3rd dvfa life science conference 08 june 2010 biosimilars ... · by making use of this document the...

3rd DVFA Life Science Conference08 June 2010

Biosimilars

BIOCEUTICALS Arzneimittel AG

Epoetin zeta – A case study

Dr. Michael Mack Member of Executive Board

BIOCEUTICALS Arzneimittel AG

BIOCEUTICALS Arzneimittel AG, 8. Juni 2010 1


By making use of this document the reader acknowledges and agrees to the following:

We accept no liability arising from the use of this document.

BIOCEUTICALS Arzneimittel AG, Bad Vilbel (in the following “BIOCEUTICALS”), has made every effort to make sure that this document contains correct and up-to-date information. However, it accepts no responsibility or guarantee whatsoever in respect of topicality, accuracy and completeness of the information and assumes no obligation to update, complete or correct the information contained therein.

The anticipated opportunities and risks to BIOCEUTICALS‘s activities have been described in detail in the Executive Board’s management reports in the annual reports. Current possible opportunities and risks are mentioned in the respective interim report.

BIOCEUTICALS‘s performance indicators are party influenced by one-time special effects and/or effects not arising from the operating business. Disclosure of key figures adjusted for these effects (so called “pro forma” key figures) by BIOCEUTICALS is only to provide a supplement to the recorded IFRS key figures for a transparent comparison to a relevant period from the previous year.

All text, pictures, trademarks, and other information contained in this document are subject to the copyright of BIOCEUTICALS orsubject to rights acquired from third parties. Trademark protection may apply even for preparations not indicated as trade marks. This document may not be reproduced in whole or in part without the express written consent of BIOCEUTICALS.

Any disputes arising out of or in connection with the content of this document, insofar as they are directed against BIOCEUTICALS, shall be subject to German law, without prejudice to mandatory provisions of foreign law. The place of jurisdiction is Frankfurt am Main to the extent legally permissible.

General information


Forward-looking statements

This BIOCEUTICALS Arzneimittel AG presentation (subsequently "BIOCEUTICALS") contains certain statements regarding future events (as understood in the U.S. Private Securities Litigation Reform Act of 1995) that express the beliefs and expectations ofmanagement. Such statements are based on current expectations, estimates and forecasts on the part of company management and imply various known and unknown risks and uncertainties, which may result in actual earnings, the financial situation, growth orperformance to be materially different from the estimates expressed or implied in the forward-looking statements. Statements with respect to the future are characterized by the use of words such as “expect”, “intend”, “plan”, “anticipate”, “believe”, “estimate” and similar terms. BIOCEUTICALS is of the opinion that the expectations reflected in forward-looking statements are appropriate; however, it cannot guarantee that these expectations will actually materialize. Risk factors include in particular: The influence of regulation of the pharmaceutical industry; the difficulty in making predictions concerning approvals by the regulatory authorities and other supervisory agencies; the regulatory environment and changes in the health-care policy and in the health care system of various countries; acceptance of and demand for new drugs and new therapies; the influence of competitive products and prices; the availability andcosts of the active ingredients used in the production of pharmaceutical products; uncertainty concerning market acceptance wheninnovative products are introduced, presently being sold or under development; the effect of changes in the customer structure; dependence on strategic alliances; exchange rate and interest rate fluctuations, operating results, as well as other factors detailed in the annual reports and in other Company statements. The above mentioned applies also as far as certain statements within this presentation are made in coordination with STADA Arzneimittel AG with respect to product SILAPO. BIOCEUTICALS not assume any obligation to update these forward-looking statements or adapt them to future events and developments.

