01 HOT TOPIC Pharmacokinetics & Immunogenicity Bioanalysis in Biosimilar Development

04 REGULATORYFRAMEWORK UPDATE

05 BIOSIMILARSAPPLICATIONS Approved & Under Review

HOT TOPIC

Pharmacokinetics & Immunogenicity Bioanalysis in Biosimilar Developmentby Martin NemanskyScientific Director, Bioanalytical Lab

A biosimilar should demon-strate similarity to the reference medicinal prod-

uct in terms of quality characteristics, biological activity, safety and efficacy based on comprehensive comparability studies. Foremost, comparability of a biosimilar with the reference medic-inal product is demonstrated in the production (CMC) phase by using ap-propriate physico-chemical, and in-vi-tro biological tests. Subsequently, non

clinical and clinical studies are per-formed to demonstrate comparability regarding dose exposure, safety, phar-macodynamics and non clinical and clinical response. During these studies, the analytical methods to determine PK, to monitor immunogenicity (an-ti-drug antibody, ADA, assays) and to assess key PD parameters are pivotal and directly influence marketing au-thorization of a biosimilar and safety of the patients. Therefore, accurate per-

formance of PK, immunogenicity and efficacy PD studies is essential for the successful development of a biosimi-lar. Similarity between the biosimilar and its reference product(s) should be demonstrated during the validation phase of each method. The methods should be designed to detect possible (non-)clinical dissimilarities and per-formance of the relevant analytical methods and handling of the samples should be focused on avoiding the

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B I O S I M I L A R S N E W S L E T T E RVolume 4 , October 2014

Welcome

Welcome to the fourth edition of Biosimilars Newsletter, a quarterly publication dedi-cated to keeping you updated on current biosimilars news, including the global regula-tory landscape, biosimilars articles and reports, and company news as reported by the company press releases.

The “hot topic” for this edition discusses the crucial, but often overlooked, part played of bioanalytical method development and validation in the marketing authorization of a Biosimilar and safety of patients. The article discusses several of the practical steps which should be taken into account during validation and bioanalysis required to de-termine pharmacokinetics (PK), to monitor immunogenicity (anti-drug antibody, ADA, assays), and to assess key pharmacodynamic parameters (PD).

INSIDE THIS ISSUE:

01. Biosimilars Newsletter

Welcome

Hot Topic

04. Regulatory Framework Update

Europe

United States

Rest of World

04. Regulatory Meetings

05. Approved & Under ReviewEuropeUnited StatesRest of World

06. Articles & Reports of Interest

07. Company News

08. Next Edition

02

generation of any additional impreci-sion. The following discusses several practical aspects which should be tak-en into account during validation and bioanalysis. PK & ADA Assay Methods

For PK assays supporting biosimilar trials, a single method is validated for all studied compounds (ie, the biosim-ilar and all reference compounds). The different compounds must be detected equally in a single PK assay. All rele-vant assay parameters are validated in such a way that it is ensured, that any detected differences from the (non-) clinical trial, are not due to analyti-cal or handling variations. Similarity should be observed during pre-study validation. In addition, the validated precision of the PK assay can serve as an indicator for the statistical signifi-cance of any detected variations from the (non-) clinical trial.

Current international guidelines, white papers and conference reports provide no clear answer as to whether a single ADA method should be used, or if sep-arate methods (Figure 1) are needed for each studied compound1.

Health Authorities indicate that either approach is suitable if based on good science, and thoroughly and appropri-ately validated. We would recommend that identical analytical platforms with compound-specific coatings are used as this ensures a scientifically comprehen-sive approach. Using separate coating reagents, specific for each compound will ensure detection of any potential ADAs, including those directed against possible unique compound-specific epitopes. By keeping all other parame-ters equal, this should ensure using the same method. This approach towards ADA assays has implications regarding validation and sample analysis, in par-ticular regarding unblinded testing of ADA study samples, as discussed below.

