re going to come to market,

and they will obviously compete on price, right?

A lot of those markets, as soon as they lower their price, we are going to have to actually, by way the payer system works, have to lower our

price as well, right?

It’s going to make, in those markets, it extremely difficult for the biosimilars to get

meaningful share.”

Bill Chase – CFO, AbbVieCowen Healthcare Conference, March 2014Fe

b-14

Mar-1

4

Apr-14

May-1

4Jun-14

Jul-14

Aug-14

Sep-14

Oct-14

Nov-14

Dec-14Jan-15

Feb-15

Mar-1

50

10

20

30

40

50

60

70

80

90

100

Percentage Share Of Norway In-fliximab Market

Remsima Remicade

Remsima at 39% discount

Remsima at 69% discount

Source: Norwegian Medicines Agency.

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View Of US Pharmacists

1 2 3 4 50

5

10

15

20

25

30

35

40

45

Confidence In Biosimilar Substitution (% Of Respondents)

If both products share the same ac-tive ingredient or non-proprietary name?If both products did NOT share the same active ingredient or non-proprietary name?If both products did not share the same active ingredient or non-pro-prietary name because of a prefix or suffix?

Level of confidence1 = not confident 5 = very confident

Source: Journal of Managed Care & Specialty Pharmacy, Vol 21, No. 3, March 2015.

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Outlook For Biosimilars

• Biosimilar market to stratify according to product/country

• Country uptake will be determined by need to control healthcare spending

• Interchangeable biosimilar in the US will be major development

• More education/advocacy/petitioning and will involve all stakeholders

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