The BIOCEUTICALS Executive Board:Christof Schumann, Dr. Michael Mack


Contents

! BIOCEUTICALS Arzneimittel AG – a short overview

! Introduction to Epoetin zeta

! The regulatory environment past the last 10 years

! Regulatory strategy

! Development of Epoetin zeta

! Control of production – a key factor for success

! Epoetin zeta in the market

! SummaryBIOCEUTICALS Arzneimittel AG, 8. Juni 2010 4


Contents









BIOCEUTICALS Arzneimittel AGOverview:


STADA‘s engagement as of December 31, 2009


STADA Arzneimittel AG

No of Shares[%]

used credit line[Mio EUR]

used capital guarantee[Mio EUR]

6.0

15.86

36.8

License Contracts Epoetin zeta

Hospira Inc., USA

! European License and Marketing Agreement (EU)

! North American Development and License Agreement (US, Canada)

Cell pharm, Germany (a STADA subsidiary)

! License and Marketing Agreement (Germany semi exclusive)

Hemofarm, Serbia! License and Marketing Agreement (Serbia, Macedonia, Bosnia and

Herzegovina, Montenegro, Russia)

Nobel Ilac, Turkey

! License and Marketing Agreement (Turkey)


Commercialization Risk LowHigh Commercialization Risk

Mar

ket P

oten

tial (

Valu

e)H

igh

Low

Mar

ket P

oten

tial (

Valu

e)H

igh

Low

G = GenericsB = non-glycosylated

BiosimilarsB G = glycosylated

BiosimilarsNME =New Molecular

EntitySource: Biologicals International

G

B

NME

B G

Commercialization Risk LowHigh Commercialization Risk

Mar

ket P

oten

tial (

Valu

e)H

igh

Low

Mar

ket P

oten

tial (

Valu

e)H

igh

Low

G = GenericsB = non-glycosylated

BiosimilarsB G = glycosylated

BiosimilarsNME =New Molecular

EntitySource: Biologicals International

GG

BB

NMENME

B GB G

Lower Risk Business Model for Biosimilars


BIOCEUTICALS Generation of Expertise

Expertise in Biotechnology, in combination with the traditional one,

had been established internally and externallywithin the last ~ 8 years

Traditional expertise, grown historically

within the company

Biotechnological Expertise Development, Manufacturing

Implementation of (pre) clinical studiesExtensive regulatory discussions

Patent ExpertiseBusiness IntelligenceProject Management

Distribution EfficiencyRegulatory Expertise (Generics)

Highest quality standardsLonger development timesHigher development costs



Contents









Introduction to Epoetin zeta

Epoetin zeta drug substance! is a recombinant human erythropoietin produced in a CHO cell line! is the active substance in the approved products Silapo® and Retacrit®

Epoetin zeta drug product! Silapo/Retacrit have been developed as a biosimilar product referring to

epoetin alfa, authorised in the EU, e.g. under the brand names Eprex®(Janssen-Cilag Ltd.) and Erypo® (Ortho Biotech, a division of Janssen-Cilag GmbH)

! It was shown that quality, safety and efficacy of Epo zeta and Eprex®/Erypo® are comparable

! Indications: renal anaemia and chemotherapy-induced anaemia! Brand new: s.c. application for nephrology (April 2010)



Contents







! Epoeti zeta in the market


What kind of product do we have?

biogeneric

subsequent-entry biologic

generic biopharmaceutical

multi-source biopharmaceutical

second-entry biological drug

follow-on biological drug

biosimilar product

biocomparable product

well-established use

essential similarity


INN „Epoetin zeta“

! An INN identifies a pharmaceutical substance or active pharmaceutical ingredient (API) by a unique name that is globally recognized and is public property. A non-proprietary name is also known as a generic name.

! For epoetins, the INN is typically connected with a specific producer clone and hence BIOCEUTICALS concluded that the INN of the reference product (Epoetin alfa) cannot be used.

! Moreover, a unique INN was further regarded as advantage for marketing activities (“a biosimilar with an own INN” as a “standalone feature”).

! The INN "Epoetin zeta" was assigned by the WHO.! The issue of allocation an INN has to be distinguished from any scientific

data obtained (e.g. comparability of the glyco-profile) and hence this topic is not relevant with respect to the “biosimilar”-pathway at the EMA.