Alternatively, one may select the “one

ADA assay” approach, utilizing one specific coating for all studied com-pounds. In that case, the Biosimilar compound must be used for detection of all ADAs as the first priority of the ongoing (non-) clinical development is the safety of the Biosimilar.

Independent of the choice for a single ADA assay or several specific ones, it is imperative that all ADA assays are capable of detecting any antibod-ies that can be potentially produced against any part/epitope of their spe-cific target compounds. This is par-ticularly important for “segmented compounds” which include linkers and for example, stabilizing agents. In addition, ADA assays should be able to detect potential drug-specific IgM, as well as IgG antibodies.

As a follow-up characterization, iso-typ-ing and antigen-typing of confirmed positive samples can be performed when different ADA responses are detected for the different dosed compounds.

Reagents, Reference Materials & Calibrators

Reagents, such as capture and detec-tion antibodies, must be suitable and characterized for both the biosimilar and all reference compounds. There should be no difference in response values for either compound in the assay. For PK studies, this is demon-strated during validation using multi-ple sets of compound-specific valida-tion samples.

Reference materials (ie, the biosim-ilar and all reference compounds) must be well characterized. For each reference compound, including the biosimilar, a Certificate of Analysis must be available. In practice, this may be challenging for the reference compounds, which are usually com-petitor products, obtained commer-cially through a pharmacy. In that case, pharmaceutical analysis can be performed on all reference materials

BIOSIMILARS NEWSLETTER | Volume 4, October 2014

* The cut point of the assay is the level of re-sponse of the assay at or above which a sam-ple is defined to be positive, and below which it is defined to be negative.

Figure 1

(including the biosimilar) to establish the nominal concentrations and to obtain QC certificates. Drug Product, which is the Drug Substance processed into the final formulation, must be used, which is identical to the applied dosage form during the (non-) clinical study. For initial method development, the unformulated Drug Substance can be used; however for pre validation, validation and sample analysis, the ac-tual Drug Product must be used.

For PK assays, one calibration curve will be prepared using either the bio-similar, or one of the reference com-pounds. Preferably, the biosimilar is used, as this compound will be read-ily available and most extensively characterized. Before this calibration curve can be used for sample analysis, linearity between the Biosimilar and the reference compound(s) should be demonstrated.

Positive Controls, Cut Points & Titers

Ideally, independent positive controls (PCs) should be tested during method development for each ADA assay. These PCs should:

• contain ADAs for each specific compound separately

• include ADAs representative for the (non-) clinical formulation of the drug (eg, lot of the drug, impu-rities, host cell proteins, etc.)

• be polyclonal of nature

• be from the target species

If PCs for human assays are not avail-able, the PCs should include antibod-ies resembling the human response as closely as possible (e.g. primate or rabbit antibodies, as rabbits have a high somatic hyper mutation). If a PC demonstrates similar cross re-activity in all used ADA assays (e.g. leading to similar titers), it can be used for validation and during sam-ple analysis. Typically, this should be a PC with ADAs against the biosim-ilar compound. This holds also true, in case only one PC is available, and when the one-assay approach is used.

Cut points* are determined for the bi-osimilar and any reference compound independently using the same individ-ual matrix samples. These cut points must be similar for the different com-pounds, which can be demonstrated by similarity of titers (eg, maximal varia-tion of one titer unit). Validation Samples & Comparability

For PK assays, a full set of validation samples should be used for each com-pound tested. All validation exper-iments, including stability testing, should be performed for all com-pounds. Each set of validation samples

Innovator

Innovator

Biosimilar

Biosimilar

ADA ADA

Label Light Label Light

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must have the same concentration lev-els for each compound and must fulfill its acceptance criteria, demonstrating that the method is capable of detecting all compounds equally. Corresponding sets of precision and accuracy samples for the biosimilar and the reference compound(s) are preferably analyzed within the same validation run. Ideally, the same concentration levels are ana-lyzed on the same plate or at least by the same technician within the same day using identical equipment.

To demonstrate that the method can be used for sample analysis containing both the biosimilar and the reference compounds, comparability between the two is calculated during pre-study validation using the results from each set of precision and accuracy vali-dation samples at five concentration levels. This is performed by compari-son of the overall mean concentration results at each validation level. Ratios are calculated between the different reference compounds in each possible combination (eg, Biosimilar/Reference US, Biosimilar/Reference EU and Reference US/Reference EU). Ratios between the mean concentrations of the different compounds must all be between 0.8 and 1.25.

Study Sample Analysis

PK study samples must be analyzed in a blinded manner. Technicians must be blinded towards the actual dosing when analyzing samples from either the biosimilar, or the reference com-pound arm(s) of the clinical study. Incurred sample reproducibility (ISR) must be performed for a representative set of study samples. The ISR samples must be selected randomly covering all subjects, periods and groups to eventu-ally contain samples for both the bio-similar and each reference compound.For ADA assays, for a multi-assay ap-proach, study samples can be analyzed unblinded. This ensures that each set of samples is analyzed using its appro-

priate method. When ADA samples are analyzed unblinded, it must be ensured that only the relevant technicians are unblended, and that any personnel out-side the analytical team (eg, the clinical or the PK team) remains blinded. Bioan-alytical results can initially be reported as blinded results using mock identifiers.

Alternatively, if it is deemed necessary that ADA sample analysis is performed in a blinded manner, all samples can be analyzed using all ADA methods. This approach is not preferred, as it is time and cost consuming, and elaborate man-agement of the generated multiple data sets is required. Alternatively, the “one ADA assay approach” can be selected.

If ADA samples are analyzed blinded, blinding will also apply for samples from either the biosimilar and refer-ence compound arm(s) from the clinical study. All samples should be analyzed simultaneously.

All samples from one subject should be analyzed within the same analytical run, when possible. Only upon reanal-ysis (including ISR), it is acceptable to have single samples of a specific sub-ject in a different run. For “parallel” methods (such as ELISA) “segmented runs” can be used, in which the official designation of a run is defined as one ELISA plate; however, it is ensured that any handling variations are limited to the minimum. Therefore, these plates are initially run in parallel on the same day, under identical conditions and by the same technician. Each plate has its own full set of calibrators and QC sam-ples. If one of these plates is rejected, it can be repeated, keeping all conditions as similar as is practically possible.

Quality Control Samples (QC) For PK assays, when similarity is demonstrated during pre-study valida-tion, one set of quality control samples can be used during bioanalysis. Most likely, the QC samples will be prepared

References

Guidelines

• FDA Guidance for Industry: Bioanalytical Method Validation - May 2001• FDA Guidance for Industry: Assay Development for Immunogenicity Testing

of Therapeutic Proteins - Draft December 2009• EMA Guideline on Bioanalytical Method Validation - February 2012• EMA Guideline on Immunogenicity Assessment of Monoclonal Antibodies

Intended for in vivo Clinical Use - December 2012

White Papers on Bioanalytical Method Validation

• Findlay et al., J. Pharm. Biomed. Anal. 21 (2000) 1249-1273• DeSilva et al., Pharm. Res. 20 (2003) 1885-1900• Lee et al., Pharm. Res. Vol. 23 No 2 (Feb 2006), 312-328

White Papers on Immunogenicity Assessment

• Mire-Sluis et al., J Immunol Methods 289 (2004) 1-16• Gupta et al., J Immunol Methods 321 (2007) 1-18• Koren et al., J Immunol Methods 333 (2008) 1-9• Shankar et al., J Pharm Biomed Anal 48 (2008) 1267-1281• Gupta et al., J Pharm Biomed Anal 55 (2011) 878-888

using the biosimilar reference material, as this compound will be readily avail-able and most extensively characterized. Alternatively, individual sets of QC samples representing each separate Biosimilar and reference compound can be used for run acceptance during sample analysis. Acceptance criteria are specific for any reference material used (ie, the biosimilar and any reference compound), and described in advance in a study plan. When multiple sets of QC samples are used for run acceptance, all sets need to be accepted in order to approve the analytical run.