Regulatory Environment

2000 Project initiation2001 The concept of comparability is emerged by the Guideline

CPMP/BWP/3207/00 (20.09.2001)! only applicable for established products! introduces the terminology „similarity“: „[…] there is a need to consider the

necessity for conducting comparability studies for situations where […] a biotechnology-derived product claimed to be similar to one already authorised

2003 Directive 2003/63/EC (25.06.2003) amends Directive 2001/83/EC! Concept of similar biological medicinal products is introduced into EU

legislation by revision of the annex: ! Annex I, Part II No. 4: Specific marketing authorisation dossiers and

requirements – similar biological medicinal products! Legal basis not yet clarified2004 Directive 2004/27/EC (31.03.2004) amends Directive 2001/83/EC ! Introduction of a legal basis (Art. 10 para. 4) for biosimilars


Guidelines on biosimilars

2005 The EMEA publishes an overarching guideline on similar biological medicinal products (CHMP/437/04 – 30.10.2005)

2006 Two guidelines were finalised for biosimilars concerning quality and non-clinical/clinical issues. In addition, product specific guidelines concerning the non-clinical and clinical requirements were published (Erythropoietin (March 2006), GCSF, Insulin, Somatropin)

! June 2006: Submission of marketing authorisation application for Epoetin zeta to the EMEA

2009 Guidelines on LMW Heparins and Interferon alphaConcept paper on monocloncal antibodies

2010 Concept Papers on follicle stimulation hormone (FSH) and interferon beta

! The EU was the first regulated region in the world having a defined legal framework for the approval of biosimilars



Contents









Regulatory strategy

Right from the start of the development of Epoetin zeta, BIOCEUTICALS followed the – at that time nascent – concept of „similarity“. In this context, the following aspects are considered to be the „key to success“from the regulatory perspective:

!STADA‘s expertise and leading role in the field of European regulatory affairs activities for generic medicines!a close collaboration with competent authorities on national and European level due to the lack of existing guidelines!the annotation of draft guidelines during the consultation phase


Regulatory strategy

Nov 2002 Initial scientific advice at BfArM (Germany)! Quality, non-clinical, clinicalJul 2003 Follow-up scientific advice at BfArM (Germany)! ClinicalApr 2004 Initial scientific advice at EMEA! Quality, non-clinical, clinicalDec 2005 Follow-up scientific advice at EMEA! ClinicalMar 2006 Publication of Guidance on similar medicinal products containing

recombinant erythropoietinsJun 2006 Submission of marketing authorisation application to the EMEADec 2007 Approval. Product names: Silapo® (cellpharm/STADA) , Retacrit®

(Hospira)Successful development and registration even without established guidelines !

BIOCEUTICALS Arzneimittel AG, 8. Juni 201020

The big success

! On December 19, 2007, Marketing authorization for Epoetin zeta received from the EU Commission for the treatment of anaemia associated with chronic renal failure (i .v. administration) and chemotherapy.

! Epoetin zeta was on the second place in time to market - only few months after the first Epo Biosimilar approval.

! Until today only 2 sources for EU-approved Epo Biosimilars exist (Sandoz, BIOCEUTICALS/STADA).

! Some of the major players failed so far to reach the market by their own.



Contents









Development Strategies

! Own Development, ´Fully Integrated´

! BIOCEUTICALS

! Own Development, Production CMO

! Co-Development, Production CMO

! In-Licensing

Control of Success Cost Control EBITDA-Margin

100 %

0 %

100 %

0 %

High

Low

High

Moderate

Risk


Development of Epoetin zeta (1)Chemistry, Manufacturing and Control (CMC)

! CHO host cell line: best established mammalian expression system! GMP-master- and working cell banks: characterization in accordance with

the applicable ICH guidelines! cell culture: without serum, proteins, insulin and antibiotics

− pilot scale process for clinical trial material− scale-up for commercialisation

! purification: validated multi-step process (incl. virus safety)! fill and finish:

− 11 presentations from 1,000 IU to 40,000 IU (prefilled syringes)− patented formulation (EP 1 723 172)


Development of Epoetin zeta (2)Analytics

! highly sophisticated analytical methods were/are applied− during process development (cell culture, purification and fill-and-finish)− within the comparability-exercise for the marketing authorisation

application− during routine production

! the EMA commented the analytical data provided with the marketing authorisation application as follows (citation from the assessment report for Silapo/Retacrit):Very extensive, high quality studies were performed to compare SB309 to the reference product Eprex/Erypo at both the drug substance and the drug product level. Likewise the characterisation of the drug substance and the comparability studies to compare drug substance from different scale manufacturing process is considered high quality with an extreme level of detail applying state-of-the art analytical methods.