Stability

Final PK results for both the Biosimilar samples and samples containing the refer-ence compound(s) must be supported by relevant stability data. However, validat-ing long-term frozen stability of a polyclonal ADA response is scientifically less relevant as antibodies are generally perceived to be very stable and the expected ADA response is dissimilar from the available controls during validation.

PK and ADA method development and validations can take up to 6 months. It is also critical to have the methods ready before going into the clinic to ensure samples are processed appropriately. Inclusion of bioanalytical activities in the project plan upfront is crucial for timely delivery of the data package.

NemanskyMartin@prahs.com

BIOSIMILARS NEWSLETTER | Volume 4, October 2014

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FDA Releases Draft Guidance on Reference Product Exclusivity for Biologicals

The US Food and Drug Admin-istration (FDA) has issued new

draft guidance concerning biosimilars. The draft guidance (dated 5 August 2014) is intended to assist sponsors in determining the date of first licensure for a reference product.

The date of first licensure is important as it will determine when a biosimilar manufacturer can submit an applica-tion to FDA via the abbreviated bio-similars pathway, which was brought into law as part of the US Biologics Price Competition and Innovation (BPCI) Act of 2009.

The guidance makes it clear that orig-inator biologicals will enjoy a period of 12 years of marketing exclusivity and that biosimilar applications may only be submitted to FDA once four years from the date of first licensure have passed.

The agency goes on to point out that originator companies will gain an ad-ditional six-month period of exclusiv-ity over and above the 12- and 4-year periods, respectively, if the sponsor conducts pediatric studies.

The guidance also proposes the type of information required in order to deter-mine the date of first licensure.

Link to document:http://www.fda.gov/

FDA Releases “Purple Book”

The FDA has released the "Purple Book" to act as a reference guide

for approved biologics similar to the "Orange Book," used for small molecule drugs and their generic equivalents.

The lists may include the date a bi-ological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity un-der section 351(k)(7) of the PHS Act. A determination of the first date li-censure has not been made for every biological product listed and current-ly marketed. The FDA have explained that a determination of the date of first licensure will, controversially,

generally be made for reasons of regu-latory necessity and/or at the request of the 351(a) application holder. The “Purple Book” will also enable a user to see whether a biological product li-censed has been determined by FDA to be biosimilar to or interchangeable with a reference biological product.

Link to FDA “Purple Book”:http://www.fda.gov/

United States

Regulatory Framework Updates Europe/ Rest of the World

New Zealand Guidelines for Biosimilars

The regulatory body for approval of medicines in New Zealand Medical Devices Safety Authority (Medsafe), has provided a definition of a bio-similar, and that approval is based on pharmacokinetic and pharmacody-namic studies, as well as comparative clinical studies.

However, consensus regarding the in-terchangeability of a biosimilar medi-cine and its reference product has yet to be reached.

Medsafe does not cite any specific New Zealand guidelines for biosimi-lars, but refers biosimilars manufac-turers to both the US Food and Drug Administration draft guidelines and the European Medicines Agency guidelines for more information.

Link to Medsafe Medcines Biosimilar site

http://www.medsafe.govt.nz

Regulatory MeetingsEurope/US/Rest of World None reported

BIOSIMILARS NEWSLETTER | Volume 4, October 2014

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FDA Accepts Sandoz Application for Biosimilar Filgrastim (ZARZIO®)

S andoz, a Novartis Group compa-ny, has announced that the US

Food and Drug Administration (FDA) has accepted its Biologics License Application for filgrastim, which was the first ever filing of a drug under the new biosimilar pathway, created in the Biologics Price Competition and Innovation Act of 2009 (BPCIA).

The reference product – Amgen’s NEUPOGEN® – is indicated to de-crease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignan-cies receiving myelosuppressive anti-

JAPANSandoz Receives Approval for Biosimilar Filgrastim in Japan

S andoz announced today that Sandoz Japan has received mar-

keting authorization approval for its biosimilar Filgrastim. The product is the second Sandoz biosimilar to be approved in Japan.

Filgrastim is used with certain cancer patients to accelerate recovery of in-fection-fighting white blood cells after chemotherapy (prevention of neutro-penia) and is also used to stimulate mobilization of hematopoietic stem cells for collection and transplanta-tion. Sandoz Filgrastim is approved in Japan for the same range of indica-tions as the reference product GRAN®.

Link to Sandoz press release dated 24 March 2014:http://www.sandoz.com/

cancer drugs associated with a signif-icant incidence of severe neutropenia with fever.

Link to Novartis press release dated 24 July 2014: http://www.novartis.com/

FDA Receives Biosimilar Application for Monoclonal Antibody

S outh Korean biopharmaceuti-cal manufacturer Celltrion has

announced that it has filed an ap-plication for approval with the FDA for Remsima, its biosimilar version of Jannsen's Remicade (infliximab). The company's biosimilar filing is the second-ever filing of a drug through FDA's new 351(k) biosimilar pathway,

KOREAGreen Cross Receives Korean Marketing Authorization for Neulapeg®

G reen Cross, a South Korean biopharmaceutical company, have announced that South Korea’s Ministry of Food and Drug Safety has granted market-

ing authorization for Neulapeg® (pegfilgrastim), a treatment for abnormally low level of neutrophils in patient undergoing chemotherapy.

Company press release dated 18 August 2014: http://www.greencross.com/

TURKEYCelltrion’s ‘Remsima’ Receives Turkey Ministry of Health Approval

The Ministry of Health (MoH) in Turkey has granted marketing approval for Celltion’s RemsimaTM (infliximab). Celltrion has received approval from

the MoH for all applied indications, which are for the treatment of rheumatoid arthritis, ankylosing spondilitis, Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis.

Press release dated 16 July 2014: http://www.celltrion.com/

and reportedly the first-ever mono-clonal antibody (mAb) to seek ap-proval through the pathway.

Celltrion anticipates receiving FDA approval within 12 months, though it cautioned that a patent on the drug owned by Janssen expires in 2018. It is challenging all remaining patents in court—a process which could slow approval.

Remsima has already received ap-proval by the regulatory agencies in over 50 countries worldwide, includ-ing most of the advanced regulatory agencies including Europe, Canada, and Japan.

Link to Celltrion press release dated 11 August 2014 http://www.celltrion.com

European Commission Grants Lilly and Boehringer Ingelheim's Biosimilar Insulin Glargine Marketing Authorization in Europe

P artners Eli Lilly and Boehringer Ingelheim have announced that

they had received European Com-mission (EC) approval for its biosim-ilar insulin glargine product Abasria (LY2963016), a first for Europe.

The news follows, as previously re-ported in Edition 3 of the PRA Health Sciences Newsletter, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) positive recommendation of 27 June 2014.

Company Press Release dated 10 September 2014:http://www.boehringer-ingelheim.com

CHMP Approves a Biosimilar Filgrastim

On 24 July 2014, the CHMP ad-opted a positive opinion, recom-

mending the granting of a marketing authorisation for the medicinal prod-uct Accofil (L03AA02), a filgratsim, intended for the treatment of neutro-penia. The applicant for this medici-nal product is Accord Healthcare Ltd.

Accofil is a biological medicinal prod-uct similar to the reference product Neupogen authorized in the EU. Studies have shown Accofil to have a comparable quality, safety, and effi-cacy profile to Neupogen (filgrastim).