Development of Epoetin zeta (3)Pre-clinical and Clinical Studies

Pre-clinical studies:! pharmacodynamic studies (in vitro and in vivo)! toxicological studies (dogs and rats)! local tolerance (rabbits)

Pivotal Clinical studies:! Phase I-studies: two comparative pharmacokinetic studies (total: 75 patients)! Phase III-studies:

− comparative dose titration study (609 patients)− comparative study for maintenance therapy i.v. (313 patients)− followed by: open follow-up safety trial (745 patients)− oncological safety trial (approx. 216 patients)− comparative study for maintenance therapy s.c. (462 patients) with open

safety follow-up



Contents









Control of production –a key factor for success for Biosimilars

In order to ensure the commercial supply of Epoetin zeta in the required quantities and quality, BIOCEUTICALS initiated the joint-venture Norbitec GmbH in 2003. Norbitec is located at the site of Nordmark Arzneimittel GmbH & Co. KG in Uetersen (near Hamburg).With its engagement in Norbitec, BIOCEUTICALS managed to achieve the following:! key personnel involved in the pilot-scale development of Epoetin zeta could

be hired thereby ensuring best possible know-how transfer! with its majority in the advisory board of Norbitec, BIOCEUTICALS is enabled

to influence/control management decisions! as the major stakeholder in Norbitec, BIOCEUTICALS does directly benefit

from Norbitecs earnings



Contents









Marketing hurdles widely spread by some Originators claiming quality and safety deficiencies of all Epoetin Biosimilars......would not meet the Ph. Eur. specifications ...would have higher immunogenic risk...would be contaminated with bacterial endotoxines...production process may would lead to higher variations between the batches...would have less experience than the Originators...would have lower potency, etc.

This unqualified and incorrect marketing campaign was not a surprise – the Generic industry had similar experience with Originators strategies against normal generics 30 years ago. However similar campaigns are still part of the argumentation used by some Originators against Biosimilars.

An important statement refering to this kind of campaign made by Nicolas Rossignol from the EU commission pharmaceutical unit is self-explanatory.

Epoetin zeta in the market



! BIOCEUTICALS as well as STADA always anticipated these kind of hurdles by the Originators.

! Thus, their forecast for Biosimilars was always based on a penetration speed significantly lower than for normal generics.

! The cellpharm/STADA plan for Silapo® in Germany is unchanged since years and has a target of 20 Mio. € in the third marketing year.

! So far Silapo is well in line with German sales of 4,6 Mio. € in Y1 (2008) and 13,2 Mio. in Y2 (2009). Thus, cellpharm is aiming in this year 2010 (Y3) for the 20 Mio. € sales level.

! This sales level could be reached despite intensive competition− Today one can find 5 Epo Biosimilars by 2 different product sources and

2 ‚new‘ Epo Originator products by one source (Epoetin theta) in the german market.

! For legal reasons we cannot disclose Hospira sales in this presentation.


! BIOCEUTICALS is convinced that Biosimilars and especially Epoetin Biosimilars will catch in the long term – 5 to 8 years after launch – in most markets the same penetration level as it is today usual for generics (e.g. in Germany approx. 60% by value and 80% by volume).

! And as more and more Epoetin Biosimilars are recognized as well established and cost-saving products in the EU – demonstrating day for day the same therapeutic success but for a lower price than originator products –we see the chance for a regulatory breakthrough in the US, too.

Future Potential Epo-zeta



Contents







! Epo-zeta in the market


! Development of Epoetin zeta, even without established registration guidelines

! Epoetin zeta EMA approval within the first wave in Europe! Own Production (drug substance) ramped-up! establishment of out-licensing partnerships and the necessary logistic

functions! Basis for development of US dossier (in partnership with Hospira)


3rd DVFA Life Science Conference08 June 2010

Biosimilars

Thank you for your attention !


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