Link to Summary of opinion (initial authorization): http://www.ema.europa.eu/

Biosimilars Applications Approved & Under Review

Europe United States

Rest of World

BIOSIMILARS NEWSLETTER | Volume 4, October 2014

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Biosimilars Naming, Label Transparency and Authority of Choice – Survey Findings Among European Physicians

Dolinar RO et al.: Ge-nerics and Biosimilars Initiative Journal (GaBI Journal). 20143;3(2):58-62.

The Alliance for Safe Biologic Medicines (ASBM) completed a

survey of 470 European physicians for the following reasons:

• To examine attitudes of European physicians on biosimilar naming and substitution

• To assess physician knowledge, sources of information and need for further education on biosimilars

• To provide data to put policy developments at EU and national level into perspective and inform policy recommendations

This article presents and discusses the findings of the survey, which point to some confusion among physicians in Europe in the area of biological and biosimilar medicines.

Click here to read/locate the article http://gabi-journal.net/

The Challenge of Indication Extrapolation for Infliximab Biosimilars

Feagan BG et al.: Biologi-cals 42 (2014) 177e183

C an clinical studies that satisfy concerns regarding safety and

efficacy in one condition support “in-dication extrapolation” to other con-ditions? This question is addressed by reviewing the case of a biosimilar to infliximab that was approved recently in South Korea, Europe, and Canada for multiple indications through ex-trapolation. The principles discussed should also apply to biosimilars of other monoclonal antibodies that are approved to treat multiple distinct conditions.

Click here to read/locate the article http://www.sciencedirect.com/

Biosimilars Entering the Clinic Without Animal Studies: A Paradigm Shift in the European Union

van Aerts LA et al.: MAbs. 2014 Aug 5;6(5). [Epub ahead of print]

R ecently, a paradigm shift in regu-latory thinking on the non-clin-

ical development of biosimilars has emerged in Europe: In vivo testing should follow a step-wise approach rather than being performed by de-fault. To not require animal testing at all in some instances can well be seen as revolutionary, but science-based, step. This paper describes the main arguments, internally discussed ex-tensively by the European Union (EU) regulators, which have led to this par-adigm shift

Click here to read/locate the article http://www.ncbi.nlm.nih.gov/

Barriers to Market Uptake of Biosimilars in the US

Abigail EF et al.: Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3): Epub ahead of print.

This publication examines the challenges and opportunities

with respect to market uptake of biosimilars in the US, from the per-spectives of payers and physicians. The authors reviewed Medline index manuscripts and grey literature pub-lished in the past five years, on topics of biosimilar development and mar-ket uptake. The data collected from the review formed the basis of the development of two stakeholder sur-veys for payer and physicians. The report discusses the findings from the two surveys and goes on to de-bate policy implications related to the study’s main findings.

Click here to read/locate the article http://gabi-journal.net/

Articles & Reports of InterestThe Biosimilars Naming Game…Investor Statement on Board Oversight of Biosimilar IssuesA group of 19 institutional investors, under the lead of the United Auto Workers (UAW) Retiree Medical Benefits Trust, which represents $430 million in assets, is asking 25 pharma and biotech companies to agree to a set of business principles to guide corporate boards on policy and oversight responsibilities related to biosimilar activities.

The principles call on boards to ensure that information provided to policymakers on patient safety is balanced, investor dollars used for political lobbying is aligned with shareholder interests, and disclosure on significant business partnerships is transparent. The investors also voiced concern about the naming debate stating that it would be a mis-take to give biosimilars different names from the originator products "In our view, assigning different names communicates to providers that the biosimilar is less effective, causing providers not to prescribe it and ultimately making it difficult for pharmacists to dispense". Pharmacy ben-efits managers have also voiced support for uniform naming policies.

In responses to the coalition, the two companies, Amgen and Sandoz, have affirmed support for the principles and noted existing policies and practices that also advance the principles. Link to Investor letter: http://freepdfhosting.com

On the Other Hand… Physicians Believe Biosimilars Should Have Different Names US physicians have now added their opinion to the debate on how to name biosimilars. The physicians wrote that distinct names are needed to avoid confusion: if a biologic and its biosimilars share a common name, physicians may incorrectly assume that the products are approved for all of the same indications, even if the FDA disagrees. The physicians also argue that unique names for biosimilars will help doctors track adverse events by allowing them to correctly identify what product caused the event.Link to letter dated 14 August 2014: http://freepdfhosting.com

And to Try and Resolve the Issue…WHO Proposal Offers Clarity for Biosimilar Nomenclature to Try and Deal with the Biosimilars Naming IssueFollowing requests from drug regulatory authorities worldwide, the World Health Organization (WHO) has released a draft Biological Quali-fier (BQ) proposal on which to base a globally recognized naming scheme for biological products, including biosimilars. According to the proposal, a four-letter alphabetic code – the BQ – would be added after the INN.

The recommendation, from the International Nonproprietary Names (INN) expert group of the WHO, follows extensive discussion on the naming of biosimilars and is intended to halt the proliferation of differ-ent names and nomenclature policies in different countries.BQ codes are intended as unique identifiers of the active substance from a given source. The INN expert group concludes that the BQ scheme will be used by and useful for, regulatory authorities, health authorities, pharmacists, physicians, healthcare workers, and patients.Link to proposal dated July 2014: http://www.who.int

BIOSIMILARS NEWSLETTER | Volume 4, October 2014

Coherus Announces Initiation of Phase 3 Trials of CHS-0214 (Etanercept Biosimilar) in Rheumatoid Arthritis and Chronic Plaque Psoriasis

C oherus BioSciences, as part of collaboration with Baxter, has

announced the start of its Phase 3 trial of CHS-0214, an investigational etaner-cept biosimilar, in rheumatoid arthritis (RA) (press release dated 23 June 2014) and Chronic Plaque Psoriasis (RaPsO-dy) (press release dated 16 July 2014).

Company Press Release 23 June 2014: http://www.coherus.com/

Company Press Release 16 July 2014:http://www.coherus.com/

Liomont & Oncobiologics Partner to Launch Biosimilars in Mexico

Oncobiologics and Laboratorios Liomont have announced a

strategic partnership for the devel-opment, manufacture and commer-cialization of biosimilar monoclonal antibody products for the Mexican market. The scope of the agreement includes exclusive commercialization in Mexico by Liomont, of two biosim-ilars developed by Oncobiologics.

Under the agreement, Liomont will provide Oncobiologics with upfront licensing and development mile-stone payments, as well as royalties once the medicines are commer-cialized. Oncobiologics will oversee global clinical trials and will provide commercial supply manufacturing for launch in the Mexican market.

Company Press Release 26 June 2014: http://oncobiologics.com/

Neuclone Announces a Worldwide Partnership with Serum Institute of India Ltd to Produce a Portfolio af Biosimilar Drugs

N euClone Pty Ltd (NeuClone) in Australia and The Serum In-

stitute of India Ltd (Serum Institute) have announced a licensing agree-ment and joint development part-nership to manufacture and supply 10 biosimilar monoclonal antibody drugs globally for treatment of dis-eases such as cancer and autoim-mune disorders.

NeuClone retains license to the jointly developed biosimilars for the developed markets of USA, Europe, Canada, Australia, Taiwan, Japan and South Korea. For the rest of the world, including India, China, South East Asia, the Serum Institute will have exclusive license for marketing and sales.

Company Press Release June 2014: http://www.neuclone.com

Epirus & Zalicus Complete Merger

Epirus Biopharmaceuticals, Inc. has announced the completion of

a merger with Zalicus Inc. which forms part of Epirus’s strategy in “building a global biosimilar enterprise”. The com-bined company will be renamed Epi-rus Biopharmaceuticals, Inc.

Epirus is currently developing a pipe-line of biosimilars, including BOW015, a biosimilar to Remicade®, BOW050, a biosimilar to Humira®, and BOW030, a biosimilar to Avastin®.

Company Press Release 15 July 2014: http://ir.epirusbiopharma.com

PlantForm & PharmaPraxis Establish Joint Venture

P lantForm of Canada and Phar-maPraxis of Brazil have an-

nounced a joint venture to develop, manufacture, and commercialize bio-similar and/or biobetter versions of six key biopharmaceuticals, for the Bra-zilian market, using PlantForm’s low-cost manufacturing system - a tobac-co-plant-based manufacturing system.

The joint venture will first develop a biosimilar/biobetter version of the oncology drug Avastin® (bevacizum-ab), in collaboration with the Fraun-hofer Center for Molecular Biology in Newark, Delaware, USA, which will produce the active pharmaceutical in-gredient (API) for clinical trials.

Company Press Release 20 June 2014: http://www.plantformcorp.com

Daiichi Sankyo Initiates Phase 3 Trial of CHS-0214 (Investigational Etanercept Biosimilar) in Japan (RApsody)

D aiichi Sankyo Company has announced the start of the Phase

3 trial of CHS-0214, an investigational etanercept biosimilar, in rheumatoid arthritis (the RApsody trial) in Japan. Daiichi Sankyo is a co-sponsor of this trial, in collaboration with Coherus BioSciences.

The trial is a randomized, double-blind, active-control, parallel-group, mul-ticenter, global study, comparing the efficacy and safety of CHS-0214 with Enbrel® in subjects with active RA who have demonstrated an inadequate re-sponse to methotrexate. The primary endpoint is ACR 20 at 24 weeks.

Company press release 18 August 2014:http://www.daiichisankyo.com/

Amgen Announces Positive Phase III Results of Biosimilar Candidate ABP 501

Amgen have announced that their Phase 3 study evaluating

the efficacy and safety of biosimilar candidate ABP 501 compared with Humira® (adalimumab) in patients with moderate-to-severe plaque pso-riasis met its primary endpoint.This is the first of two Phase 3 studies intended to form the basis for global regulatory submissions for ABP 501.ABP 501 is being developed as a bi-osimilar to adalimumab which is approved in many countries for the treatment of a number of inflamma-tory diseases.

Press release dated 08 October 2014: https://www.amgen.com/

Coherus Announces CHS-1420 (Investigational Adalimumab Biosimilar) Meets Primary Endpoint in Pivotal Pharmacokinetic Clinical Study

C oherus BioSciences have an-nounced that CHS-1420, its

proposed biosimilar of adalimumab (Humira®), met the primary end-point in a pivotal clinical pharma-cokinetic (PK) similarity study that compared CHS-1420 to Humira® in healthy subjects. The parallel-group, single-dose study met the criteria for clinical PK similarity on all defined PK endpoints. Both investigational medicinal products were well toler-ated and there were no differential safety findings observed between the two agents in this study.

Company Press Release 14 August 2014http://www.coherus.com/

Company News(The information provided is sourced directly from the company websites)

07

BIOSIMILARS NEWSLETTER | Volume 4, October 2014

Next EditionLook out for the next edition

of the Biosimilars Newsletter

due January 2015

Contact Rodeina Challand,

Executive Director Biosimilar Development, Scientific Affairs

ChallandRodeina@prahs.com

Hazel Gorham,

Director Biosimilar Development, Scientific Affairs

GorhamHazel@prahs.com

PRA Health Sciences4130 ParkLake Avenue, Suite 400, Raleigh, NC 27612 U.S.A.

Phone: +1 (919) 786-8200 Email: prahs@prahs.com

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BIOSIMILARS NEWSLETTER | Volume 4, October 2014